Neuropathic Pain: An Update on Effective Management Strategies

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Neuropathic Pain: An Update on Effective Management Strategies CE

Disclosures

Mary Lynn McPherson, PharmD, BCPS

Introduction

Pain adversely affects millions of people every year, impacting their physical and emotional functioning, diminishing quality of life, and reducing functional capabilities. Chronic pain frequently results in absenteeism from work (about 50 million lost workdays each year), as well as "presenteeism," which is defined as reduced productivity at work.[1] Up to 40% of the US population experiences chronic pain annually, and at least 4 out of 10 chronic pain patients do not achieve adequate pain relief.[2,3]

Many common medical conditions are associated with pain, including cancer, sickle-cell disease, arthritis, low-back problems, diabetes, headache, multiple sclerosis, spinal cord disorders, infectious diseases (eg, herpes zoster, AIDS), cerebrovascular accidents, and others. Pain is frequently accompanied by comorbid conditions such as anxiety and depressive disorders, and patients with persistent pain are more likely to have unfavorable health perceptions compared with patients not experiencing pain.[4]

Pharmacists frequently interact with patients suffering from chronic pain, and thus are in an excellent position to participate in their management plans. The etiology and management of chronic pain were discussed in sessions at the recent annual meeting of the American Pharmacists Association, held March 17-21, 2006, in San Francisco.
Categorizing Pain

Pain can be categorized in many different ways. For example, we can compare and contrast acute vs chronic pain, or malignant vs nonmalignant pain, or we can consider the pathogenesis of the pain. One noted pain researcher has classified pain as adaptive (protecting the body from injury or injury progression) or maladaptive (pain as disease).[5]

Adaptive pain includes nociceptive pain and inflammatory pain. Nociception is the term used to describe the processing of stimuli that damage normal tissue (or may do so with continued exposure to the stimulus) into a conscious pain experience. Clearly, nociceptive pain has some value, because it serves as an early warning system of potential injury from a damaging stimulus.

There are 4 steps in the nociceptive process: transduction (the conversion of a noxious stimulus into electrical activity in the afferent primary peripheral neurons); transmission (moving the neural impulse from the site of transduction to the brain); perception (interpreting the neural impulse relayed from the periphery as pain); and modulation (changing or inhibiting the pain impulse).

Inflammatory pain occurs when the body shifts its attention to healing the injured tissue. For example, the injured area is far more sensitive to further injury, and the person is motivated to protect the damaged area. If you had a broken arm, you would inherently protect the injured arm from further injury, and any stimulus (eg, touch or pressure) would readily evoke pain as a protective mechanism.

Neuropathic pain is a prime example of maladaptive pain. The International Association for the Study of Pain (IASP) has defined neuropathic pain as "pain initiated or caused by a primary lesion or dysfunction of the nervous system."[6] These lesions may be in the peripheral or central nervous system, and frequently both systems are involved with chronic neuropathic pain states. Many commonly experienced persistent pain states are partially or completely neuropathic in nature. Examples include phantom limb and spinal cord injury pain, painful diabetic neuropathy, postherpetic neuralgia, sciatica, trigeminal neuralgia, and drug-induced (eg, vinca alkaloids) neuropathy.

Backonja[7] defines neuropathic pain and differentiates it from other types of pain as follows:
Pain and sensory symptoms that persist beyond the healing period.

Presence, in variable degree, of neurological sensory signs manifesting as negative and positive sensory phenomena.

Presence, in variable degree, of other neurological signs, including motor, manifesting as negative and positive motor phenomena or autonomic signs.

Reference to the presence of negative and positive sensory phenomena indicates abnormal sensations that are seen on physical exam. Neuropathic pain may be "stimulus-evoked" by light touch, pressure of clothing or bedding, or either hot or cold temperatures. Pain in response to a nonpainful stimulus is referred to as "allodynia." An exaggerated pain response to a painful stimulus (eg, a pinprick) is termed "hyperalgesia."[8] Patients also may complain of hypoesthesia (diminished sensation), paresthesia (an abnormal sensation), or dysesthesia (an unpleasant abnormal sensation).[8]

Spontaneous neuropathic pain is usually described by the patient as a constant burning, plus intermittent pain that may be described as "shooting" or "electric shock-like." Patients with painful diabetic neuropathy, for example, frequently describe the pain as though they were "walking on broken glass," "buzzing," or feeling the sensation of bugs crawling on their feet.

Negative sensory phenomena refer to loss of sensation, such as loss of feeling secondary to pinprick, thermal, tactile, or vibratory sensation. For patients with diabetic neuropathy, it is important to explain the importance of the loss of this protective sensation.

So what pathophysiologic changes occur to produce symptomatic, persistent neuropathic pain? Changes may occur in both the peripheral and central nervous systems.[5,9]

Changes in the peripheral nervous system include the following:
Ectopic discharge and ephaptic conduction. After nerve injury, there is an increase in the level of spontaneous firings from newly formed nerve sprouts, or neuromas, which have grown from the injured nerve. This ectopic activity is likely due to changes in the sodium channels. After some period of time, atypical connections may develop between the nerve sprouts and neighboring afferent neurons, leading to "ephaptic conduction" or "cross-talk" between neurons. Therefore, pain that results from peripheral nerve damage may originate in injured or intact sensory neurons.


Alterations in ion channel expression. Sodium channels are critical to the physiology of excitable membranes, such as neurons, and are likely increased in number and density with neuronal damage. Calcium channels may also be affected with peripheral nerve injury.


Other causes of peripheral sensitization include heightened responsiveness to inflammatory mediators released by damaged cells, collateral sprouting of primary afferent neurons, and sprouting of sympathetic neurons in the dorsal root ganglion.

Changes in the central nervous system, referred to as "central sensitization," include the following mechanisms[5,9-11]:
Just as it takes less stimulus to evoke pain in the periphery, a similar phenomenon is seen centrally. Central sensitization amplifies and facilitates the synaptic transfer from primary afferent neurons to secondary neurons in the dorsal horn. This phenomenon is sometimes referred to as "wind-up," which is characterized by an increasing response to repeated input from C-fibers resulting in enhanced spinal cord excitability.


Some studies suggest that glutamate acts in the spinal cord and at supraspinal sites at excitatory amino acid receptors (eg, N-methyl-D-aspartate [NMDA]) to amplify sensory input from the periphery.


The gamma-aminobutyric acid (GABA) pathway is an inhibitory neurotransmitter system in the central nervous system, and its suppression is associated with neuropathic pain.


Research has also shown that there is likely upregulation of the calcium channel in the central nervous system with nerve damage, particularly the alpha-2-delta subunit.

After peripheral nerve injury, there is considerable reorganization of the spinal cord. With normal physiology, myelinated A-delta fibers and unmyelinated C-fibers (that transmit the pain impulse) terminate in the superficial laminae (I and II) of the dorsal horn. Low-threshold sensory fibers (eg, A-beta fibers) that are activated by pressure, vibration, touch, and normal temperature exposure terminate in the deep laminae of the dorsal horn (eg, laminae III and IV). Within several weeks of nerve damage, new growth of the central terminals of the low-threshold afferents (sensory fibers) terminate where the pain impulse neurons usually terminate exclusively. This pathophysiologic change explains how the normal sensation of touch can be perceived as pain.

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Treatment of Neuropathic Pain

Pharmacists who attended the APhA annual meeting had an opportunity to attend an educational session titled "Neuropathic Pain." In this session, pharmacists learned about the pathogenesis and clinical presentation of neuropathic pain, as well as treatment options.

When considering pharmacologic options to treat chronic pain, we first think of nonopioids (eg, acetaminophen, nonsteroidal anti-inflammatory agents), opioids, and co-analgesics. Generally speaking, the nonopioids are unlikely to provide any significant degree of pain relief in patients with neuropathy. Given the complicated nature of neuropathic pain, it is not surprising to find that, at best, an opioid or co-analgesic agent will effect a 30% reduction in the pain severity rating. In fact, this response is considered to be "clinically important" and, at this level, patients will report "moderate relief" or say they are "much improved." The medications used to treat neuropathic pain commonly cause adverse effects and are frequently involved in drug interactions. Careful analgesic selection and dosage titration are required, as many patients with neuropathic pain are elderly, take multiple medications, and have numerous comorbid conditions.

At present there are only 5 co-analgesic agents that carry US Food and Drug Administration (FDA)-approved indications for neuropathic pain. These are carbamazepine (Tegretol [Novartis]) for trigeminal neuralgia, gabapentin (Neurontin [Parke-Davis]) and transdermal lidocaine (LidoDerm [Endo]) for postherpetic neuralgia, duloxetine (Cymbalta [Eli Lilly]) for diabetic neuropathy, and pregabalin (Lyrica [Pfizer]) for both diabetic neuropathy and postherpetic neuralgia. However, there is a significant body of literature demonstrating the effectiveness of these and other co-analgesics in treating a wide variety of neuropathic pain states.

Robert Dworkin and colleagues[12] considered the evidence base of analgesics and co-analgesic clinical trials in the management of neuropathic pain. They concluded that first-line recommendations included gabapentin, the 5% lidocaine transdermal patch, opioid analgesics, tramadol hydrochloride, and tricyclic antidepressants (TCAs). Since that time, Dworkin has published further reports that add the serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants (eg, venlafaxine and duloxetine) and pregabalin as first-line medications for neuropathic pain.[13]
Alpha2-Delta Ligands

Gabapentin was the first alpha2-delta ligand introduced to the market as an antiepileptic drug. At least 8 clinical trials have shown gabapentin to be effective in treating a variety of neuropathic pain states, including postherpetic neuralgia, painful diabetic neuropathy, mixed neuropathic pain syndromes, phantom limb pain, Guillain-Barré syndrome, and spinal cord injury pain.

Adverse effects associated with gabapentin therapy include somnolence, dizziness, gait and balance problems, and, less frequently, gastrointestinal complaints and peripheral edema. To maximize tolerability and acceptance of gabapentin therapy, it is vital that the practitioner start at a low dose (eg, 100 mg qhs to 300 mg qhs) and titrate upward. After starting with a single bedtime dose, increase to twice-daily dosing, then to 3 times daily. Keeping the 3 times daily dosing interval, increase the total daily dose as tolerated, making adjustments every 1-7 days as tolerated by the patient. It may take several weeks to get to the target dose for an individual patient, and this may range from 1800 to 3600 mg per day.

Pregabalin is another alpha2-delta ligand that is closely related to gabapentin. Not surprisingly, pregabalin has adverse effects that are quite similar to those seen with gabapentin, although patients seem to tolerate more rapid dosage titration. The recommended starting dose is either 50 mg 3 times daily or 75 mg twice daily, with titration to 300 mg daily after several days. Dosage of both gabapentin and pregabalin should be adjusted in patients with renal impairment.
Opioid Analgesics

Opioid analgesics have been the backbone of management of moderate to severe pain for thousands of years. Of interest, opioids have been unfairly maligned as ineffective analgesics for the management of neuropathic pain. Several double-blind, randomized clinical trials published in the last decade have demonstrated the effectiveness of opioids in treating a variety of neuropathic pain conditions such as postherpetic neuralgia, painful diabetic neuropathy, and a variety of mixed peripheral and central neuropathic pain syndromes. Using opioids adjunctively with other co-analgesics, both at lower doses, has also been an effective strategy. For example, a study recently published in The New England Journal of Medicine[14] showed the combination of morphine plus gabapentin was more effective than either drug alone at higher doses.

The most common adverse effects associated with opioid therapy include constipation (to which tolerance will not develop), nausea, sedation, and confusion. All patients taking opioids chronically will develop some physical dependence, so therapy cannot be stopped abruptly. However, in patients with no previous history of drug abuse or diversion, psychological dependence is unlikely to develop when using these agents to treat chronic pain.

Some practitioners recommend starting with a short-acting opioid and switching to a longer-acting opioid once the effective daily dose is reached. Others begin with the lowest dose of a long-acting opioid and titrate accordingly. Oral long-acting opioids include morphine (MS Contin [Purdue Frederick], Kadian [Alpharma], Avinza [Ligand], and generic long-acting), oxycodone (OxyContin [Purdue Frederick] and generic long-acting), and methadone (dosed every 8-12 hours for pain control). Transdermal fentanyl is also available, and the patch is usually changed every 72 hours (some patients require that it be changed every 48 hours). Caution is advised with "combination" analgesics such as hydrocodone plus acetaminophen (Vicodin [Abbott] or Lortab [UCB Pharma]) or oxycodone plus acetaminophen (Percocet [Endo]). Even though there is no ceiling dose for the opioid component, the total daily acetaminophen dose should not exceed 4 grams.
Tramadol

Tramadol (Ultram [Ortho McNeil]; tramadol with acetaminophen as Ultracet [Ortho McNeil]) is a norepinephrine and serotonin reuptake inhibitor that has a weak mu opioid agonist as one of its metabolites. Tramadol is effective in treating painful diabetic neuropathy and polyneuropathy of various causes. Adverse effects include nausea, somnolence, constipation, dizziness, and orthostatic hypotension. Tramadol has also been shown to lower the seizure threshold. Caution should be used with other medications that increase serotonin levels because of an increased risk of serotonin syndrome.

The initial dose should be 50 mg once or twice daily, increased every 3-7 days by 50 to 100 mg. The maximum daily dose is 400 mg in patients younger than 75 years, and 300 mg in older patients. Dosage should be further reduced in renal impairment.
5% Lidocaine Transdermal Patch

There are 2 published clinical trials demonstrating efficacy of the 5% lidocaine transdermal patch in treating postherpetic neuralgia. Additional data have been published on the efficacy of this product in treating osteoarthritis of the knees and for other nonapproved indications.

The FDA-approved dosing schedule is 12 hours on (with patches cut as needed and applied directly to the painful sites) and 12 hours off. With normal hepatic function, blood levels are minimal and the lidocaine does not accumulate. Adverse effects are minimal and include erythema or rash at the application site. The maximum recommended dose is 3 patches worn concurrently.
Tricyclic Antidepressants

TCAs were among the earliest medications shown to have analgesic efficacy as "adjuvants" or "co-analgesics." Early clinical trials used amitriptyline, but later research has demonstrated the effectiveness of other TCAs such as desipramine and nortriptyline, which tend to be better tolerated than amitriptyline. Adverse effects can be considerable with the TCAs and include anticholinergic effects (eg, dry mouth, blurred vision, constipation, urinary retention, and cognitive impairment), sedation, and orthostatic hypotension. Of particular concern are the cardiovascular adverse effects and the risks associated with overdose.

Dosing should begin with 10 mg (older adults) or 25 mg at bedtime, and should be increased every 3-7 days as tolerated. Generally, pain relief is achieved with 75-100 mg per day.

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SNRI Antidepressants

The SNRIs are the latest group of co-analgesics used to treat neuropathic pain. Venlafaxine (Effexor [Wyeth]) and duloxetine have both been shown to be efficacious in treating neuropathic pain conditions, although duloxetine is the only SNRI with an FDA-approved indication for neuropathy (painful diabetic neuropathy).
Second-Line Co-analgesics

There are a variety of co-analgesics that could be considered "second-line" beyond those described above. Other antiepileptic agents include the first-generation agents (eg, phenytoin and carbamazepine) and second-generation agents (eg, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide). There are fewer data evaluating the role of these agents in the treatment of neuropathic pain.

The SSRIs have been disappointing in terms of pain relief, although they are better tolerated than the TCAs. Other co-analgesics include capsaicin, clonidine, dextromethorphan, and mexiletene.
Selecting a Co-analgesic Agent

As with the pharmacotherapeutic management of any condition, there are many variables that affect drug therapy selection. Consider comorbid conditions (eg, renal impairment or osteoarthritis), risk factors for adverse effects, age and cognitive status, and financial implications of therapy. Because any one co-analgesic is unlikely to completely relieve the neuropathic pain, some have suggested that combinations of analgesics be selected based on complementary mechanisms of action.

For example, co-analgesics that act to reduce peripheral sensitization are drugs that affect the sodium channels (eg, carbamazepine, oxcarbazepine, phenytoin, topiramate, lamotrigine, lidocaine, and mexiletine). Co-analgesics that address central sensitization by affecting calcium channels include gabapentin, pregabalin, levetiracetam, oxcarbazepine, lamotrigine, topiramate, and ziconotide. TCAs, SNRIs, tramadol, and opioids will enhance the descending inhibitory pathway.[15]

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