US Pharm. 2007;32(5):55-61.

Chronic pain--pain that lasts longer than three to six months--affects over 75 million Americans, making it one of the most common and debilitating health problems in the United States today. 1 Although chronic pain is a common reason for seeking medical care, it is often undertreated, and patients may be exposed to potentially toxic and/or addictive side effects of currently available medications. Treatment failure may lower patients' quality of life and increase their economic burden. 2 Providing adequate analgesia for patients with moderate to severe pain may require the use of multiple medications, often at high dosages. This can lead to unwanted adverse effects, which can become intolerable for some patients. Chronic use of systemic NSAIDs is associated with multiple adverse effects, including gastrointestinal upset, gastric ulcer formation, renal dysfunction, and increased cardiovascular risk. While the use of opiate narcotics and related analgesics may be helpful for acute pain, chronic use of these medications can lead to dependence and/or abuse. Opiate drugs produce sedation, tolerance, constipation, and allergic and pseudoallergic reactions.

Due to a high rate of suboptimal treatment response and unwanted side effects from these medications, clinicians are seeking alternative therapy to manage chronic pain. New research has led to a better understanding of the pathophysiology and mechanisms of pain transmission, suggesting the possibility of using alternative drug classes to treat chronic pain.1,2 Two major drug classes being increasingly used to treat chronic pain are antidepressants and anticonvulsants. Thus, this article examines the evidence for using these drugs as treatment for nonmalignant chronic pain.

Mechanism of Pain
The process of pain transmission involves many neural pathways and neurotransmitters within the central and peripheral nervous systems. An external stimulus activates pain receptors (also known as nociceptors), which produce an action potential that is transmitted to the spinal cord along afferent nerve fibers. These nerve fibers are classified according to the type of pain they transmit. Sharp, well-localized pain is transmitted along Ad nerve fibers, whereas dull, aching, poorly localized pain travels along C nerve fibers. The action potential then travels to the dorsal horn of the spinal cord where pain neurotransmitters, such as glutamate and substance P, are released. The transmission then continues up the spinal cord via ascending pathways to higher areas of the brain where pain is consciously experienced. Once the brain senses the painful stimulus, it releases inhibitory stimuli through the descending pathways back to the spinal cord to inhibit the sensation of pain. The modulation of pain is achieved through a variety of neurotransmitters, including endogenous opioids, serotonin (5-HT), norepinephrine (NE), and g -aminobutyric acid (GABA).3 The role of these inhibitory neurotransmitters has led to the rationale of using antidepressants and anticonvulsants to treat chronic pain.  

Pain can be divided into two categories: nociceptive and neuropathic. Nociceptive pain is more commonly known as acute pain and is further categorized as somatic and visceral pain. Somatic pain usually arises from muscle or tissue injury. It is well localized and is often described as aching, throbbing, or shooting sensations. Visceral pain is often referred from an internal organ. This type of pain is usually treated with traditional pain medications, such as opioids and NSAIDs.3

Neuropathic pain is mechanistically different from nociceptive pain, warranting different pharmacologic agents for treatment. The mechanism of neuropathic pain is more complex and not as well understood as that of nociceptive pain. It is theorized that neuropathic pain occurs as a result of dysfunction of or damage to both the central and peripheral nervous systems.4 The malfunction in the central nervous system (CNS) can lead to several different processes (e.g., increased cell firing, decreased inhibition of neuronal activity, and sensitization) that are responsible for chronic pain. Neuropathic pain is often described as burning, shooting, tingling, and possibly accompanied by numbness. Hyperalgesia (the exaggerated response to normally noxious stimuli) and allodynia (the painful response to a normally nonpainful stimulus) often occur in neuropathic pain syndromes. Chronic pain can present as a manifestation of both nociceptive and neuropathic pain, suggesting a combined pharmacologic approach for optimal treatment.3-5

Antidepressants have been used for many years to treat pain. Historically, the most common class of antidepressants used to treat chronic pain is the tricyclic antidepressants (TCAs), such as amitriptyline. Other drugs included in this class are nortriptyline, desipramine, and imipramine. Their role in pain modulation correlates with their ability to increase the amount of circulating inhibitory pain neurotransmitters, NE and 5-HT, through reuptake inhibition. 6 The analgesic activity of TCAs likely occurs independently of their antidepressant activity.6 This theory is supported by both the smaller dosages needed to achieve analgesia and the faster time for analgesic response in comparison to their antidepressant effects (days versus weeks). Their efficacy in the treatment of neuropathic pain syndromes is supported by several review articles.7,8 The utility of TCAs in the treatment of neuropathic pain is limited by their tolerability. Not only do they act on NE and 5-HT receptors, but they also act on histamine and muscarinic receptors, which causes unwanted anticholinergic side effects (e.g., sedation, dry mouth, blurred vision, and urinary retention). Due to their unfavorable side-effect profile, researchers have turned to new classes of antidepressants for the treatment of chronic pain syndromes, specifically duloxetine, a dual reuptake inhibitor.

Duloxetine (Cymbalta) was approved by the FDA in 2004 for the treatment of depression and diabetic peripheral neuropathy (DPN). Duloxetine works similarly to TCAs by inhibiting the reuptake of both norepinephrine and serotonin but differs in that it does not affect histamine or muscarinic receptors. Thus, the anticholinergic side effects commonly seen with TCAs are not present with duloxetine. Compared to other dual reuptake inhibitors, such as venlafaxine (Effexor), duloxetine differs by its balanced affinity between NE and 5-HT receptors. Venlafaxine is predominantly selective for 5-HT at lower dosages and has increased NE affinity as dosages increase. Clinical studies have shown duloxetine to be an effective treatment for DPN with dosages of 60 mg once daily.9

Wernicke et al. studied the efficacy of duloxetine in DNP in dosages of 60 mg daily and 60 mg twice daily versus placebo.9 The primary outcome tested was the weekly mean score of 24-hour average pain severity on the 11-point Likert scale. At the end of week 1 through week 12, both duloxetine 60 mg daily and 60 mg twice daily led to a significant decrease in pain severity versus placebo (P <.001), with no significant difference between the two active treatment groups.

There is also evidence supporting the use of duloxetine for the treatment of fibromyalgia.10 Arnold et al. conducted a 12-week, randomized, double-blind, placebo-controlled trial to assess the efficacy of duloxetine in 354 women who had fibromyalgia. Patients were randomized into three treatment groups: duloxetine 60 mg once daily, duloxetine 60 mg twice daily, and placebo. The primary outcome was the Brief Pain Inventory average pain score and response to treatment, defined as less than a 30% reduction in the pain score. At 12 weeks, a significantly higher percentage of participants in the duloxetine group had a reduction of 30% or more in their pain symptoms (P <.001 for 60 mg once daily; P <.002 for 60 mg twice daily). There was no significant difference in pain response between duloxetine 60 mg once daily and 60 mg twice daily. The most common side effects seen with duloxetine included somnolence, nausea, dry mouth, decreased appetite, and constipation. Patients taking duloxetine 60 mg twice daily experienced more somnolence, jitteriness, and nervousness. Both treatment groups experienced slight increases in alkaline phosphatase. There were no statistically significant changes in blood pressure in either treatment group.

To reduce the side effects associated with duloxetine, treatment can be initiated at lower dosages (e.g., 20 mg/day) and titrated on a weekly basis to achieve the desired therapeutic effect. If chronic treatment is discontinued, it must be gradually tapered, rather than stopped abruptly. Duloxetine is a moderate inhibitor of the cytochrome P450 (CYP) 2D6 isoenzyme and a substrate for both CYP2D6 and 1A2 isoenzymes. Duloxetine should be used with caution when coadministering drugs that may inhibit or induce CYP2D6 and 1A2. Duloxetine is available in 20-, 30-, and 60-mg capsules. Compared to TCAs, an advantage of duloxetine is better tolerability; however, disadvantages include  higher cost and lack of long-term safety data.

Although selective serotonin reuptake inhibitors, such as fluoxetine and sertraline, are first-line treatments for depression, their role in treating chronic pain is limited. This is most likely due to their sole activity on 5-HT receptors and lack of activity on NE receptors.8

Anticonvulsants, such as carbamazepine, gabapentin, and pregabalin, have also been used to treat neuropathic and other types of chronic pain. They exert their pharmacologic action at many different sites that may be involved in pain transmission. Possible mechanisms include inhibition of voltage-gated sodium and calcium channels, potentiation of GABA, and inhibition of glutamate receptors, all of which lead to decreased neuronal excitation and enhanced inhibition. Gabapentin (Neurontin) and pregabalin (Lyrica) are classified as second-generation anticonvulsants and are typically better tolerated and have fewer drug interactions than the first-generation anticonvulsants (e.g., carbamazepine).11,12 For this reason, the following discussion of anticonvulsants in the treatment of neuropathic pain is limited to gabapentin and pregabalin.

The popularity of gabapentin, initially indicated as adjuvant treatment for partial seizures, rose with its success in treating neuropathic pain. Studies have been conducted to assess the efficacy of gabapentin in neuropathic pain.13 According to a recent Cochrane Review of the use of gabapentin in the treatment of acute and chronic pain,13 the number needed to treat (NNT) for improvement in chronic pain is 4.3 (95% confidence interval [CI], 3.5–5.7). This review included all trials from 1998 to 2005 involving gabapentin as treatment for neuropathic pain. Categorized into individual neuropathies, the NNT for effective pain relief in diabetic neuropathy was 2.9 (95% CI, 2.2–4.3) and for post­ herpetic neuralgia (PHN), 3.9 (95% CI, 3.0–5.7). Gabapentin exerts its pharmacologic action by binding to the a 2d subunit of voltage-gated calcium channels. Studies show a relationship between the a2d Ca2+ channel and pain modulation.14 Although the mechanism is not fully understood, the binding of gabapentin to the a2d Ca2+ channel is thought to inhibit the release of excitatory neurotransmitters.14

Gabapentin was well tolerated in trials assessing its efficacy in neuropathic pain. The number needed to harm (NNH) for adverse events leading to trial withdrawal was not significant. The NNH for minor harm was 3.7 (95% CI, 2.4–5.4).13 The most common side effects associated with gabapentin were somnolence, dizziness, and ataxia. The dosage range for neuropathic pain is 1,800 to 3,600 mg/day in three divided doses. To lower the risk of side effects, the dosage should begin at 300 mg at bedtime and be titrated to 300 mg twice daily on day 2, then 300 mg three times daily on day 3. An adequate course of gabapentin should allow six to eight weeks for dosage titration and an additional one to two weeks at the maximum dosage. Gabapentin exhibits large interpatient variability; therefore, the dosages should be titrated based on tolerability and therapeutic effect. If the drug must be discontinued, it should be tapered over one week. Gabapentin is renally eliminated and should be used in reduced dosages for patients with renal insufficiency.

Pregabalin is the newest second-generation anticonvulsant approved by the FDA for use in DPN and PHN. Similar to gabapentin, pregabalin exerts its pharmacologic action by binding to the a2d subunit of voltage-gated calcium channels in the CNS, leading to the inhibition of excitatory neurotransmitter release.14 Dosages range from 300 to 600 mg/day depending on the treatment indication. In a randomized, placebo-controlled study of 173 patients conducted by Dworkin et al., pregabalin 300 to 600 mg /day led to a significantly higher proportion of patients receiving 50% or greater pain reduction in symptoms of PHN, compared to those receiving placebo (P =.001).15 Lesser and associates conducted a randomized, double-blind, placebo-controlled trial of 338 patients that assessed the efficacy of pregabalin in DPN.16 At dosages of 300 and 600 mg/day, there was a superior pain response in comparison to placebo (P =.0001), but no additional benefit was seen between the 300 mg/day and 600 mg/day groups. Aside from significant improvements in pain scores, both treatment groups experienced improvement in sleep. Data support pregabalin's efficacy in fibromyalgia as well. 17 In an eight-week randomized, double-blind, placebo-controlled trial (N = 529), pregabalin (450 mg/day) reduced the average severity of pain significantly, compared to placebo, in patients with fibromyalgia (P <.001).17 In the pregabalin treatment group, more patients achieved greater than a 50% improvement in pain, compared to placebo (P = .003). Treatment with pregabalin also improved prominent symptoms of fibromyalgia, including disordered sleep and fatigue.

Generally, pregabalin has been well tolerated in studies assessing its efficacy in pain syndromes. The most common side effects were somnolence and dizziness, which occurred more frequently at higher dosages. Peripheral edema, weight gain, headache, and blurred vision were side effects less commonly encountered. To reduce the incidence of side effects, initial treatment should begin at lower doses, such as 150 mg/day in two divided doses, and increased at weekly intervals to 300 to 600 mg/day based on tolerability and desired therapeutic effect. The drug dosage must be adjusted for patients with renal insufficiency (creatinine clearance < 60 mL/minute). If cessation of therapy is necessary, pregabalin should be slowly tapered over a week, rather than stopped abruptly.

Currently, no head-to-head trials have been conducted comparing gabapentin and pregabalin for the treatment of neuropathic pain. Pregabalin is FDA approved for both DPN and PHN, whereas gabapentin is approved only for the latter indication. Clinical studies have shown gabapentin to be effective in the treatment of DPN.13 When compared, pregabalin and gabapentin share the same desirable safety characteristics (e.g., no active metabolites, no significant drug interactions, and minimal side effects). Pregabalin may have some pharmacokinetic advantages over gabapentin. The plasma concentrations appear to be linear with increasing dosages; the dosing interval is twice daily versus three times daily with gabapentin; and there may be less interpatient variability in response than with gabapentin.14 While gabapentin is available in generic form, pregabalin is only available as the brand name Lyrica. A one-month supply of gabapentin 600 mg three times per day costs about $90, whereas a one-month supply of pregabalin 150 mg twice daily costs approximately $124.

Topical Therapy
In patients with chronic pain that is more localized, patients at risk for adverse effects with systemic NSAIDs or opiates may benefit from local therapies. Novel topical nonsteroidal anti-inflammatory agents, such as diclofenac solution (Pennsaid) and diclofenac epolamine topical patch 1.3% (Flector), will soon be available in the U.S. Based on evidence from short-term clinical trials, topical diclofenac solution appears to be both efficacious and safe to use in patients with osteoarthritis of the knee.18,19 Other topical agents with proven efficacy for chronic pain include capsaicin cream and transdermal lidocaine.20,21

Chronic pain continues to afflict millions of Americans daily. Current treatment options for chronic pain are often ineffective and limited by side effects, tolerance, and even addiction, leaving clinicians in need of better alternative drug classes. Certain antidepressants and anticonvulsants have been proven useful to treat chronic pain syndromes. Specifically, newer agents such as duloxetine, gabapentin, and pregabalin effectively treat pain with more favorable side-effect profiles, compared to TCAs and first-generation anticonvulsants.

Pharmacists should have knowledge of the multiple effective therapies available to treat patients with chronic nonmalignant pain, especially in those at risk for adverse effects from opiates and NSAIDs. Novel anticonvulsants and antidepressants are becoming first-line for neuropathic pain, such as diabetic neuropathy and PHN. Larger clinical trials are needed to establish their role in chronic musculoskeletal pain (e.g., osteoarthritis and fibromyalgia). Localized chronic pain may be treated with topical agents, such as capsaicin cream, transdermal lidocaine, and topical NSAIDs.

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