Pharmaceutical treatments for radiculopathy include opioid, antiinflammatory (steroidal and nonsteroidal), neuromodulating, topical, and adjuvant treatments. These medications act locally, peripherally, or centrally on the neural axis. This article reviews the history of medication use for radiculopathy and the available literature along with the breadth of current treatment and indications.
Radiculopathy often presents clinically with a neuropathic component. The neuronal damage or irritation is felt as radicular pain. In the lumbar spine, this condition may be called sciatica by the lay press when the pain is radiating down the back of the leg. However, the term sciatica is misleading because radiating pain may occur without nerve irritation, and neuronal pain can present in different dermatomes and myotomes.
The pain pathway is a complex feedback loop of peripheral and central pathways, inflammatory mediators, and receptor modulation. Hence, the use of pharmaceuticals in radiculopathy can be multifaceted, targeting any of these potential components of the neuropathic pain response to improve function. A variety of pain medications have been developed to intercept differing areas of the pain pathway, including opioids, nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, antidepressants, antiepileptics, muscle relaxants, and topical treatments. The decision to initiate one of these pharmaceutical agents is complementary to the entire treatment plan. Consideration is given to pain severity and chronicity, secondary functional limitations due to pain, and future enrollment in physical therapy or further interventions.
The relatively recent focus on pain as a fifth vital sign has helped hasten the evolution of oral analgesia. Research, development, manufacturing, and marketing of pharmaceuticals for analgesia make up a multibillion dollar industry with physicians near the end of the line helping guide patients to the correct treatment plan. Unfortunately, there are no medications developed specifically for radiculopathy, and there are currently no consensus guidelines to recommend a uniformly accepted treatment algorithm. The general lack of consensus guidelines may stem from the lack of robust available literature on the topic. Therefore, the decision to initiate a treatment must be tailored to the individual with the choice of analgesic agent based on the patient’s comorbid medical conditions and specific pain complaints, including frequency, quality, and severity. Careful identification of the cause along with proper subgrouping of patients may lead to more effective use of medications and resources. For instance, those with chronic back pain have little chance of sustained recovery if a medication is used as initial therapy. However, NSAIDs seem to be effective in the acute phase of radiculopathy. Systemic corticosteroids do not seem to be indicated for any group of patients with low-back pain. Muscle relaxants are not indicated as the first-line treatment of low-back pain but can be a good adjunct in the acute phase. Also, alterations in neural pathways occur in those with chronic pain, including central sensitization. That development, combined with a peripheral increase in sodium and calcium channels, leads to increased excitability throughout the entire pathway and abnormal transmissions perceived as pain by the patient. Therefore, the medication choice may vary depending on the chronicity, severity, and character of pain.
In general, analgesic agents can be divided into 2 major categories. First-line treatments include those medications that are efficacious with favorable safety profiles, low cost, and sometimes over-the-counter access. The second category encompasses medications that are helpful in a specific subgroup of patients but otherwise has questionable efficacy or significant adverse effects. This article reviews the literature for each major category of commonly used medication in the treatment of painful radiculopathy.
Nonopioid analgesia
Acetaminophen is used extensively for the treatment of low-back pain and may also be used for radiculopathy. The analgesic properties of acetaminophen stem from the inhibition of central prostaglandin synthesis. (p150) Acetaminophen is particularly useful in older persons with multiple comorbidities because opioids can increase fall risk, and selective NSAIDs may increase the risk of cardiovascular disease, bleeding, gastrointestinal (GI) irritation, and renal toxicity. Despite the lack of evidence supporting the efficacy of acetaminophen for treating radiculopathy, the American College of Physicians recommends using acetaminophen as a first-line option for low-back pain because of its relatively benign safety profile. Acetaminophen’s onset of action is rapid, and it is considered an excellent medication for mild to moderate pain. Because acetaminophen is metabolized by the liver, excessive acetaminophen ingestion is associated with hepatotoxicity. The current recommended dose is less than 4 g/d. If the patient responds to a small dose, one may consider increasing the total daily dose of acetaminophen before adding another medication. Dosages higher than the 650 mg standard do not seem to have incremental benefit, so there may be a ceiling effect. (p150) Caution should be advised against concomitant alcohol consumption to avoid the rare complication of fulminate hepatic necrosis.
Opioids
Opioids remain one of the most versatile and useful medications for analgesia. Opioids are the workhorses of severe pain treatment but they are also polarizing in the social and political realm because of their abuse and addiction potential. The decision to initiate opioid analgesia can be a boon or burden to the patient depending on the management of adverse effects, which can be profound. The potency of analgesia is dose dependent and often limited only by the adverse effects for the patient.
Opioids have been demonstrated to be helpful in neuropathic pain conditions. Eisenberg and colleagues had shown in an 8-week trial that intermediate opioid treatment significantly decreased neuropathic pain compared with gabapentin. In a randomized, double-blind, placebo-controlled study by Gilron and colleagues, the greatest symptomatic improvement was from gabapentin combined with morphine. However, most of these studies were performed in patients with neuropathic pain from causes other than lumbar or cervical radiculopathy. In studies of nerve root–related symptoms and neuropathic pain, opioids did not demonstrate significant improvement in symptoms, even when combined with the antineuropathic medications.
Common adverse effects from opioid medications range from somnolence and mild GI upset to nausea, vomiting, and constipation. Constipation occurs via the same mechanism of analgesia, μ receptor activation. (p113) Some adverse effects can be anticipated and easily managed. For instance, stool softeners should be routinely offered to anyone starting to use opioid analgesia to help mitigate the inevitable constipation associated with these medications. Histamine-releasing effects, such as pruritus, and anticholinergic effects, such as hypotension and bradycardia, can also be seen. When severe, patients may experience respiratory suppression and die. Caution should be used in the elderly because opioids can worsen gait disturbances and increase fall risk. Although the risk of addiction is relatively low, physical dependence happens frequently for patients who take these medications chronically, and patients should be counseled accordingly. The long-term effects of chronic opioid use may be associated with the development of tolerance and immunologic and endocrine changes.
Tramadol is a synthetic molecule with 2 moieties, on one side a weak opioid and on the other, a weak serotonin-norepinephrine reuptake inhibitor (SNRI). Therefore, tramadol activates the opioid μ receptor and inhibits the reuptake of norepinephrine and serotonin. The molecule then undergoes hepatic metabolism and renal excretion. Tramadol has demonstrated only minimal efficacy over placebo alone. Common adverse effects include nausea, dizziness, somnolence, and headache. In a study of 7198 patients on tramadol for chronic pain, 7.1% experienced unspecific central nervous system (CNS) irritation and coordination disorders, 5.3% had dizziness, 4.8% had nausea, and another 2.4% complained of sedation. Caution should be taken with patients on a tricyclic antidepressant (TCA) because of an increased risk of seizures. Seizure risk is rare (<1%) but increased with a history of alcohol abuse, stroke, brain injury, or renal dysfunction. (p126) Administering multiple serotonergic medications may lead to serotonin syndrome.
Opioids
Opioids remain one of the most versatile and useful medications for analgesia. Opioids are the workhorses of severe pain treatment but they are also polarizing in the social and political realm because of their abuse and addiction potential. The decision to initiate opioid analgesia can be a boon or burden to the patient depending on the management of adverse effects, which can be profound. The potency of analgesia is dose dependent and often limited only by the adverse effects for the patient.
Opioids have been demonstrated to be helpful in neuropathic pain conditions. Eisenberg and colleagues had shown in an 8-week trial that intermediate opioid treatment significantly decreased neuropathic pain compared with gabapentin. In a randomized, double-blind, placebo-controlled study by Gilron and colleagues, the greatest symptomatic improvement was from gabapentin combined with morphine. However, most of these studies were performed in patients with neuropathic pain from causes other than lumbar or cervical radiculopathy. In studies of nerve root–related symptoms and neuropathic pain, opioids did not demonstrate significant improvement in symptoms, even when combined with the antineuropathic medications.
Common adverse effects from opioid medications range from somnolence and mild GI upset to nausea, vomiting, and constipation. Constipation occurs via the same mechanism of analgesia, μ receptor activation. (p113) Some adverse effects can be anticipated and easily managed. For instance, stool softeners should be routinely offered to anyone starting to use opioid analgesia to help mitigate the inevitable constipation associated with these medications. Histamine-releasing effects, such as pruritus, and anticholinergic effects, such as hypotension and bradycardia, can also be seen. When severe, patients may experience respiratory suppression and die. Caution should be used in the elderly because opioids can worsen gait disturbances and increase fall risk. Although the risk of addiction is relatively low, physical dependence happens frequently for patients who take these medications chronically, and patients should be counseled accordingly. The long-term effects of chronic opioid use may be associated with the development of tolerance and immunologic and endocrine changes.
Tramadol is a synthetic molecule with 2 moieties, on one side a weak opioid and on the other, a weak serotonin-norepinephrine reuptake inhibitor (SNRI). Therefore, tramadol activates the opioid μ receptor and inhibits the reuptake of norepinephrine and serotonin. The molecule then undergoes hepatic metabolism and renal excretion. Tramadol has demonstrated only minimal efficacy over placebo alone. Common adverse effects include nausea, dizziness, somnolence, and headache. In a study of 7198 patients on tramadol for chronic pain, 7.1% experienced unspecific central nervous system (CNS) irritation and coordination disorders, 5.3% had dizziness, 4.8% had nausea, and another 2.4% complained of sedation. Caution should be taken with patients on a tricyclic antidepressant (TCA) because of an increased risk of seizures. Seizure risk is rare (<1%) but increased with a history of alcohol abuse, stroke, brain injury, or renal dysfunction. (p126) Administering multiple serotonergic medications may lead to serotonin syndrome.
NSAIDs
NSAIDs may be indicated for short-term use to treat inflammation and pain caused by radiculopathy. NSAIDs have both analgesic and antiinflammatory properties. The mechanism of action of NSAIDs is cyclooxygenase (COX) and leukotriene inhibition, preventing the conversion of arachidonic acid to prostaglandins. NSAIDs vary in dosage, potency, and degree of COX-1 and COX-2 inhibition. In addition to mediating pain and inflammation, COX-1 is associated with platelet aggregation, gastric protection, and renal and vascular smooth muscle activity. (p144) Therefore COX-1 inhibition can have adverse effects on those systems. One common demarcation used for NSAIDs is selective (preferentially COX-2) versus nonselective (both COX-1 and COX-2) inhibition. Commonly used nonselective NSAIDs include naproxen, ibuprofen, and diclofenac. Meloxicam, etodolac, and nabumetone are semiselective. Collectively, nonselective NSAIDs are indistinguishable from each other in terms of tolerability but may have some slight differences in efficacy. However, nonselective NSAIDs are not indicated for chronic use, particularly in the elderly because of the risk of GI irritation, ulceration, and bleeding (COX-1 inhibitory effects). Concomitant use of a proton pump inhibitor can decrease the gastric adverse effects. COX-2, or selective NSAIDs, allows for fewer GI effects but may increase cardiotoxicity and should also be avoided in the elderly population. Limited studies have been conducted specifically for the use of COX-2 in radiculopathy; however, meloxicam has been shown to have a significant improvement in sciatic pain at both the 7.5 mg and 15 mg dose when taken for a week compared with placebo. Meloxicam was also shown to be superior in efficacy to diclofenac. Overall, compared with controls, NSAIDs as a class has been shown to improve symptoms of low-back pain, but the literature is less robust for radiculopathy.
Oral Steroids
Although the efficacy of epidural corticosteroid injections in radicular pain has been elucidated, the role of oral and intravenous steroids remains unclear. There are various theories as to the mechanism of effect of corticosteroids because they demonstrate effects beyond pure antiinflammation. In the case of spinal stenosis, steroids may help mitigate the inflammation of neural elements and address the chemical radiculitis. In addition to the antiinflammatory mechanism, steroids may also block the development of prostaglandins centrally from the dorsal horn neurons (so-called central sensitization). Steroids may also directly stabilize the membrane of nociceptive C-fibers, blocking transmission and preventing ectopic discharge. In a double-blind controlled clinical trial by Holve and Barkan, 27 subjects were assigned to a 9-day tapering course of prednisone versus placebo for acute radiculopathy. Although there seemed to be a trend of improved and faster pain relief, the results did not reach statistical significance. Older studies of intravenous and intramuscular steroid showed that it was no better than placebo. The adverse effects of these medications were also poorly described. Nonetheless a short duration (<3 weeks) of low-dose corticosteroid use has relatively few complications regardless of the method of administration. Long-term steroid use, on the other hand, has been linked to hyperglycemia, GI ulceration, weight gain, insomnia, hypertension, hypoadrenocorticism, osteoporosis, friable skin, depression, immunosuppression, osteoporosis, muscular weakness, and rarely avascular necrosis of the femoral head.
Neuromodulatory Medications
Neuromodulatory medications can be largely divided into 2 categories, antidepressants and membrane stabilizers or anticonvulsants. Within the antidepressant category there are selective serotonin reuptake inhibitors (SSRIs), SNRIs, and TCAs.
SSRIs are commonly used as an adjuvant to manage emotional components of neuropathic pain. Despite the fact that SSRIs do not seem to have primary analgesic properties, they seem to have a role in treating pain, (p125) which may be because of the affective component of pain and an extremely high frequency of psychiatric illness in the pain population. Psychiatric illness is associated with worse pain intensity and related disability. There are data that citalopram and paroxetine may be beneficial in the treatment of peripheral neuropathic pain; however, there is no evidence of their efficacy in radiculopathy. Common adverse effects include GI bleeding and headaches. The risk of GI bleeding is increased with concomitant NSAID use. To mitigate the adverse events, gradually increasing the dose may be helpful. As a class, SSRIs undergo hepatic metabolism and may alter the CYP-450 pathway. A rare but well-documented drug-drug interaction to consider is serotonin syndrome. This syndrome can arise from the use of multiple serotonergic agents including, SSRI, SNRI, TCA, and tramadol. Clinically, patients may present with profuse sweating, tremor, agitation, hyperthermia, tachycardia, and hypertension. This syndrome is a potentially lethal complication that may lead to cerebral vasoconstriction, stroke, and even death.
SNRIs modulate both serum serotonin as well as norepinephrine levels by inhibiting reuptake. The addition of norepinephrine reuptake inhibition has been shown to improve analgesia and decrease the likelihood of depression remission. Duloxetine (Cymbalta) and venlafaxine (Effexor) are the best-studied medications in this group. Duloxetine has been shown to be effective in diabetic peripheral neuropathy according to 3 randomized control trials. However, the use of duloxetine in other types of neuropathy has not been validated. Duloxetine has a relatively favorable safety profile with nausea being the most common symptom. At higher dosages (60 mg twice daily), there is a higher incidence of somnolence, hyperhidrosis, anorexia, vomiting, and constipation. As opposed to duloxetine, which affects serotonin and norepinephrine equally, venlafaxine essentially behaves as an SSRI at low dose and as an SNRI at higher doses. Again, there is literature to suggest that venlafaxine is efficacious in diabetic peripheral neuropathy and other painful polyneuropathies. There are, however, no data to recommend the use of venlafaxine in other central neuropathic pain syndromes. Several adverse effects are seen with venlafaxine, including nausea, withdrawal/discontinuation syndrome, sexual dysfunction, and dose-dependent cardiovascular problems. In fact, in one study, as many as 5% of patients on venlafaxine developed electrocardiographic changes. Thus, one must use discretion in patients with preexisting cardiac conditions.
Discovered in the 1950s, TCAs are so named because they contain 3 rings of atoms. TCAs nonselectively inhibit the reuptake of serotonin and norepinephrine to provide analgesia. TCAs are also theorized to stabilize nerve membranes. TCAs are inexpensive, dosed once daily, and well studied to relieve neuropathic pain, all with similar efficacy. The relatively rapid analgesic effect of TCAs is thought to be separate from the antidepressant properties. However, there is no evidence documenting its utility in chronic low-back pain or radicular pain. Adverse effects, well studied and documented, include sedation, falls, anticholinergic effects (dry mouth, urinary retention, constipation), orthostatic hypotension, cardiac conduction blocks, arrhythmias, and myocardial infarction. For this reason, the use of TCAs has been supplanted by the newer and safer SSRIs and SNRIs. When TCA use is necessary, screening electrocardiograms are routinely recommended for patients older than 40 years before initiating therapy. For those patients in whom a TCA is appropriate, the adverse effect profile can be considered as the deciding factor. For instance, amitriptyline and imipramine tend to be more sedating, and nortriptyline is less anticholinergic.
Antiepileptic medications inhibit voltage-gated sodium and calcium channels to decrease excitatory neurotransmitter (glutamate) release, to potentiate γ-amino butyric acid (GABA) transmission, and to stabilize neural membranes. Carbamazepine has not been studied extensively, but small studies have found effectiveness for sciatica. Studies of the use of carbamazepine in other peripheral neuropathic conditions have produced variable results. Although gabapentin and pregabalin are structurally related to GABA, they do not bind to GABA A or GABA B receptors. Instead, gabapentin and pregabalin are calcium channel blockers with α 2 /δ 1 subunits. The most significant distinction between these drugs is that pregabalin has an excellent bioavailability and linear pharmacokinetics. In a study by Yildirim and colleagues, 50 patients with lumbosacral radiculopathy who were randomly assigned to oral gabapentin ranging from 900 to 3600 mg/d or to placebo for 8 weeks were described. Those who received gabapentin were shown to have improved motor and sensory function, lumbar flexion range of motion ( P <.001), and pain at rest. Similarly, a prospective study of 1304 subjects with inadequately managed cervical and lumbar radiculopathy were started on either pregabalin as monotherapy or adjuvant therapy versus acetaminophen, NSAIDs, or tramadol. The investigators found a significant reduction of pain severity and resource consumption in those receiving pregabalin. Both gabapentin and pregabalin are fairly well tolerated and have similar adverse effect profiles consisting of dizziness, somnolence, peripheral edema, and vertigo/ataxia.
Topiramate and lamotrigine block sodium channels, which helps to decrease the excitability of actively firing neurons. Topiramate and lamotrigine also block glutamate, the excitatory neurotransmitter responsible for pain transmission. (p137) In addition, topiramate enhances GABA, and in one study, topiramate produced small analgesic effects at 200 mg in those with imaging-confirmed radiculopathy. Another study cited that at 500 mg daily, topiramate reduces pain and improves mood and quality of life. Lamotrigine is commonly used in trigeminal neuralgia; however, it has a high incidence of undesirable adverse effects such as paresthesia, fatigue, weakness, sedation, and diarrhea. In a small study of 14 patients published in the European Journal of Pain in 2003, lamotrigine at 400 mg/d improved intractable radicular pain. Levetiracetam is a relatively new antiepileptic whose mechanism of action is still unclear. The use of this antiepileptic was found to improve pain scores, activity, ambulation, and mood in 26 patients with radiological and electrophysiological evidence of lumbar radiculopathy at 1500 mg twice a day ( P ≤.001). Associated adverse effects include sedation, GI upset, headache, and blurry vision.
Oral Muscle Relaxants
Benzodiazepine medications are commonly thought to work indirectly; relaxing the muscle spasm that is caused by underlying injury by binding to the GABA receptor. These medications are administered under the presumption that the muscle spasm itself is painful. Benzodiazepines are also CNS depressants that act on the limbic system, brainstem reticular formation, and cortex. For this reason they are also useful for anxiety and panic attacks. A Cochrane review found skeletal muscle relaxants better than placebo 2 to 4 days after the acute onset of low-back pain. Other articles specifically studying cyclobenzaprine and tizanidine also support these findings. However, there is no evidence that this effect translates to radiculopathy. In one study by Asiedu and colleagues, the direct pain-relieving properties of benzodiazepines were explored. Carbonic anhydrase, which normally assists in replenishing intracellular neuronal mediators, was inhibited after intrathecal administration of midazolam with acetazolamide. This administration resulted in decreased neuropathic pain from a peripheral nerve injury. Tizanidine was administered in an escalating dose from 6 to 36 mg total daily for an 8-week period in another noncontrolled study of 23 patients with neuropathic pain, showing improvements in quality of life and pain.
The side effects from muscle relaxants may be their most desirable attribute. The sedative effect is powerful and occurs in up to 50% of subjects in a variety of studies. Patients with insomnia in the setting of low-back pain can take these medications at night to assist with sleep. Based on available data, there is currently no role for muscle relaxants as a first-line agent in lumbosacral radiculopathy.
Anti–tumor Necrosis Factor α
Early evidence is conflicting regarding the role of anti–tumor necrosis factor α agents in radiculopathy. Most studies are on open-label use and not controlled, which limits the utility of the data. Smaller studies without controls often show improvements in pain and function because of the natural history of most radicular pain. For example one uncontrolled study of 10 subjects with sciatica treated with infliximab revealed improved radicular pain and return to work in all patients. That said, a follow-up study of 40 patients in a placebo-controlled study revealed no difference between groups because both improved. At present, larger, controlled, and randomized studies are lacking in this area.
Topical Treatments
Topical treatments offer an adjunct or alternative to orally administered medications. Palliation of neuropathic pain may also occur with topical use of the medications already discussed. However, topical treatments have been studied primarily in those with pain from postherpetic neuralgia or diabetic peripheral neuropathy. By extrapolation, a more proximal peripheral nerve lesion due to a herniated disk affecting the ventral ramus should respond accordingly, but this is not borne in the literature. In randomized, double-blind, controlled studies, lidocaine 2.5% and 5% gel and patch have been effective in alleviating localized allodynic and nonallodynic pain complaints. The patch is particularly useful when an occlusive dressing is desirable. Because of the action on sodium channels and possible effects on cardiac conduction, topical lidocaine should be avoided in those on antiarrhythmic medications. Lidocaine undergoes hepatic clearance, and thus its long-term use is not safe in those with severe hepatic dysfunction because blood levels of lidocaine elevate steadily. This observation is in contrast to that with topical diclofenac. This NSAID offers a systemic absorption of less than 10% when applied topically compared with an equivalent oral dose.
Derived from chili peppers, capsaicin cream offers an interesting alternative in peripheral neuropathic pain control. Again, because studies have focused primarily on postherpetic neuralgia and diabetic peripheral neuropathy, the ability to justify the use of capsaicin in neuropathic pain caused by radiculopathy is limited. Because capsaicin directly causes substance P release from neurons, it simultaneously induces pain while depleting the pain mediator and causing a dying-back phenomenon of nociceptive C-fibers in the dermis. The application of capsaicin can occur with a strong 1-time or 2-time application of 8% capsaicin or a slow graded increase in dose from 0.1% to 2.0% to allow for improved tolerability. The stronger doses may be less tolerated because of pain; however, a graded application requires frequent application for efficacy. Thus, patient compliance is important for successful treatment.
Depending on the desired route of delivery, traditionally, oral medications can sometimes be compounded into a topical gel, cream, or ointment. Beyond the commercially available topical patches, a treatment compounded into a pluronic lecithin organogel or dimethyl sulfoxide carrier may have similar local or systemic effects of the medication. For instance, an anesthetic agent can be combined with an antispasticity medication for very specific local effects. Before prescribing, consideration should be given to the bioavailability, stability, and cost of topical treatments.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
