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13 Articles in Volume 11, Issue #5
Case Study: Patient With Fibromyalgia And Sleep Apnea
Current Treatments for Phantom Limb Pain
Doctor Shopping
Effective Protocol for the Management of Plantar Fasciitis
Giving Severe and Chronic Pain a Name: Maldynia
Is the New Pain Vocabulary Helping Patient Care?
Medications for Chronic Pain—Other Agents
New Technique Combines Electrical Currents and Local Anesthetic for Pain Management
Pain Management Dilemmas of Sickle Cell Disease
Sleep Apnea in Patients With Fibromyalgia: A Growing Concern
The Essential FDA/PDR Indications and Warnings For Opioid Prescribing
The Role of the Clinician In Determining Disability and Pain
Why Does Acute Postoperative Pain Become Chronic and Can It Be Prevented?

Medications for Chronic Pain—Other Agents

In part 3 of our 3-part series reviewing medications for the treatment of chronic pain, the author discusses specific guidelines for the use of adjuvant therapies and other medications in the treatment of chronic pain.

Chronic pain is frequently treated with opioid and non-opioid analgesics. In addition, a variety of medications that were originally developed for indications other than analgesia are emerging as effective agents for the treatment of pain. Medications such as anti-depressants and anticonvulsants are commonly considered adjuvant analgesics because traditionally they have been used in combination with opioid or non-opioid analgesics for the treatment of pain.1,2 More recently, however, these medications have become primary therapy for neuropathic pain, pain related to fibromyalgia, and chronic pain. This review, part 3 of a 3-part series on medications for chronic pain, will focus on medications used for pain that are neither opioid nor non-opioid analgesics. Anticonvulsants, antidepressants, skeletal muscle relaxants, pramipexole, topical agents, and intrathecal medications will be included in this review.

Place in Therapy

Pain can be classified as nociceptive or neuropathic.3 Nociceptive pain results from stimulation at pain receptors, whereas neuropathic pain arises in the peripheral or central nervous system. Many patients with chronic pain have a combination of nociceptive and neuropathic pain. The medications included in this review (with the exception of skeletal muscle relaxants) are more effective for neuropathic pain, including diabetic neuropathy and postherpetic neuralgia.1 Many of these medications also are useful for fibromyalgia. Fibromyalgia is a complex pain syndrome of unknown pathophysiology. Patients have a lower pain threshold and other symptoms including fatigue, sleep disturbances, and alterations in mood.4

Numerous clinical practice guidelines for the treatment of chronic pain have been developed by professional organizations. A summary of selected guidelines that describe a role for the agents included in this review can be found in Table 1.5-10

Table 1. Select Recommendations for Other Pain Medications in Chronic Pain


Tricyclic antidepressants (TCAs) were the first antidepressants found to be useful for neuropathic pain.2,11 Amitriptyline, desipramine, and nortriptyline are the TCAs with the most evidence for efficacy in the treatment of chronic pain.1 Although effective for neuropathic pain of various etiologies, the TCAs have an undesirable side-effect profile due to their antihistaminic and anticholinergic actions. Common adverse effects include dry mouth, constipation, blurred vision, mental status changes, tachycardia, and urinary hesitation.12 These effects are minimized with newer antidepressant agents, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs).

The evidence for the use of SSRIs in neuropathic pain is conflicting, and their use is generally limited to patients who have failed therapy with other antidepressants.13 They are recommended for fibromyalgia in clinical practice guidelines, with fluoxetine having the most evidence for efficacy.7,8

The SNRI antidepressants that have been shown to be effective for chronic pain include venlafaxine, duloxetine, and milnacipran. Venlafaxine was the initial agent in this drug class and was primarily developed for the treatment of depression. Studies with duloxetine have focused on its use as a primary treatment of chronic muscoskelatal pain, neuropathic pain, and fibromyalgia, while milnacipran has been used to treat fibromyalgia.

Antidepressants are especially useful for fibromyalgia because they not only improve pain, but they also improve symptoms of depression, fatigue, and insomnia related to the disorder.14 In fact, duloxetine and milnacipran have been FDA-approved as a primary therapy for fibromyalgia. Duloxetine also recently received approval as a primary therapy for chronic muscoskelatal pain. The adverse effects of SNRIs are similar, with subtle differences among the agents. Duloxetine is associated with less cardiovascular and sexual adverse effects compared to venlafaxine; however, due to a potential for elevated serum liver transaminases, the drug should not be used in patients with hepatic impairment.12 In addition, the SNRIs are associated with a rise in blood pressure. Table 2 provides a summary of the antidepressants used for chronic pain.1,10,12,15,16

Table 2. Antidepressants

Table 2. Antidepressants


The anticonvulsants are a pharmacologically diverse class of medications. In general, their efficacy for both pain and seizure disorders is based on their ability to control neuronal excitability.2 Carbamazepine has been used for many years for the treatment of trigeminal neuralgia, and also is effective for diabetic peripheral neuropathy.2,13 However, carbamazepine has not been shown to be very effective for postherpetic neuralgia.1

The efficacy of oxcarbazepine and lamotrigine for diabetic peripheral neuropathy is questionable, and newer agents such as gabapentin and pregabalin are more commonly used for both diabetic peripheral neuropathy and postherpetic neuralgia.13 The exact mechanism by which gabapentin and pregabalin exert their effects is unknown, but it may be inhibition of neurotransmitters as a result of alpha-2-delta-calcium-channel antagonism in the brain and spinal cord.11,17 Gabapentin and pregabalin are better tolerated, have fewer drug interactions, and require less monitoring than other anticonvulsants used for chronic pain; therefore, they are the primary anticonvulsants used at this time.17 Gabapentin and pregabalin may be used in combination with an opioid or TCA.10,13

Table 3 summarizes the indications, dosing, and formulations of anticonvulsants used for chronic pain.9,10,12,18

Table 3. Anticonvulsants

Table 3. Anticonvulsants

Skeletal Muscle Relaxants

Skeletal muscle relaxants are a heterogeneous group of drugs used for a variety of musculoskeletal disorders.12,19 They are frequently used as adjunctive medication in the treatment of acute low back pain. Their use in chronic pain is more limited.

Cyclobenzaprine has been shown to be more effective than placebo for the treatment of fibromyalgia.11,19 However, it is generally considered less effective than antidepressants and is recommended in the American Pain Society guidelines only as an agent for sleep.8 Baclofen often is used as an antispasmodic agent in patients with cerebral palsy or multiple sclerosis, but it may be used for trigeminal neuralgia.1,2 Tizanidine, which also is used for spasticity, may be used for a variety of pain types and is well-studied for low back pain.6,12 The indications, dosing, and formulations of cyclobenzaprine, baclofen, and tizanidine are summarized in Table 4.

Table 4. Skeletal Muscle Relaxants


Pramipexole is a dopamine agonist used for the treatment of Parkinson’s disease; this agent has been recommended by the European League Against Rheumatism for patients with fibromyalgia based on a single study.7,12,20 The majority of patients in this study continued their current fibromyalgia therapy including anti-convulsants, antidepressants, and opioids; therefore, the role of pramipexole is largely adjunctive at this time.20

Topical Pain Medications

Lidocaine, an anesthetic agent, is available as a topical patch formulation for the treatment of neuropathic pain.10,21 It provides local analgesia, with few systemic effects. The lidocaine 5% patch primarily has been studied for postherpetic neuralgia and is most effective for neuropathies that are limited to a specific area. Lidocaine may be used as a single agent or in combination with another agent, such as an antidepressant or anticonvulsant.10

Capsaicin is available in several topical nonprescription formulations and as a high-concentration topical patch that is effective for 3 months.12 When used at low concentrations, capsaicin is believed to reduce pain through modulation of substance P, a neurotransmitter for pain impulses. At high concentrations, it is believed to reduce pain through the reduction of transient receptor potential vanilloid 1 (TRPV1) nociceptive nerve endings. Nonprescription formulations of capsaicin primarily have been studied for musculoskeletal pain, but the 0.075% strength has been shown to be effective for diabetic neuropathy.9,12 The 8% topical patch formulation must be applied by a healthcare professional and has been shown to be effective for pain resulting from postherpetic neuralgia.10

The indications, dosing, and formulations of topical lidocaine and capsaicin are summarized in Table 5.10,12,22,23

Table 5. Topical TherapyTable 5. Topical Therapy


Intrathecal Pain Medications

Although opioids are the primary agents administered intrathecally for the management of chronic pain, clonidine, ziconotide, and baclofen also can be administered using the intrathecal route.24 Clonidine is an alpha-agonist that has been used alone and in conjunction with intrathecal opioids for neuropathic and cancer pain. Ziconotide is a novel agent that only is approved for use as an intrathecal agent.12 Its pharmacology is not fully understood, but it binds to calcium channels in the spinal cord, blocking neurotransmitter release. Although several studies support the efficacy of ziconotide in patients with severe neuropathic pain, it is associated with severe psychiatric and neurologic symptoms and must not be used in patients with a preexisting psychiatric condition.25 Baclofen has been used intrathecally for neuropathic pain, typically in combination with an opioid agent. Its pharmacologic action may be due to its properties as an analog of gamma-aminobutyric acid (GABA).12,24 Generally, the use of intrathecal agents is limited to patients whose pain is not controlled with other analgesics or in those who are intolerant of oral agents. The indications, dosing, and formulations of these intrathecal agents are summarized in Table 6.12,24,26-29

Table 6. Intrathecal Agents


Aside from traditional analgesics, a number of other medications are useful for the treatment of pain. These agents may be used in conjunction with analgesics or may, in some cases, provide effective control of chronic pain when used alone. Antidepressants and anticonvulsants are two classes of medications commonly used in the treatment of chronic neuropathic pain or for pain and other symptoms of fibromyalgia. Skeletal muscle relaxants have a limited role in chronic pain but remain an option for select patients. Topical lidocaine and capsaicin may be effective and often are combined with oral therapy. In patients with refractory chronic pain, intrathecal agents such as clonidine, ziconotide, or baclofen may be necessary.


Last updated on: September 20, 2011
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