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
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
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.
Gabapentin
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
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
Conclusion
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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