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18 Articles in Volume 11, Issue #9
Pain and Sleep: A Delicate Balance
Management of Insomnia: Considerations For Patients With Chronic Pain
PPM Editorial Board Outlines Management Strategies for Chronic Pain Patients With Insomnia
Attention Deficit Hyperactivity Disorder And Patients With Pain
Dry Needling Offers Relief From Chronic Low Back Pain
Etiology of Chronic Pain and Mental Illness: How To Assess Both
Temporomandibular Disorder: Examining the Cause And Treatments
Highlights From PAINWeek 2011
Is Your Patient Using Heroin?
Medications For Low Back Pain
Nonpharmacologic Treatments for Patients With Sleep Disorders and Pain
Man With Constant, Daily Headache Pain, Photophobia, Phonophobia, and Nausea
Successful Nonoperative Treatment of Persistently Painful Knees Following Total Knee Arthroplasty—A Case Series
Insomnia in Chronic Pain Patients
What Is Going Wrong With Research? Finding the Right Answer
Testing Positive for Marijuana in Urine
Hydrocodone, Carisoprodol, and Alprazolam—A Most Lethal Combination
Pro-inflammatory Diet

Medications For Low Back Pain

This educational review summarizes the different classes of medications commonly used in the treatment of low back pain, discussing the mechanism of action, efficacy, complications, contraindications, and current clinical research for each class or group of medications.

Low back pain (LBP) is one of the most common complaints encountered by primary care practitioners. LBP, which may radiate from the back into the lower extremities, hips, and buttocks, is considered acute if it lasts 6 weeks or less and chronic if it lasts longer than 12 weeks.

A thorough assessment of the underlying etiology, including a complete history and physical examination, is necessary to correctly identify the underlying pain trigger. Understanding the potential etiologies, such as inflammatory, biomechanical, infectious, neoplastic, and/or psychological processes, will help guide the treatment plan. This allows clinicians to use the appropriate class(es) of medications advantageously.

NSAIDs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the world’s most frequently prescribed medications.1,2 In 2000, the US Medical Expectations Panel Survey found that of the 44 million prescriptions written for the 24.5 million patients with both acute and chronic LBP, 16.3% were for nonselective NSAIDs and 10% were for selective cyclooxygenase (COX)-2 inhibitors.3

NSAIDs are a class of medications that cause a reversible blockade of COX isoenzymes; they block the inflammatory process in which arachidonic acid is converted into the prostaglandins that mediate inflammation and sensitize peripheral nociceptors. This is the means by which this class of medications exerts both anti-inflammatory and analgesic effects.4-6 NSAIDs also affect inflammation locally by inhibiting neutrophil function and phospholipase C activity.

NSAIDs can further be divided into two groups consisting of older, nonselective NSAIDs that inhibit both COX-1 and COX-2 enzymes, and newer COX-2 selective NSAIDs that block only the COX-2 isoenzyme. The only COX-2 selective inhibitor currently on the market is celecoxib (Celebrex); rofecoxib (Vioxx) and valdecoxib (Bextra) were voluntarily withdrawn from the market because of cardiovascular safety concerns. There are various subtypes of NSAIDs, each with various properties and side-effect profiles (Table 1).

Most over-the-counter (OTC) NSAIDs are fairly inexpensive. However, the consideration of cost should also include the cost of side effects. In a Canadian study on the cost of NSAID-related gastrointestinal (GI) side effects in elderly patients, Rahme et al found that for each $1 spent on nonselective NSAIDS, an extra $0.66 was spent on treating adverse events (AEs).7

A more recent article looked into both GI and cardiovascular AEs and compared three groups of medications: nonselective NSAIDs, NSAID plus proton pump inhibitor (PPI) combination therapy, and COX-2 selective agents. The investigators found that nonselective NSAIDs were most cost-effective in low-risk patients, whereas NSAID plus PPI combination therapy was more cost-effective for preventing ulcers in patients taking aspirin or otherwise at high risk for a GI or cardiovascular AE.8

Contraindications for NSAIDs include peptic ulcer disease, bleeding disorders, and allergic reactions to NSAIDs. Additionally, patients with congestive heart failure and renal disease should be monitored closely and perhaps not prescribed NSAIDs.9 Nonselective NSAIDs are contraindicated in the last trimester of pregnancy, during the perioperative period for cardiac surgery, and in patients who are at high risk for bleeding.5 Celecoxib is contraindicated in patients with sulfonamide hypersensitivity and should be used with caution in those with cardiac disease and hypertension.10

With respect to efficacy, one systematic review found that NSAIDs were effective for short-term relief of chronic LBP.11 Of the randomized controlled trials (RCTs) used for European guidelines, the only “high-quality” (30-patient) trial showed better pain relief with diflunisal than with placebo.1,12 In a more recent Cochrane systematic review of 65 studies that compared NSAIDs with placebo, the authors concluded that NSAIDs are slightly more effective than placebo at providing short-term pain relief in patients with LBP without radiating symptoms.13  In patients with radiating lower extremity symptoms, NSAIDs were no more effective than placebo. In addition, this review found that COX-2 selective NSAIDs were not more effective than nonselective NSAIDs, but caused fewer side effects, especially gastric ulcers. However, the authors acknowledge that COX-2 inhibitors present cardiovascular risks for some patients. The authors also found that NSAIDs are equally as effective as other medications (eg, paracetamol/acetaminophen, narcotic analgesics, and muscle relaxants). However, this review conceded that fewer than half of the studies were high quality, many had small patient numbers, and few contained data on long-term results and side effects.

Based on recent evidence regarding the efficacy of NSAIDs, these agents are best used in standard daily doses over a short time frame (<2 weeks) in patients with LBP without associated radiculopathy who do not have contraindications; however, they are not indicated for long-term treatment of LBP. Although COX-2 selective NSAIDs have fewer side effects than nonselective NSAIDs, it is well documented that they present cardiovascular risks for some patients.

Muscle Relaxants
Muscle relaxants are a group of medications used as adjunctive treatment of mild to severe acute LBP (Table 2). These medications work by inhibiting central polysynaptic neuronal events that act indirectly on skeletal muscle.5 They can be subdivided into antispasmodic and antispastic medications.14

Antispasmodic muscle relaxants can be further subdivided into benzodiazepines and nonbenzodiazepines. Benzodiazepine antispasmodic medications, such as alprazolam, clonazepam, dalmane (Flurazepam), diazepam, and hydroxyzine act as skeletal muscle relaxants, sedatives, hypnotics, anticonvulsants, and anxiolytics. It is important to note that patients often develop tolerance to their muscle relaxant effects. Because of potential for abuse, these agents should be used cautiously in patients with a history of addiction.

Nonbenzodiazepines, which act centrally at the brain or spinal cord level to decrease muscle spasms, include medications such as cyclobenzaprine and tizanadine. Tizanadine acts as an α2-adrenergic agonist to inhibit presynaptic motor neurons. Cyclobenzaprine works at the brain- stem level, whereas metaxalone works via generalized central nervous system (CNS) depression.5,6

Antispastic medications, in contrast, work to reduce spasticity associated with upper motor neuron disorders. These medications include baclofen and dantrolene. Baclofen’s exact mechanism of action is unknown, but it is thought to work as a γ-aminobutyric acid (GABA) analog at GABA-B receptors, inhibiting presynaptic motor neurons.5,6 Dantrolene is a direct muscle relaxant that works by affecting the contractile response of muscle by interfering with the release of calcium from the sarcoplasmic reticulum. However, dantrolene should be used with caution, and liver enzymes should be monitored closely because of the potential for hepatotoxicity that can even occur with even brief courses of this medication.5

The CNS effects associated with muscle relaxants must be taken into consideration before prescribing these agents. They should not be used in situations in which impaired mental clarity would be harmful. Additionally, sudden discontinuation of chronic use of benzodiazepines can cause delirium tremens, whereas sudden discontinuation of baclofen can cause seizures.5

Benzodiazepines and cyclobenzaprine are contraindicated in patients with narrow angle glaucoma.5 Cyclobenzaprine has the same contraindications as tricyclic antidepressants (TCAs) in that it should not be taken within 14 days of monoamine oxidase inhibitors or in patients with cardiac arrhythmias, coronary artery disease, or hypothyroidism.5,6

To evaluate the efficacy of muscle relaxants in LBP, Van Tulder et al conducted a systematic review of 30 RCTs, 23 of which were high-quality studies and 24 of which were in patients with acute LBP.15 They found that muscle relaxants are better than placebo at decreasing the degree of discomfort and hastening recovery in the treatment of acute LBP and in the short-term treatment of chronic LBP.15

The studies evaluated did not provide any evidence for long-term use of muscle relaxants in chronic LBP. In nearly all of the trials, muscle relaxants showed more CNS AEs, such as dizziness and sedation, compared with placebo.15 Because of high relative risk for CNS side effects, Van Tulder et al recommended that physicians weigh the risks and benefits of their use in each patient and exercise caution.

Within the studies included in the systematic review, there were several high-quality studies that demonstrated strong evidence for short-term pain relief with the use of nonbenzodiazepines in acute LBP.16-19 Alternatively, the evidence for benzodiazepines is based on a few studies evaluating tetrazepam, which is not available for use in the United States.20,21 There was one high-quality study showing that carisoprodol was superior to diazepam, but none of the other muscle relaxants was found to be superior to any of the others.22

Several additional studies reviewed by Van Tulder are worthy of note. A review on the use of cyclobenzaprine for back pain found it to be more effective than placebo but with greater risk for AEs.23 A study on the use of dantrolene sodium in LBP showed considerable pain relief at a dose that had no significant side effects.24

However, as previously mentioned, this medication has a well-known side-effect profile that includes hepatoxicity and muscle weakness, and this study had a small sample size, making the results of questionable significance.5,24 Baclofen was shown to be more effective than placebo for short-term pain relief in acute LBP, decreasing muscle spasms and resulting in overall improvement after 10 days in one study.25

Despite the positive effects found for these antispastic medications, Van Tulder et al considered the clinical relevance of these data for LBP to be debatable because they are more commonly used in the treatment of spasticity in neurologic conditions including cerebral palsy, multiple sclerosis, and spinal cord injuries.15

There were some limitations to the Van Tulder review. None of the studies in the review dealt with patients with sciatica (ie, symptoms radiating down the lower extremities). Furthermore, the authors acknowledged that the studies did not provide adequate data comparing muscle relaxants with NSAIDs and other analgesic medications in the treatment of LBP, noting that future trials are needed.

In summary, muscle relaxants are useful for the treatment of acute LBP or short-term treatment of chronic LBP without radiculopathy, but these agents must be used cautiously because of well-known CNS side effects. They should not be used long-term because of lack of proven efficacy and proven withdrawal effects.

Simple Nonopioid Analgesics
This category encompasses a broad class of analgesic medications that are nonopioid and not discussed in other categories (Table 3).

Acetaminophen
Acetaminophen is a para-aminophen derivative that has both analgesic and antipyretic properties; it also weakly demonstrates anti-inflammatory properties by inhibiting COX isoenzymes, thereby inhibiting prostaglandin synthesis without inhibiting neutrophils.5

In January 2011, the FDA announced that it was asking all manufacturers of combination prescription drug products that contain acetaminophen to limit the amount of acetaminophen in these products to no more than 325 mg.26 This change was a result of numerous reports of liver injury and rare reports of anaphylaxis and other types of allergic reactions occurring with use of acetaminophen-containing products. Many cases of liver injury were a result of unintentional overdoses of the agent. The FDA is also requiring a boxed warning on all prescription products that contain acetaminophen, highlighting the potential for hepatic injury and allergic reactions with this drug. This change does not affect OTC products, but the FDA noted that it is continuing to evaluate ways to reduce the risks associated with OTC acetaminophen products.

Thus, patients should be given adequate education regarding the safe allowable daily dosing of this OTC medication if it is to be included in their treatment plan. Acetaminophen should be avoided in patients with a history of liver disease and in those who consume more than three alcoholic beverages per day.5

Acetaminophen commonly is used as a first-line analgesic in the treatment of mild to moderate acute LBP because several studies have shown it to be superior to placebo in the treatment of osteoarthritic pain.4 In a 1991 study, Bradley et al evaluated the analgesic properties of acetaminophen in the treatment of pain associated with osteoarthritis of the knee and found it to be as efficacious as both a low-dose analgesic and high-dose anti-inflammatory regimens of ibuprofen for both pain relief and improved functional outcome.27

In one small study, 30 patients with chronic LBP that was thought to be facet-mediated were randomized into treatment with the NSAID/salicylate derivative diflunisal or acetaminophen for 4 weeks; patients reported good to excellent improvement with both treatments, with no significant difference in pain relief.12

Tramadol
Although tramadol is chemically unrelated to opioid analgesics that are only partially affected by the opiate antagonist naloxone, it acts similarly to opioids by weakly binding μ- and δ-opioid receptors and by interfering with serotonin and norepinephrine reuptake in the descending inhibitor pathways.9,28

Tramadol is believed to increase the risk for both seizure activity and serotonin syndrome in patients taking selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). In addition, tramadol is associated with increased risk for suicide.5,29

Tramadol at a dosage of 200 to 400 mg daily was found to be more effective than placebo in reducing pain and disability after 4 weeks in patients with chronic LBP.30 In two studies comparing the combination of tramadol 37.5 mg and acetaminophen 325 mg versus placebo, the combination was more effective for relief of LBP.31,32 In one study comparing immediate- and extended-release tramadol, no significant difference was found in the treatment of chronic LBP.33

Topical Medications
Topical medications include diclofenac patches and gel, lidocaine patches (Lidoderm) and gel, and capsaicin cream. Diclofenac is a topical NSAID, the exact mechanism of action of which is unknown, but it inhibits COX and lipoxygenase, thereby reducing prostaglandin synthesis. Lidocaine patches and gel work by inhibiting sodium channels, thereby stabilizing neuronal cell membranes and inhibiting nerve impulse initiation and conduction. Topical capsaicin’s exact mechanism of action is unknown, but it selectively binds nerve membrane transient receptor potential vanilloid type 1 (TRPV1) receptors, initially stimulating and then desensitizing and degenerating cutaneous nociceptive neurons. It also may reduce pain impulse transmission to the CNS via substance P depletion.34

Contraindications to these topical medications include hypersensitivity to the drug or class, or broken or inflamed skin. Topical diclofenac shares the same contraindications as oral NSAIDs, including increased risk for cardiovascular thrombotic events, a contraindication in perioperative coronary artery bypass graft patients, and increased risk for GI AEs.6

In a Cochrane systematic review on the use of topical NSAIDs in acute musculoskeletal pain of various etiologies, the number needed to treat (NNT) was 4.5 patients for 6 to 14 days for clinical success of 50% pain relief.35 Topical diclofenac, ibuprofen, ketoprofen, and piroxicam were all similar in efficacy, whereas topical indomethacin and benzydamine were not significantly better than placebo. The primary AE of local skin reaction was mild and transient, and there were few systemic AEs.35 In this systematic review, 1 of 16 RCTs were on LBP.

A systematic review of capsaicin plasters for musculoskeletal and neuropathic pain found that capsaicin had moderate to poor efficacy; the NNT was eight patients to achieve a 50% decrease in pain measures. Additionally, despite only a small significant improvement with capsaicin, there was a high placebo effect, and the incidence of local side effects was 54% with capsaicin versus 15% with placebo.34

Keitel et al found that capsaicin provided 60.8% positive improvement in nonspecific chronic LBP over a 3-week period.36 There were local AEs but a similar dropout rate in the capsaicin and placebo groups. The same group conducted another study and found a 67% positive response rate compared with 49% with placebo plasters.37 Lidocaine patches have shown promising results to reduce pain in observational pilot studies.38,39

Antidepressants and Antiepileptics
Adjunctive analgesics have become more popular in the treatment of chronic LBP; however, clinicians must understand the etiology of the pain to choose the appropriate analgesic. Most chronic LBP is nociceptive, meaning that it stems from tissue injury. This can refer pain to the lower extremity from a variety of structures such as the disk, facet, and nerve root. Neuropathic pain stems from nerve injury and usually presents with altered sensory complaints and findings. This distinction should be made in the initial patient evaluation, because adjunctive analgesics such as antidepressants and antiepileptics are better used for neuropathic pain.40

Antidepressants
Antidepressants are commonly used for a variety of psychiatric diagnoses, but there is now evidence that these agents are beneficial as adjunctive analgesics for pain syndromes, including neuropathic pain. TCAs, SSRIs, and SNRIs have been used in this setting (Table 4). 

These agents are thought to work by enhancing the descending inhibition of the pain pathway by increasing levels of serotonin and norepinephrine and via nerve membrane stabilization.41 Neuropathic pain relief appears to take place independent of antidepressant effects and occurs earlier than the several weeks it takes to achieve antidepressant effects.42

TCAs
Of all the antidepressants, TCAs have the longest history of use in chronic pain syndromes. The dosages of TCAs used in treating pain syndromes are lower than those used for treating depression. Advantages of TCAs are their already long-term use in chronic pain and their low cost. Disadvantages of TCAs include cardiovascular side effects such as hypertension, postural hypotension, and arrhythmias.5,6 For this reason, they are contraindicated in patients with heart failure or serious cardiac conduction abnormalities, and caution must be exercised when these agents are used in the elderly, who are at particular risk for orthostatic hypotension.5,6 Dosages should be monitored and adjusted as appropriate for patients being treated for hypertension with angiotensin-converting enzyme inhibitor-thiazide combinations or diuretics because interactions can result in additive effects.6,43-45 The sedating side effect can be advantageous for patients reporting inadequate sleep.

A review of seven studies conducted before 1992, found insufficient evidence to recommend the use of TCAs in chronic LBP.46,47 A 1997 review of four studies also failed to find evidence for clinical benefit for antidepressants in patients with chronic LBP.48

Two meta-analyses, one in 2002 that reviewed nine studies and another in 2004 that reviewed seven studies, concluded that antidepressants were more effective than placebo in chronic LBP.11,49 However, this meta-analysis did not distinguish among different classes of antidepressants. Another review in 2003 concluded that both TCAs and tetracyclic antidepressants produced moderate symptom reduction for patients with chronic LBP, independent of the presence of comorbid depression.50

In a more recent 2008 Cochrane systematic review of 10 RCTs that compared antidepressant medication and placebo for patients with nonspecific LBP and used at least one clinically relevant outcome measure, there was no difference in pain relief between antidepressants and placebo.51

There is conflicting evidence regarding the efficacy of TCAs in chronic LBP, but TCAs appear to have better efficacy in the treatment of neuropathic pain. In one 1996 systematic review of antidepressants in neuropathic pain conditions, 30% of patients had more than 50% pain relief.52 Although one study stated that the NNT to achieve at least 50% pain relief is 2.6 for neuropathic pain conditions,53 a more recent review indicates that the NNT may vary based on different neuropathic pain diagnoses and the use of drug-level measurements to obtain optimal dosing.42

Although it is difficult to compare individual TCAs because studies vary in their use of titrating doses based on benefits or side effects versus plasma drug concentrations, there appears to be a better effect with balanced TCAs than with noradrenergic TCAs.42,54

SSRIs and SNRIs
SSRIs and SNRIs also have been used in chronic and neuropathic pain syndromes. SSRIs address the emotional disturbance that may relate to neuropathic pain, rather than working through neuropathic pain pathways. The SNRIs, which affect both serotonergic and noradrenergic pathways, include venlafaxine, which is primarily serotonergic at low doses and noradrenergic at high doses, and duloxetine (Cymbalta). Duloxetine, however, does not change at varying doses.55 Duloxetine has been shown to be effective in patients suffering from chronic LBP without signs of radiculopathy or spinal stenosis. A dose of 60 mg daily was found to be effective in a 12-week study by Sklijarevski et al.56 SSRIs have failed to demonstrate efficacy in the treatment of chronic LBP as well as in various neuropathic pain conditions, and thus the medical literature does not support their use.42,50,52,54,57-60

Antiepileptics
Antiepileptic medications are additional adjunctive analgesics used in the treatment of LBP. They originally received FDA approval for neuropathic pain conditions, including postherpetic neuropathy and diabetic peripheral neuropathy (DPN). Carbamazepine is approved for trigeminal and glossopharyngeal neuralgia, and gabapentin is approved for postherpetic neuralgia, although in some studies it has shown efficacy in DPN.61,62 Pregabalin (Lyrica) is FDA-approved for both diabetic peripheral neuropathy and postherpetic neuralgia.63 Whereas antiepileptics are not FDA-approved for chronic LBP, many are used off-label for neuropathic or radicular pain.40 Table 4 provides characteristics of these approved antiepileptic agents.

First-generation antiepileptics, such as carbamazepine, oxcarbazepine, and phenytoin, work by inhibiting voltage-gated sodium channels and stabilizing neuronal membranes. The second-generation antiepileptics include gabapentin, which is an α2δ-ligand and is structurally related to GABA and acts at voltage-gated calcium channels. It inhibits excitatory neurotransmitter release but does not bind directly to the GABA receptor. The third-generation antiepileptics include pregabalin, topiramate, and lamotrigine. Pregabalin is also an α2δ-ligand that does not bind GABA, and acts on calcium channels similarly to gabapentin. Topiramate blocks voltage-dependent sodium channels, potentiates GABA transmission, and inhibits excitatory neurotransmission. Lamotrigine blocks sodium channels and stabilizes neural membranes.5,6

Two case studies reported the efficacy of carbamazepine for treatment of sciatica, but no clinical studies have shown its efficacy in chronic LBP or radicular symptoms.64

Although no studies have shown efficacy for either gabapentin or pregabalin in chronic LBP, their off-label use for neuropathic or radicular pain is generally accepted.40

One study showed a small but real analgesic effect with topiramate, but the study was limited by a significant 26% dropout rate due to intolerable side effects including paresthesias (38%), fatigue/weakness (34%), sedation (34%), and diarrhea (30%).65

Another study evaluating topiramate in the treatment of chronic LBP showed a reduction in pain symptoms and an improvement in mood and quality of life.66 In a small study of lamotrigine, a reduction of pain was seen in patients with intractable sciatica; the most common AEs noted were dizziness and diarrhea.67

There are numerous concerns regarding AEs that necessitate caution in the use of the antiepileptic agents. Carbamazapine can cause serious side effects, such as Stevens-Johnson syndrome, agranulocytosis, aplastic anemia, and hepatic toxicity. Phenytoin is known to have serious toxicity, and gabapentin and pregabalin can cause AEs including dizziness, somnolence, ataxia, and peripheral edema.5

Opioid Analgesics
Opioids have been the standard of care for treatment of cancer pain for many years and occupy the second rung on the World Health Organization’s analgesic ladder.68 They also have been used commonly for postoperative pain control, but initially were not widely accepted for the treatment of chronic pain. By 1999, however, several case series suggested that they were safe and effective in well-selected patients with chronic LBP.69,70

Opioids work by binding to multiple types of opioid receptors that are typically bound by endogenous opioid compounds and are located in both the periphery (on sensory nerve and immune cells) and CNS (spinal cord and brain stem). They work by inhibiting transmission of nociceptive input from the periphery to the spinal cord, activating descending inhibitory pathways and altering brain activity.45,71

The effects of a particular opioid depend on the specific receptor to which it binds, the agent’s unique affinity for the receptor, the magnitude with which it is activated, and whether that particular opioid is an agonist or antagonist. The efficacy is assessed by measuring perception of pain, reaction to pain, and pain tolerance.72-75

Many spine centers implement long-term opioid therapy as a part of the treatment plan for moderate to severe refractory chronic LBP.69,76,77 As per Schofferman, the primary indication for opioid therapy is as follows: “[L]ong term opioid therapy is indicated for patients with moderate to severe refractory chronic LBP who are psychologically healthy and have failed to respond to other forms of care.”78 The primary contraindication is an allergy to that specific opioid. A history of addiction is not a strict contraindication to long-term opioid therapy; however, patients with a history of addiction must be managed in collaboration with other mental health specialists, including addiction specialists.79

Opioids can be divided into two categories: sustained-release opioids (SROs) and immediate-release opioids (IROs) (Table 5, see page 118 ).78 SROs, such as morphine extended-release, oxycodone controlled-release, oxymorphone extended-release, and transdermal fentanyl, work by releasing medication continuously from the GI tract or transdermally. IROs have a fast onset of pain relief and are used for breakthrough pain.

Opioid medications can be administered either on a “pain-contingent” schedule, in which the medication is taken as needed (“prn”) when the pain occurs, or a “time-contingent” schedule, in which it is taken “around the clock” on a regular schedule despite the presence of pain at any given moment. Usually SROs are used on a time-contingent schedule. Between the two methods of administration, timed schedules tend to provide better pain relief in patients with chronic pain because of better overall pain control without frequent peaks and troughs in pain levels; this leads to improved overall adherence to a prescribed treatment plan and fewer AEs.78

Within a time-contingent plan, IROs can be prescribed for breakthrough pain, with the ultimate goal of requiring minimal amounts of IROs so as to have a stable baseline level of pain control throughout the day.78 An important fact regarding opioid therapy is that there is no true ceiling effect and, thus, no universally established dosing rule; rather, opioids should be titrated in each individual patient to maximize efficacy and minimize side effects.80,81

Responses to opioids are partially genetically predetermined; however, at this time it remains difficult to predict response and side effects in the individual patient.82 Physicians frequently may need to try several different opioid regimens, including trials of time-contingent regimens with IROs, with which patients sometimes have better results. However, the treatment of chronic pain with opioids should be systematic rather than haphazard.

Schofferman and Mazanec included guidelines for opioid therapy in their review of opioid treatment for chronic LBP.78 The first step involves a comprehensive evaluation that includes a history, physical exam, and review of imaging and other medical records. Next, it is important to establish realistic goals of therapy with the patient when prescribing the initial treatment plan. The patient should understand that the goal is not complete pain relief but rather tolerable pain levels that allow for maximal function and quality of life.

Once the patient appears to have an understanding of these goals, informed consent (whether verbal or written) should be obtained that covers the potential risks and benefits, side effects, and, most importantly, the strict consequences of abuse, diversion, or illicit use of other opioids. In many practices, this is done as a signed medication agreement in which the patient explicitly agrees to the use of one physician and one pharmacy for all prescriptions and to random urine testing.

Once the agreement is established, the physician starts an initial therapeutic trial, which is adjusted at regular follow-up visits based on efficacy, side effects, and any aberrant behavior. It is important for the physician to maintain meticulous medical records and to feel comfortable knowing when to consult mental health specialists when necessary.78

Each opioid medication has its own unique advantages, disadvantages, and characteristics that should be understood; this helps determine how to make the best use of opioids in a patient treatment plan. Morphine has been shown to be efficacious in the treatment of chronic LBP and is the cornerstone medication with which all other analgesics are compared.83,84 Transdermal fentanyl has the advantage of being a topical agent lasting 48 to 72 hours and causing less constipation than other opioids because of the transdermal route. Oxycodone CR (OxyContin) is effective for chronic LBP but has a higher prevalence of abuse and diversion compared with other opioids. Oxymorphone extended-release (Opana) is the newest opioid and one of the most studied specifically for chronic LBP.85,86 Methadone is believed to have good efficacy and biological availability despite its low cost.87-89 However, methadone dosing and titration can be challenging because it has a relatively short half-life for analgesia, whereas its active metabolites have long, highly variable half-lives. Additionally, methadone has the potential to cause QT prolongation as well as other arrhythmias, so an electrocardiographic (ECG) evaluation at the initiation of treatment and periodically during treatment has been recommended.5 Levorphanol is a long-acting opioid that has been found to be effective in treating nociceptic and neuropathic pain, but it has suffered from manufacturer shortage and inconveniently large pill size.90

One opioid medication that has proven to be a poor choice as a long-term opioid is meperidine. Its primary metabolite, normeperidine, accumulates over days to weeks, causing hyperexcitability and possibly seizures. Additionally, meperidine’s analgesic effects are not reliable because of poor absorbability.91

The most common side effects of opioids are GI side effects and sedation. There is no evidence that opioids cause liver, kidney, or brain toxicity. Constipation occurs because of decreased peristaltic contractions; increased small and large bowel tone; and decreased biliary, pancreatic, and intestinal secretions. This side effect should be managed with a regular stool softener and laxative because tolerance does not occur. Tolerance usually does develop to the nausea and vomiting caused by the direct central effect on medullary chemoreceptors.92

One of the major concerns regarding the effect of opioids on mental status is reflex responses and alertness. However, studies show that chronic pain can impair performance in and of itself and that opioid-treated patients actually perform as well as controls.93-95 Regarding the use of opioids when driving, a recent review of studies concluded that there was “generally consistent evidence for no impairment of psychomotor abilities of opioid-maintained patients.”96

Opioids may cause respiratory depression; this is rare with appropriate dosing in patients who are awake and alert and is usually seen in patients with comorbid pulmonary pathology or sleep apnea.97,98 Opioids also can cause endocrine dysfunction, including androgen deficiency due to suppression of pulsatile gonadotropin-releasing hormone by the hypothalamus. This will present in male patients as low libido, erectile difficulties, low energy, easy fatigue, and depressed mood and in female patients as decreased libido and altered menstrual cycle.99,100 Assessing testosterone and other sex hormones may be necessary in these patients.

Other important effects of opioid therapy include tolerance, pseudo-tolerance, physical dependence, and pseudo-addiction—terms often mistakenly confused with addiction. Tolerance is the need for higher doses to achieve the same degree of pain relief. This is a biological process that occurs at the cellular level and is not a significant problem in the treatment of chronic LBP.69,71 Pseudo-tolerance involves a need for increased doses of opioid due to increasing function that causes increased pain. This necessitates increasing the dose to achieve the proper balance of pain control, function, and side effects.78 Dependence, which is very common in patients being treated with opioids, is a state in which a withdrawal syndrome develops if the medication is suddenly stopped or reduced and is not a clinical problem in patients who are maintained on regular opioid dosing.101 Pseudo-addiction is a situation in which patients seek more medication because of undertreated pain. This should be distinguished from true addiction, which is a psychological issue that includes use despite biological, psychological, and social harm and is usually accompanied by “the four Cs”—adverse consequences, impaired control, compulsive use, and craving. The prevalence of addiction in patients receiving opioids is the same as in the general population.101-104

A common concern regarding opioid therapy includes a fear of disciplinary action by medical boards, specialty societies, and law enforcement agencies. However, several states and medical boards have published statements regarding the correct use of opioids for pain management and place priority on adequate pain control. If clinicians follow state regulations regarding prescription writing, maintain adequate documentation, and regularly inquire about the “four Cs” of addiction during regular follow-up visits, then this fear should not be a barrier to use of long-term opioid treatment.102-105

There are mixed data on the efficacy of opioids in patients with chronic pain.85,106,107 For mild to severe chronic LBP, sustained-release oxymorphone and sustained-release oxycodone were compared, and both were found to be superior to placebo.85 The study was limited because opioids were titrated to stable dose before randomization; hence, poorer outcomes in the placebo group could have been, in part, due to withdrawal caused by the cessation of opioids. In two systematic reviews of placebo-controlled trials, opioids were found to be moderately effective in non–cancer-related pain conditions.106,107 The most common cause of pain in both reviews was noted to be secondary to osteoarthritis and neuropathic pain.

Specifically in the area of chronic LBP, a recent Cochrane systematic review evaluated four RCTs of opioid use; the authors concluded that there are few high-quality trials assessing the efficacy of opioids for long-term management of chronic LBP.108 These studies cannot be generalized due to the fact that they have poor intention-to-treat analyses and provide inadequate descriptions of study populations and assessments of functional improvement. This review revealed that the long-term benefit of opioids for chronic LBP remains questionable and that more high-quality studies are needed.

In another recent systematic review of opioid analgesics in chronic LBP, the authors concluded that opioids “may be efficacious for short-term pain relief,” although “long-term efficacy is unclear.”109 However, there are several drawbacks of this review: It excluded several RCTs that showed the efficacy and safety of opioids for chronic LBP30,32,86; it excluded the study of longest duration (13 months)84; and it did not give much weight to long-term studies.69,76

Corticosteroids
Oral corticosteroids have proven to be effective in the treatment of inflammatory reactions, including allergic reactions, rheumatic and autoimmune diseases, and asthma exacerbations. Their mechanism of action involves interacting with receptor proteins in target tissues to regulate gene expression, thereby slowly altering protein synthesis, the results of which are seen within hours after administration. Corticosteroids reduce tissue damage by stabilizing cell membranes, reducing capillary permeability, and limiting release of pro-inflammatory substances.5,6 The anti-inflammatory and immunosuppressive effects of glucocorticoids are secondary to their inhibition of the immune responses of lymphocytes, macrophages, and fibroblasts. Occurring earlier in the inflammatory cascade than with NSAIDs, this action reduces the leukotriene- and prostaglandin-mediated inflammatory response.45 Radicular pain is thought to be the result of a chemical radiculitis involving the release of phospholipase A2, a potent inflammatory mediator released by intervertebral discs after injury.110,111

Studies designed to investigate the use of oral steroids in the setting of acute LBP are limited, and no studies have shown that oral corticosteroids used in treatment of LBP, especially with radicular symptoms, are better than placebo (Table 6).110,112-115 A 1986 study compared oral dexamethasone tapered from 64 mg to 8 mg over 7 days with placebo in the treatment of 33 patients with lumbosacral radicular pain. Early improvements (within 7 days) were not significantly different between the two groups.112 In patients with baseline radicular-type pain during straight leg raises, 8 of 19 patients treated with dexamethasone, compared with 1 of 6 patients in the placebo group, had diminished pain on straight leg raising repeated within 7 days. The limitations of this study include a small subject number, the use of additional analgesics obscuring group differences, the clinical uncertainty of a radicular process in a significant number of subjects, and the loss of several patients to follow-up after 1 year.

In a more recent 2008 double-blind, placebo-controlled trial, patients treated with a tapering course of prednisone had a more rapid return to baseline in pain, mental well-being, and disability scores and required fewer subsequent epidural injections.111 However, there was no improvement in return to work, and unlike the aforementioned earlier study, there was no difference in physical examination findings.

When they are used for acute LBP with radiculopathy, oral corticosteroids should be prescribed as a short course over 1 week. Because of the aforementioned known mechanism of action, during the initial evaluation, the clinician should ascertain if there is any underlying infection that could be exacerbated by the immunosuppressive effect of steroids, and patients with diabetes should be counseled to monitor their blood glucose closely for hyperglycemia. Additionally, clinicians should be aware of and inform patients of the potential for avascular necrosis of the hip. Other possible AEs for which patients should be monitored and about which they should be made aware include water retention, irritability, and insomnia. There are other AEs that generally are associated with prolonged use of steroids. These include hypothalamic–pituitary–adrenal axis stress, immunosuppression, pseudotumor cerebri, psychoses, cataracts, increased intraocular pressure, osteoporosis, aseptic necrosis, gastric ulcers, fluid, and electrolyte disturbances, hypertension, and impaired wound healing. The severity of these complications correlates with the dosage, duration of use, and the potency of the steroid prescribed.5,6,45,116,117

Conclusions
Several conclusions can be made to guide treatment of LBP. The Figure on page 124 provides an algorithm to help direct treatment. Short-term treatment (<2 weeks) with NSAIDs is effective for providing short-term pain relief in LBP without radiating symptoms. Although COX-2 inhibitors have fewer GI side effects, they are associated with cardiovascular side effects in some patients.13 They appear to be indicated for a short course (ie, 10-14 days) for acute LBP episodes. Muscle relaxants are useful for treatment of acute LBP or short-term treatment of chronic LBP without radiculopathy, but they must be used cautiously because of well-known CNS side effects, and they should not be used long-term because of their lack of proven efficacy.

Acetaminophen is commonly used as a first-line analgesic in the treatment of mild to moderate acute LBP based on several studies that have shown it to be superior to placebo in the treatment of osteoarthritic pain.4 Tramadol has been shown to be more effective than placebo in patients with chronic LBP,30 as well as more effective in combination with acetaminophen versus acetaminophen alone,31,32 but caution must be used in assessing patients for increased risk for seizure activity and serotonin syndrome in patients taking SSRIs and SNRIs concomitantly with tramadol. Topical medications, including both NSAIDs and lidocaine patches, appear to have some use in treating musculoskeletal pain, though their efficacy is limited, and studies specifically in LBP are limited.

Although there is conflicting evidence regarding the efficacy of TCAs in chronic LBP, there appears to be better efficacy with the use of TCAs in neuropathic pain, with a better effect noted with balanced TCAs than noradrenergic TCAs. SSRIs have failed to demonstrate efficacy in the treatment of chronic LBP and various neuropathic pain conditions. Although no studies have shown efficacy for gabapentin and pregabalin in chronic LBP, their off-label use for neuropathic or radicular pain is generally accepted.40

Opioids can be safely and effectively used in the treatment of LBP refractory to less conservative medications; they should be used within the structure of a physician–patient contract to minimize the risks for addictive behavior. Patients should be well educated prior to starting opioid therapy that the goal of treatment is not lack of pain but rather tolerable pain and maximal level of function. Dosing should be established to minimize side effects while maximizing analgesia and function. There is no evidence showing one opioid analgesic to have an advantage over another. No studies have shown that oral corticosteroids used in the treatment of LBP with radicular symptoms is any better than placebo, and further studies are needed to investigate the effectiveness of corticosteroids in lumbar radiculopathy.

Last updated on: February 8, 2016
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