Pharmacotherapy for Chronic Low Back Pain (Conservative Treatment) Part 2

Summary of efficacy data

Flexible titration allows for successful titration in the majority of opioid-treated patients. The availability of formulations administered twice daily, daily, every 3 days, or once weekly allows for individualized treatment of patients to optimize treatment compliance. Studies of long-acting oxymorphone, oxycodone, morphine, hydromorphone, fentanyl, and buprenorphine confirm the analgesic efficacy in patients with chronic low back pain. Patients who do not respond or who grow tolerant to an opioid therapy can be transitioned to a second opioid with the same mechanism of action. The impact of opioids on functional status is variable.

Summary of safety data

The most common adverse events during opioid therapy include constipation (41%), nausea (32%), somnolence/sedation (29%), vomiting (15%), dizziness (20%), itching (15%), dry mouth (13%), and headache (8%) (Kalso et al., 2004). Approximately one quarter of patients discontinue clinical trials owing to adverse events (Kalso et al., 2004). Flexible titration reduces adverse events and allows the majority of patients to be titrated to an effective dose (Peniston & Gould, 2009; Rauck et al., 2006a). In 2 trials of oxymorphone extended release, nearly two thirds (348 of 575; 60.5%) of patients were successfully titrated to a well-tolerated oxymorphone extended release dose. Opioid-nai’ve patients were started at a low dose (10 mg/ d) and opioid-experienced patients were transitioned from their previous opioid using published conversion ratios. Titration was gradual (5-10 mg every 3-7 days) and at investigators discretion. Discontinuations due to adverse events during titration (18.4%) were lower than typically observed in opioid trials (Peniston & Gould, 2009).


Similarly, in a trial comparing morphine extended release with oxycodone controlled release, use of a flexible titration schedule allowed 67.9% of patients (morphine extended release, 65.0%; oxycodone controlled release, 70.9%) to be titrated successfully (Rauck et al., 2006a). Discontinuations due to adverse events during the titration period were reported in 18.7% of patients treated with morphine extended release and 14.3% treated with oxycodone controlled release.

All opioids have a potential for clinically significant pharmacodynamic drug interactions, particularly when combined with drugs that cause respiratory depression (eg, barbiturates) or central nervous system depression (eg, alcohol, benzodiazepines), but opioids differ in their potential for pharmacokinetic drug interactions. The majority of opioids are metabolized by the cytochrome P450 system and have potential for pharmacokinetic interaction with many drugs (Smith, 2009). Exceptions to this are morphine (Coffman et al., 1997), oxymorphone (Adams et al., 2005; OPANA® ER, 2010), and hydromorphone (Hydromorphone-HP Injection 10 mg 2008), each of which primarily undergo phase 2 metabolism by glucuronidation. Selection of an opioid that is not metabolized via cytochrome P450 enzymes is important when there is a known cytochrome P450 pharmacokinetic interaction with a concurrent medication but may also be desirable in patients likely to be prescribed multiple medications, such as the elderly, patients with psychiatric illness, and patients with multiple medical problems (Smith & Bruckenthal, 2010).

The labels for all strong opioids recommend against concurrent use with alcohol because of the potential for clinically meaningful additive pharmacodynamic effects (Dilaudid® Oral Liquid and Dilaudid® Tablets, 2008; Duragesic®, 2009; Kadian®, 2007; OPANA® ER, 2010; OxyContin®, 2010). Additive effects when opioids are administered with alcohol are to be distinguished from the phenomenon of dose-dumping described previously with reference to hydromorphone extended release. Clinical trials have demonstrated the integrity of hydromorphone OROS (Sathyan et al., 2008) and morphine extended release (Barkin et al., 2009; Johnson et al., 2008) when administered with 240 mL of 4% to 40% ethanol. Coadministration of oxymorphone extended release with 240 mL of 4% and 20% ethanol, corresponding to modest and moderate alcohol consumption, did not cause premature release of oxymorphone from the extended release tablet (Fiske et al., 2011). Oxymorphone extended release administered with a 240 mL solution of 40% ethanol resulted in potentially clinically meaningful increases in oxymorphone maximum concentration (Fiske et al., 2011). It should be noted, however, that the 40% ethanol solution corresponds to heavy alcohol intake, which is to be avoided in any opioid-treated patient.

Minimize abuse potential

Before initiating opioid therapy, physicians should take a thorough patient history that includes a history of prior or current substance abuse or psychiatric disease, as well as accurate documentation of current prescribed medications. Patients should undergo a physical examination sufficient to confirm the diagnosis of chronic low back pain and determine pain intensity and the extent of disability. This will help establish that a request for an analgesic is legitimate rather than drug-seeking behavior (Cone & Caplan, 2009). Patients should also be screened for abuse risk using validated screening instruments such as the Opioid Risk Tool (Webster & Webster, 2005), Current Opioid Misuse Measure (Butler et al., 2007), and the revised Screener and Opioid Assessment for Patients with Pain (Butler et al., 2008).

Opioid therapy should be conducted using a plan that includes controlled substance agreements, frequent random urine drug testing, and confirmatory urine drug testing (Cone & Caplan, 2009; Manchikanti et al., 2008). Screening should be conducted in all patients, regardless of perceived risk of abuse (Gourlay et al., 2005). In patients believed to be at increased risk, selection of an opioid that does not produce metabolites that are identical to other opioids may simplify urine drug screening (Cone & Caplan, 2009). Positive test results for patients prescribed buprenorphine, fentanyl, oxymorphone, tapentadol, and tramadol will not be confused by the presence of multiple opioids.

Drug companies are currently attempting to develop formulations that incorporate obstacles to abuse. Most of these technologies are designed to resist common methods by which abusers tamper with an oral opioid formulation to facilitate intranasal or intravenous abuse (Katz, 2008). Tamper-resistant opioids include formulations with physical barriers to crushing, chewing, and dissolution; formulations with sequestered antagonists that neutralize opioid effects if the formulation is chewed or crushed; and formulations with sequestered noxious components that are released if the opioid is chewed or crushed.

At present, 2 tamper-resistant formulations have received FDA approval. OXECTA® is a short-acting formulation of oxycodone with sequestered ingredients that are released if the opioid is chewed or crushed (OXECTA®, 2011). In addition to oxycodone, the formulation contains several ingredients that may cause irritation if swallowed or inhaled, including colloidal silicon dioxide (Amorim et al., 2010), crospovidone (Lowe et al., 2006), microcrystalline cellulose (Teshima et al., 2002), and sodium lauryl sulfate (Engel et al., 2008).

Oxycodone controlled release has also been reformulated in a polymer matrix that resists crushing or chewing (US Food and Drug Administration, 2010) and becomes a viscous gel if the product is immersed in fluid (Schneider et al., 2010). The value of tamper-resistant formulations of oxycodone and other opioids is likely to be limited unless all opioids are reformulated with this purpose in mind. Otherwise, the availability of one opioid in a tamper-resistant formulation may simply divert abusers to another opioid that has not been reformulated. Since the approval of reformulated oxycodone, oxycodone has seen a decline in abuse, with a corresponding increase in oxymorphone abuse (Goodnough, 2011; Nassau County executive: abuse of painkiller Opana is growing, 2011). Oxymorphone extended release is not currently available in a tamper resistant formulation, although such a formulation is in development.

Adjunctive therapies

Tricyclic antidepressants are recommended in both US and European guidelines for the management of chronic low back pain. Two systematic reviews concluded that tricyclic antidepressants have modest beneficial effects on pain but limited effects on functional status (Salerno et al., 2002; Staiger et al., 2003).

Duloxetine can be administered safely with NSAIDs, acetaminophen, and opioids that do not undergo cytochrome P450 metabolism, such as oxymorphone, hydromorphone, fentanyl, or morphine (Smith, 2009). Because it is a substrate and moderate inhibitor of the cytochrome P450 enzyme 2D6, pharmacokinetic interactions with oxycodone, tramadol, and codeine are possible (Cymbalta® Delayed-Release Capsules, 2010). Given its modest efficacy (discussed previously), addition of duloxetine to ongoing opioid or NSAID therapy may be a useful alternative to switching to another medication or increasing the dose of an opioid or NSAID. Duloxetine may be of particular value in chronic pain patients with comorbid depression. In an open-label pilot study (Karp et al., 2010), duloxetine administered to patients with comorbid chronic low back pain and major depression improved both pain and depression.

Guidelines in the United States state that gabapentin has modest efficacy in patients with chronic low back pain (Chou et al., 2007), whereas the European guidelines state that there is no convincing evidence (Airaksinen et al., 2006). Other anticonvulsants are not recommended. Benzodiazepines have been recommended for use as muscle relaxants for short-term therapy in both US and European guidelines (Airaksinen et al., 2006; Chou et al., 2007). These anxiolytics have a high risk of addiction and abuse, and their combined use with opioids is of particular concern (Rich & Webster, 2011).

Invasive therapies

In US guidelines, epidural steroid injection is recommended for patients with persistent chronic low back pain and signs of radiculopathy or spinal stenosis (Chou et al., 2007). European guidelines state that epidural injections have insufficient evidence to support a recommendation (Airaksinen et al., 2006). Intrathecal opioids (morphine or methadone) have been administered for severe chronic low back pain, almost always following failed back surgery (Noble et al., 2010). Though effective, intrathecal delivery of opioids has been associated with granuloma formation (Allen et al., 2006). Neither intrathecal nor epidural opioid infusion is recommended in US or European treatment guidelines.

United States guidelines state that transcutaneous nerve stimulation has not been proven effective for chronic low back pain (Chou et al., 2007). European guidelines state that clinicians may consider percutaneous electrical nerve stimulation or neuroflexotherapy (Airaksinen et al., 2006). European guidelines also recommend against local facet nerve blocks, trigger point injections, and spinal cord stimulation (Airaksinen et al., 2006). Surgery is not recommended unless other treatment options have been unsuccessful for 1 year (US) (Chou et al., 2007) or 2 years (Europe) (Airaksinen et al., 2006).

Treatment algorithm

Treatment recommendations based on the clinical data provided previously are summarized in Figure 1. Patients with mild to moderate chronic low back pain should begin pharmacotherapy with acetaminophen or an NSAID. Acetaminophen has limited efficacy, poses risks of liver failure with cumulative/escalating use, is not recommended in patients with hepatic impairment, and should be given cautiously to patients with depression or at risk of substance abuse because of its documented use by patients wishing to inflict self-harm. Patients with dementia may have difficulties reporting pain, so clinicians should be sure that patients are not in need of more potent analgesia.

Oral NSAIDs are more effective than acetaminophen but still have only modest efficacy, making their use best reserved for mild to moderate pain that does not respond to acetaminophen. NSAIDs should be administered for the shortest period of time at the lowest effective dose, and are not generally recommended in older patients and those with current or a history of gastrointestinal bleeding or significant cardiovascular or renal comorbidities. Caution is recommended when administering NSAIDs in patients taking SSRIs, corticosteroids, warfarin, cardioprotective aspirin (ibuprofen only), diuretics and angiotensin-converting enzyme inhibitors. An oral NSAID with a gastroprotective proton pump inhibitor should not be administered to patients receiving clopidogrel.

Topical lidocaine patch is recommended for the treatment of chronic low back pain in Europe but not the United States. Lidocaine patch has shown efficacy in patients with chronic low back pain. Capsaicin plasters have shown only very modest efficacy and cause localized burning that limits tolerability. Capsaicin patches are not recommended, and their localized numbing effect is better achieved using a lidocaine patch. Topical NSAIDs have few data supporting their use for chronic low back pain and require further investigation of their potential value for this indication.

Treatment algorithm for patients with chronic low back pain. COX2= cyclooxygenase -2, NSAID=nonsteroidal anti-inflammatory drug, PGE2= prostaglandin E2, PPI=proton pump inhibitor.

Fig. 1. Treatment algorithm for patients with chronic low back pain. COX2= cyclooxygenase -2, NSAID=nonsteroidal anti-inflammatory drug, PGE2= prostaglandin E2, PPI=proton pump inhibitor.

There are limited data supporting the use of tramadol in patients with chronic low back pain. Tramadol may be administered in combination products that include acetaminophen. This imposes a dosage ceiling on the product that may limit use of tramadol. There are more robust data for tapentadol; however, it is unclear whether this is because of a difference in efficacy or to it having been studied more rigorously. Both tramadol and tapentadol are associated with typical opioid adverse events, but gastrointestinal adverse events are less frequent than with strong opioids. Though less potent than strong opioids, tapentadol may be a safer option for patients who may benefit from an opioid but want to reduce risks. As noradrenergic agents may be administered as adjunctive therapy for chronic low back pain, tapentadol affords an opportunity to utilize 2 analgesic mechanisms in a single pill.

Opioids have a growing body of evidence supporting their use in patients with chronic low back pain. Much of these data have been published after the most recent US and European guidelines were developed. Trials of long-acting formulations of oxycodone, morphine, oxymorphone, hydromorphone, and buprenorphine have shown good efficacy with acceptable tolerability in patients with chronic low back pain. Starting with a low dose in opioid-naive patients and titrating slowly based on individual response increases the likelihood that treatment will be tolerated. Opioid-experienced patients can be transitioned to a new opioid at a dose slightly lower than that considered equipotent based on established conversion ratios. Titration should proceed slowly based on individual response. Opportunities for twice-daily, once-daily, or once-weekly dosing allow clinicians to tailor treatment in order to maximum compliance. In patients receiving multiple medications, it may be advisable to prescribe an opioid that is not metabolized by the cytochrome P450 enzyme system. Opioid therapy needs to be predicated on a full history, screening for abuse potential, and agreement to regular monitoring for treatment compliance and signs of abuse. Drugs that do not produce other opioids as metabolites will simplify urine drug screening.

Epidural corticosteroid injections should be reserved for patients with persistent pain that does not respond adequately to rehabilitation and pharmacotherapy. Surgery should be reserved for patients with prolonged, disabling, nonresponsive pain. Discussions of these more invasive therapies are reserved for elsewhere in this topic.

Conclusion

Though ideally chronic low back pain would respond to self-management techniques, pharmacotherapy remains an essential component of treatment without which patients cannot maintain their levels of activity. There are clinical data that suggest uncontrolled pain can interfere with physical therapy, whereas improvements in pain are accompanied by improvements in function and response to therapy (Gross et al., 2008; Schein et al., 2008; Soin et al., 2008; Teske et al., 2008). Sufficient analgesia may be necessary to allow patients to effectively participate in a physical therapy program. The perceived choice facing clinicians is between medications with limited efficacy, but relatively benign adverse events profiles, and more potent analgesics with more substantial risks of adverse events or drug abuse.

Acetaminophen and NSAIDs have modest efficacy, but acetaminophen has significant risks of hepatic adverse events and NSAIDs with gastrointestinal, cardiovascular, renal and other systemic adverse events. Duloxetine has moderate efficacy comparable to acetaminophen or NSAIDs and is useful as an adjunctive medication. Tramadol and tapentadol offer advantages of opioid agonism paired with norepinephrine reuptake inhibition, but should not be combined with SNRIs or SSRIs. Opioids offer the greatest efficacy of available pharmacologic therapies, and, although opioids have significant risks of abuse, overdose, and distressing gastrointestinal adverse effects (nausea, constipation), they have a safety advantage over NSAIDs with respect to cardiovascular adverse events and gastrointestinal bleeding. The American Heart Association has stated that opioids may be preferred over NSAIDs in patients with significant cardiovascular risk (Antman et al., 2007).

Next post:

Previous post: