Medications for Chronic Pain—Other Agents
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
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
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
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.