Over the years, pain has always affected humans in the face of injury and humans have always known and sought relief of pain. The act of relieving pain is probably as old as the medical profession itself.^1,2 Today, pain's impact on society is still enormous, and pain remains a primary reason patients seek medical advice.

Unfortunately, healthcare providers do not receive adequate training in pain management and current discoveries are not always disseminated properly. Thus, new treatment modalities may not always be understood. Clearly, pain management may be enhanced when a multidisciplinary approach is applied. Understanding pathophysiology, assessment techniques and treatment options of pain therapy and maintaining a working knowledge of pain regimen options are important to clinicians. They are also key factors in reversing the problem of inadequate pain control.

Epidemiology

Fifty million Americans are partially or totally disabled secondary to episodes of pain.³ The annual cost is estimated in billions of dollars.¹ As more Americans work beyond sixty years of age and survive into their seventies and eighties, these numbers are expected to rise dramatically.

Unfortunately, pain often remains undertreated and continues to be a serious problem in hospitals, long-term care facilities, and the community. Seriously hospitalized patients reported a 50% incidence of pain, and 15% were dissatisfied with overall pain control.¹ In a follow-up report, Desbians and colleagues state that pain control persists as a major problem in hospitalized patients, and many patients are still in pain several months after hospitalization ends.⁴

Terminology

The pathophysiology of pain involves a complex array of neural networks and neurotransmitters in the brain that are aroused by afferent (relaying) stimuli to produce the sensory response known as pain. These dynamic mechanisms include central and peripheral nervous systems and are modulated by changes that occur secondary to tissue damage or nerve damage. In acute pain, this modulation is short-lived, but in some conditions the changes may persist, developing into chronic pain. Classifying pain in terms of nociception and neuropathic pathways involved may allow for a better understanding of both acute and chronic pain.⁵ Acute pain is best outlined by the pathophysiology of nociception, whereas neuropathy best describes a chronic condition.¹

Acute Pain: Acute pain, also known as nociceptive pain, is self-limiting and serves a protective biological function by acting as a warning of ongoing tissue damage. It is a symptom of a disease process experienced in or around the injured or diseased tissue.⁶ Physiologic symptoms are minimal and usually limited to mild or moderate anxiety. Acute pain occurs secondary to chemical, mechanical, or thermal stimulation of A-delta and C-polymodal pain receptors.¹

Chronic Pain: Conversely, chronic pain serves no protective biological function. Unfortunately, some individuals experience pain without an obvious injury or suffer protracted pain that persists for months or years after the initial injury. This pain is usually neuropathic in nature and accounts for a large number of patients presenting to pain clinics with chronic, nonmalignant pain. Unlike acute nociceptive pain, chronic pain is unrelenting and not self-limiting. If chronic pain is inadequately treated, symptoms may include anxiety, fear, depression, sleeplessness and impaired social interaction.^1,6 It involves damage to either the central nervous system (CNS) or the peripheral nervous system (PNS).

Neuropathic pain is described as burning, electric, tingling and shooting in nature.^1,6 It may be continuous or paroxysmal in presentation. Whereas nociceptive pain is caused by stimulation of peripheral A-delta and C-polymodal pain receptors by algogenic substances (substance P), neuropathic pain is produced by damage to or pathological changes in the nerve itself. Examples of pathological changes include prolonged peripheral or central neuronal sensitization, which may damage the nervous system's inhibitory functions and create abnormal interaction between sympathetic and somatic nervous systems.

Table 1. Symptoms of Neuropathic Pain

Allodynia- Painful response to normally non-noxious stimuli Tactile allodynia- Painful response to normally non-noxious touch Hyperalgesia- Exaggerated painful response to normally noxious stimuli Thermal hyperalgesia- Exaggerated painful response to normally noxious temperatures Mechanical hyperalgesia- Exaggerated painful response to normally noxious body movement

Source: Reference 1,23

The hallmark symptoms of neuropathic pain, described in TABLE 1, are classic and usually experienced by most patients with neuropathy. Common sites/conditions associated with neuropathic pain include the lower back, painful diabetic neuropathy (PDN), the jaw, spinal cord injury, multiple sclerosis and certain types of cancer-related pain.⁷ Neuropathic pain typically responds mostly to coanalgesics such as tricyclics instead of opioid or NSAID regimens.^1,5,6

Pathophysiology

Peripheral Mechanisms: Following a peripheral nerve injury (e.g., crush, stretch), sensitization occurs. Abnormal and spontaneous activity, a lowered activation threshold, and an increased response to a given stimulus characterize sensitization. If the injured nerve is a nociceptor, the increased nervous discharge may equate to increased pain.⁶ Following nerve injury, C-fiber nociceptors may develop new adrenergic receptors, which may explain the mechanism of sympathetically mediated pain.

In addition to sensitization, these damaged nerves form ectopic neuronal pacemakers, which may appear at various sites along the nerve.⁸ Abnormal or dysfunctional sodium channels are believed to be the cause of this ectopic activity. The sodium channels in damaged nerves differ in density and display different depolarization characteristics than those in uninjured nerves. These ectopic neuronal pacemakers are usually found in the proximal stump (i.e., neuroma) of the dorsal root ganglion, and in focal areas of demyelination.⁶ Neuromas are mostly composed of sprouting axons and have a significant degree of sympathetic innervation.⁹ Neuromas have been reported to accumulate sodium channels at their distal ends, which may modulate their sensitivity. They may acquire sensitivity to catecholamines, prostaglandins and cytokines.¹⁰ Novel ion channel receptors, which are not found in normal nerves, appear to be expressed in the regenerating axon.¹¹

Studies suggest that abnormal electrical connections may exist between adjacent demyelinated axons. This communication between axons is referred to as "cross-talking."⁶ "Cross-talking" may result in the transfer of nerve impulses from one axon to another, and in A and C fibers may develop in the dorsal root ganglion.¹² A similar occurrence, known as "crossed afterdischarge" has also been described, whereby the sprouts of primary afferents with damaged axons can be made to discharge or fire action potentials at high frequencies from the discharge of other nerve fibers.⁶ It is also theorized that "cross-talking" may occur between sensory and sympathetic fibers, and that these cross connections may be important in the pathogenesis of sympathetically mediated pain.

Neurogenic inflammation is a useful model for understanding pain, allodynia and hyperalgesia. Neurogenic inflammation and the cascade of events following neuronal injury have been described.¹³ Inflammatory neuropeptides, such as substance P and prostaglandins, may be released from afferent nociceptors and sympathetic post-ganglionic neurons respectively, activating nearby receptors and triggering a process of spreading activation. This mechanism may explain the clinical response from the application of topical NSAIDs and capsaicin, a drug that blocks substance P.¹⁴

The connective tissue sheath around peripheral nerves is innervated by the nervi nervorum.⁶ Injury, compression or inflammation of the sheath may cause pain. In cancer, pain associated with tumor compression of a nerve may be clinically indistinguishable from nonmalignant neuropathic pain.^6,14 This nervi nervorum-related pain may be resolved following tumor resection or treatment of tumor-induced inflammation.⁶ Anti-inflammatory medications, such as NSAIDs and corticosteroids, have been effective in some neuropathic conditions. The mechanism of pain relief may be decreased edema at the site of injury around the tumor. Thus, it may be very difficult to distinguish primary tumor-associated pain from other types of neuropathy.¹⁴

Central Mechanisms: After a peripheral nerve injury, alterations in the CNS may occur and persist long after the initial injury has healed.¹⁵ These anatomical and neurochemical changes may play an important role in the evolution of chronic, neuropathic pain. As in the case of the periphery, sensitization of neurons can occur within the dorsal horn following peripheral tissue damage. This is characterized by increased spontaneous activity of the dorsal horn neurons and an increased responsivity to afferent input.¹⁶ In the non-injured state, A fibers (large, myelinated afferents) penetrate the dorsal horn, travel ventrally, and terminate in lamina III of the spinal cord. C fibers (small unmyelinated afferents) penetrate directly, and generally terminate no deeper than in lamina II. However, after peripheral nerve injury, there is a prominent sprouting of large afferents dorsally from lamina III into laminas I and II. These large afferents gain access to spinal regions involved in transmitting high-intensity noxious signals instead of encoding low-intensity information.⁶ Studies have revealed that peripheral nerve injury may lead to increased messenger ribonucleic acid (mRNA) for specific neurotransmitters (e.g., substance P), differential temporal expression of mRNA, and decreased numbers of opioid-binding sites.

Several forms of thermal or tactile hyperalgesia may involve the intracellular messengers, nitric oxide and arachnadonic acid. Cyclooxygenase inhibition appears to suppress tactile allodynia.¹¹ Neuropathic manifestations have been prevented by blocking the activation of protein kinase C. Protein kinase C removes the voltage gating of the non-methyl D aspartate (NMDA) receptor, allowing activation of the receptor by the excitatory neurotransmitters glutamate and aspartate.⁶ When NMDA receptors are stimulated, there is a significant increase in the release of intracellular calcium and in production of nitric oxide synthetase. Subsequently, the nitric oxide and prostaglandins produced are released into the extracellular space and can further facilitate the release of excitatory amino acids and neuropeptides. Ketamine and dextromethorphan are NMDA receptor antagonists and may block this cascade of events.^1,17

Repetitive noxious stimulation of unmyelinated C-fibers can result in prolonged discharge of dorsal horn cells. This phenomenon, known as "wind up," is a progressive increase in the number of action potentials elicited per stimulus.¹⁸ Repetitive episodes of "wind up" may precipitate long-term potentiation (LTP), which involves a long-lasting increase in the efficacy of synaptic transmission. It is believed that "wind up" may only last for several minutes. LTP is thought to last hours or even months. Both LTP and "wind up" are postulated to be involved in the sensitization process of many chronic pain states. Protein kinase C may also facilitate the production of action potentials by stimulating sodium channels.^6,17

The allodynia and hyperalgesia associated with pain may be best explained by the following: 1) development of spontaneous ectopic activity, 2) the sprouting of A fibers into laminas I and II, which are areas of sensitivity in the spinal cord, 3) the sprouting of sodium channels into neuromas and the dorsal horn ganglion, 4) upregulation of receptors in the dorsal horn, which mediate excitatory processes, and 5) decrease in intrinsic modulatory processes.⁶ Although modulation may be decreased, inhibitory neurotransmitters (serotonin and norepinephrine) are released from the brain stem.^1,6 Serotonin (5-HT) and norepinephrine (NE) are secreted from the periaqueductal gray area and the rostroventral medulla, respectively.²³ Pharmaceutical agents that increase the availability of 5-HT and NE in the synaptic cleft (amitriptyline) may decrease the transmission of neuronal impulses from the brain stem to the dorsal horn. The cascade involving both peripheral and central mechanisms may be seen in FIGURE 1.

Figure 1

Assessment

Control of pain begins with proper assessment. A baseline characterization of pain may be obtained by using the PQRST technique, as demonstrated in TABLE 2. Anxiety, depression, fatigue, anger and fear all lower this threshold, whereas mood elevation and rest raise the pain threshold.¹⁹ The World Health Organization (WHO) devised a simple method for assessing pain using a numerical model and treating neuropathic, nociceptive or mixed cancer-related pain. The WHO guidelines are listed in TABLE 3.²⁰

Table 2. PQRST Characteristics of Pain
P	Palliative factors	What makes the pain better?
	Provocative factors	What makes the pain worse?
Q	Quality	Please describe the pain.
R	Radiation	Where does the pain begin and where is it now?
S	Severity	How does the pain compare with other pain you have encountered?
T	Temporal factors	How has the intensity of pain modified with time?
Source: Reference 1

Table 3. WHO Guidelines of Pain Control

Use acetaminophen (APAP), aspirin, or another NSAID for mild to moderate pain. Adjuvant drugs to enhance analgesic efficacy, treat concurrent symptoms that exacerbate pain, and provide independent analgesic effect for specific types of pain may be used at any step.  When pain persists or increases, an opioid such as codeine or hydrocodone should be added (not substituted) to the NSAID. Opioids at this step are often administered in a fixed-dose combination with APAP or aspirin because this combination provides additive analgesia. Fixed-combination products may be limited by the content of APAP or NSAID, which may produce dose-related toxicity.   When higher doses of opioid are necessary, the third step is used. At this step, separate dosage forms of the opioid and non-opioid analgesic should be used to avoid exceeding maximally recommended doses of APAP or NSAID. Pain that is persistent, or moderate to severe at onset, should be treated by increasing opioid potency or using higher dosages. Drugs such as codeine or hydrocodone, are replaced with more potent opioids (usually morphine, hydromorphone, methadone or fentanyl). Medications for persistent cancer-related pain should be administered on an around-the-clock basis, with additional "as-needed" doses, because regularly scheduled dosing maintains a constant level of drug in the body and helps prevent the recurrence of pain. Patients who have moderate to severe pain when first seen by the clinician should be started at the second or third step of the ladder.

Source: Reference 20

In 1997, Grond et al., conducted a study to determine the effectiveness of the WHO guidelines in the treatment of neuropathic pain.²¹ The study surveyed 593 patients treated by a pain service following the WHO guidelines for relief of cancer pain. Of the patients, 380 presented with nociceptive pain, 32 with neuropathic pain, and 181 with a mixed syndrome involving neuropathic and nociceptive pain. In patients with nociceptive, mixed and neuropathic pain, the average duration of evaluated pain treatment was 51, 53 and 38 days, respectively. Non-opioid and opioid analgesics were administered to 99%, 96%, and 79% of patients, antidepressants to 8%, 25%, and 19% of patients, and anticonvulsants to 2%, 22%, and 38% of patients, respectively. Systemic analgesics were supported by palliative antineoplastic treatment in 48%, 56% and 38% of patients, respectively. Analgesic treatment resulted in significant pain relief in all groups of patients as the mean pain intensity decreased throughout the treatment period. The authors concluded the success of pain treatment was not predicted by the designation of nociceptive, mixed or neuropathic and the majority of patients may be treated following the WHO guidelines.

Although the WHO guidelines demonstrated efficacy in controlling cancer-related neuropathic pain, a pain scale specific to neuropathy was desired. This assessment tool should be designed to measure the various aspects of neuropathic pain, such as sharpness, heat/cold, intensity and surface vs. deep pain. Current assessment tools, such as the Visual Analog Scale (VAS), the WHO Guidelines, the McGill Pain Questionaire (MPQ), and Verbal Descriptor Scales (VDS) may have limitations in evaluating neuropathic pain. For example, although VAS and VDS have been proven to be reliable and valid as measures of pain intensity and unpleasantness, these two pain dimensions do not adequately cover the domain of the neuropathic pain experience.²²

In 1997, Galer and Jensen developed the Neuropathic Pain Scale (NPS) to address the need for a measure sensitive to a variety of pain qualities common to neuropathic pain syndromes. This study described the initial development and validation of the NPS. The authors argued that not only should the scale involve numerical measurements, but also it should evaluate various neuropathic descriptors (intensity, sharpness, temperature, dullness, itching, shooting, etc.). This theory was based on the fact that humans may disagree on various distinctions such as the taste of pie. One might argue that a pie is good, but should be sweeter, whereas, another may believe that same pie is too sweet. Pain is the same: One may feel an extremely sharp pain, without heat or itching, whereas, another may experience a combination of all three. The study was conducted using the aforementioned descriptors and was able to display positive changes in patients diagnosed with post-herpetic neuralgia (PHN), reflex sympathetic dystrophy, painful diabetic neuropathy (PDN), and peripheral nerve injury. Although the two-part study was not double-blind or randomized, it provided preliminary support for the potential importance of assessing distinct pain qualities among individuals with neuropathic pain. In the future, the NPS may prove more sensitive than other assessment tools for neuropathy, but further studies are warranted. An example of the NPS is displayed in FIGURE 2.

Figure 2. Neuropathic Pain Scale

Treatment

Early recognition, proper assessment and aggressive management of neuropathic pain are essential to a successful outcome. In many instances, an interdisciplinary team prescribes various treatment modalities. Numerous options are available, including systemic medications, physical rehabilitation, behavioral modification, and invasive procedures. Unfortunately, most neuropathic syndromes respond poorly to NSAID and opioid analgesics. The mainstay of treatment is predominantly tricyclic antidepressants (TCAs) and anticonvulsants. Other pharmacologic agents that have proven efficacious include topical therapy with substance P depleters, NMDA antagonists, and some autonomic agents. Studies suggest that if multiple agents are administered, optimal treatment should involve drugs with different mechanisms of action. A stratification of these agents according to their major putative antineuralgic mechanisms of action is shown in FIGURE 3.²³

Figure 3. Mechanistic Approach to Neuropathic Pain Management

Antidepressants

Tricyclic Antidepressants: The TCAs have been successfully used for the treatment of neuropathic pain for over 20 years. The mechanism for alleviating neuropathic pain is thought to be due to inhibition of NE and 5-HT reuptake within the dorsal horn, although another possible mechanism is thorough modulation of sodium channels. Therapy with TCAs should be started at low doses (10 mg to 25 mg at night, due to sedating effects) and increased slowly by 10-25 mg per week.²⁴ These agents should be used with caution in patients with heart disease, narrow angle glaucoma or prostatism. The TCAs may be associated with a number of adverse effects such as sedation, weight gain, orthostatic hypotension and anticholinergic symptoms (e.g., dry mouth, constipation, and urinary retention).

There are two classes of TCAs, the secondary and tertiary amines, prescribed for neuropathic pain. Amitriptyline is the prototypical tertiary amine most often prescribed for this condition. Doses of TCAs used for neuropathy are considerably less than those prescribed for depression.^1,6,24 The typical dose for amitriptyline may be simply 10 mg orally at bedtime with a gradual escalation in increments to a maximum of 50 mg at bedtime. Furthermore, the onset of analgesia may occur over several days versus the two weeks that are required for the onset of antidepressant effects.²⁴ Although effective, the tertiary TCAs have been associated with an increased incidence of orthostatic hypoten sion and sedation and should be administered with caution in the elderly.²³

SSRIs: The selective serotonin reuptake inhibitors (SSRIs) have not proven as effective in treating neuropathic pain as anticipated. Fluoxetine only appears to relieve pain in patients suffering from comorbid depression.^6,24 As a general rule, the SSRIs are only partially effective in treating neuropathic pain, but not to the extent of the TCAs. Venlafaxine may have better analgesic effects since, like the TCAs, it inhibits reuptake of 5HT and NE.²⁵ Its side effects profile is similar to that of the SSRIs and may include agitation, insomnia, gastrointestinal distress, somnolence and inhibition of sexual functioning.

Anticonvulsants

Carbamazepine: Carbamazepine is an iminostibene derivative chemically related to the TCAs.²⁶ It has been shown to inhibit action potentials in rats.²⁷ It has been administered to patients having a variety of painful syndromes, including diabetic neuropathy, trigeminal neuralgia and cancer-related pain, although the analgesic efficacy of carbamazepine has been most frequently documented in trigeminal neuralgia and painful diabetic neuropathy. TABLE 4 provides the doses of anticonvulsants recommended for treatment of neuropathy.

Table 4. Anticonvulsants
Anticonvulsants - Modify voltage-sensitive Na+ channels, thereby stabilizing neuronal membranes Adverse Effects - Sedation, dizziness, fatigue, ataxia, and confusion
Medication	Initial dose	Maintenance Dose	Contraindications	Monitoring Parameters	Costa
Carbamazepine	100 mg bid	400-1,000 mg/d	Hypersensitivity to TCAs; bone marrow suppression; MAO inhibitor use	CBC, LFT, serum concentrations, urinalysis	$10-$20
Oxcarbazepine	300 mg bid	900-2,400 mg/d	Hypersensitivity	Serum electrolytes (especially Na+), LFT, CBC	$150-$200
Lamotrigineb	25 mg/day	200-400 mg/d (bid)	Hypersensitivity; children <16 yrs	Seizures & rash	$175-$185
Phenytoin	200-300 mg/day (qd-bid)	200-350 mg/d (qd-bid)	Bradycardia; 2nd & 3rd degree AV block; Stokes-Adams syndrome, SA block	BP, plasma levels, LFT, CBC	$10-$30
Topiramate†	25-50 mg/day	200-400 mg/d (bid)	Hypersensitivity	SrCr; BUN	$90-$240
Levetiracetamc	250 mg/day	1,000-3,000 mg/d (bid)	Hypersensitivity	SrCr, BUN	$48-$113
aprices obtained from Clinical Pharmacology; 30 day supply unless indicated bmay exhibit is action via the inhibition of glutamate (an excitatory neurotransmitter), which would then decrease calcium efflux †believed to enhance gamma-aminobutyric acid (GABA) activity and block glutamate activity cMechanism of action is unclear, but does not seem to involve excitatory or inhibitory neurotransmission
Anticonvulsants - Mechanism unclear; believed to bind to receptors in the neocortex and hippocampus Adverse Effects - Ataxia, dizziness, fatigue, nystagmus, somnolence, and tremor
Medication	Initial Dose	Maintenance Dose	Contraindications	Monitoring Parameters	Cost*
Gabapentin**	300 mg	HS 900-3600 mg/d	Hypersensitivity	Not mandatory	$80-$300
Anticonvulsants ­ Increases brain levels of gamma-aminobutyric acid (GABA) Adverse Effects ­ Drowsiness, sedation, constipation, diarrhea, heartburn, vomiting, and rash
Medication	Initial Dose	Maintenance Dose	Contraindications	Monitoring Parameters	Cost*
Valproic Acid	600 mg/day	Titrate up to max 1,200 mg/d	Hypersensitivity & hepatic disease/dysfunction	Serum levels, CBC, LFT	$30-$150
*Cost is an approximation (in US dollars) of a month supply (in generic if available) **Mechanism of action is unclear, but some sources believe it to be related to calcium regulation Adapted from reference 24,30

Campbell et al., conducted a double-blind, placebo-controlled, crossover trial that reported positive results using carbamazepine vs. placebo in trigeminal neuralgia.²⁸ The dosage administered ranged up to 400 mg/day and response rates ranged from 70% to 89% after 5 to 14 days of treatment. However, the clinicians did not provide a washout period during this study, which limits the ability to prevent a carry-over effect. This makes it difficult to determine whether the data from this trial represents a specific and therapeutic effect of carbamazepine.

Adverse effects seen include drowsiness, dizziness, ataxia, nausea and vomiting. Although this trial has limitations, it still provides proof of carbamazepine's efficacy in treating trigeminal neuralgia. Beydoun also suggests that carbamazepine's effectiveness in trigeminal neuralgia is superb.²³ Moreover, he advises that if a patient has been diagnosed with trigeminal neuralgia and carbamazepine is ineffective as an initial treatment option, the physician should reevaluate the diagnosis. Unfortunately, in some cases, carbamazepine has been discontinued after a year of treatment secondary to tolerance or adverse effects. In those instances, oxcarbamazepine has subsequently been initiated with success and without the adverse effects experienced with carbamazepine.²³

There were also trials evaluating carbamaze-pine's effectiveness in PDN. Rull and colleagues demonstrated symptomatic relief of pain and parasthesia in 28 out of 30 patients after two weeks of therapy.²⁹ The dose administered was 600 mg/day. However, carry-over effects occurred during placebo administration and no statistical analysis was performed. Carbamazepine has also been compared with tricyclic neuroleptic combinations and there were dramatic improvements from baseline with both therapies, but no significant difference between the two treatment groups. Overall, carbamazepine has demonstrated efficacy in a variety of trials where dosages may range from 300-2,400 mg/day in divided doses.³⁰ In these studies, dizziness and somnolence were the most frequently reported adverse effects.

Phenytoin: Phenytoin was the first anticonvulsant to be used in neuropathic pain after Bergouigan reported success in patients with trigeminal neuralgia.³⁰ The analgesic effect is achieved through the blockage of sodium channels, inhibition of glutamate release and suppression of ectopic discharges. There have been five randomized clinical trials published involving phenytoin. Two out of the five trials involved phenytoin for treatment of PDN at a dose of 300 mg/day; the rate of adverse effects was approximately 10%, overall, in both trials.³¹ A common adverse effect observed was giddiness. Recent data have appeared supporting the hypothesis that phenytoin may also have antinociceptive properties.³⁰ Other studies should be conducted to validate this theory.

Valproic Acid: Valproic acid inhibits sustained neuronal firing in spinal neurons. This effect is mediated by prolonging repolarization of voltage activated sodium channels. Also, valproic acid increases the amount of gamma amino butyric acid (GABA), an inhibitory neurotransmitter in the brain, by inhibiting GABA degradation enzymes. These initial reports regarding valproic acid in neuropathy appeared in the early 1980s. In these studies, valproic acid relieved pain in 50% to 80% of patients with trigeminal neuralgia.³² Many of the patients had already been treated with carbamazepine, phenytoin and clonazepam alone or in combination. Unfortunately, the only double-blind, placebo-controlled trial of valproic acid for treatment of neuropathic pain due to spinal cord injury showed no statistical significance between drug and placebo. This may be attributed to the small sample size of patients.³⁰

Lamotrigine: Lamotrigine blocks voltage-dependent sodium channels and inhibits glutamate release.^26,30 Lamotrigine 50-400 mg/day has demonstrated efficacy in relieving pain in patients with trigeminal neuralgia refractory to other treatments, such as carbamazepine, phenytoin or both. Several patients experienced adverse effects such as dizziness, constipation, nausea, somnolence and diploplia. There is clinical evidence that warrants the use of lamotrigine in other painful conditions, but other studies are needed.

Gabapentin: Gabapentin is perhaps the best-studied anticonvulsant used in the treatment of neuropathic pain. It was originally developed as a structural GABA analogue, but it has no GABA-like action, nor does it affect GABA uptake or metabo lism.^1,23,30 Gabapentin blocks the tonic phase of nociception induced by formalin and carrageenan, and it exerts a potent inhibitory effect in several neuropathic pain models.³⁰ There is also evidence of a possible effect of gabapentin on calcium channels. Some investigators have demonstrated that gabapentin has more of a central effect, whereas others have shown that gabapentin inhibits ectopic discharges from injured peripheral nerves.

Gabapentin has demonstrated efficacy in relieving PHN and PDN. The dosage used in these studies ranged from 900-3,600 mg/day in three divided doses. Dizziness and somnolence were the most frequently observed adverse effects.³⁰ With the recent approval of gabapentin for postherpetic neuralgia, this agent may become first-line therapy for neuropathic pain. However, studies need to be conducted to prove its efficacy as a first-line agent.

Miscellaneous Agents

Amantadine, tramadol, oxycodone, buproprion and capsaicin have all been proven efficacious in the management of neuropathic pain. The recommended doses are shown in TABLE 5. Amantadine is an NMDA antagonist and its success in neuropathy is limited to case reports because of its high toxicity.³³

Table 5. Miscellaneous Agents
Medication	Initial dose	Maintenance Dose	Contraindications	Adverse Effects	Monitoring Parameters	Cost‡
Alpha-2 Adrenergic Agonist
Capsaicin	0.075% qid		N/A	Irritation or burning at site of application	N/A	$20-40
Analgesics
Tramadol	25 mg/d every 3 days up to 25 mg qid	100-400 mg/d (qid)	Acute intoxication with alcohol, hypnotics, other centrally acting analgesics, opioids or psychotropic drugs	Dizziness, vertigo, fatigue, drowsiness, headache, somnolence, nausea, constipation	Vital signs, orthostatic hypotension, bowel and bladder function, ambulation, seizure activity	$150.00-600.00
Oxycontin	10 mg every 12 h	Titrate up as needed	Hypersensitivity	Hypotension, fatigue, drowsiness, dizziness, nausea, vomiting, xerostomia, headache nervousness, shortness of breath, anorexia	BP, respiratory and mental status	$20.00- 149.99
Antiarrhythmic
Mexiletine	150 mg/d for 3 days	450-675 mg/d (tid)	Cardiogenic shock, pre-existing 2nd or 3rd degree AV block (without pacemaker)	Dizziness, tremor, nervousness, incoordination, nausea, vomiting, heartburn	Baseline BP and HR, therapeutic range (0.5 2 µg/mL), compliance	$70.00-79.99
Anxiolytic
Bupropion	150 mg qd-bid		Seizure disorder, current or history of bulimia or anorexia, within 14 days of MAOI therapy	Anorexia, dry mouth, rash, sweating, agitation, dizziness, insomnia, nausea, constipation	Weight loss	$40.00-49.99
‡prices obtained from Clinical Pharmacology; 30 day supply unless indicated Source: References 24,34-37

Tramadol, a non-narcotic analgesic, binds selectively to m receptors. It has been studied extensively for the treatment of PDN. Harati et al., found this agent to be effective for the treatment of PDN, and the average dose administered in this study was 210 mg/day in divided doses.³⁴ Patient's pain scores with this agent were significantly better than with placebo, but further studies are warranted.

Oxycodone, an opiate that binds to m receptors, has been studied in a variety of neuropathic disorders. The extended-release form has been extensively studied in the treatment of PHN. The dose administered was 10 mg vs. placebo every 12 hours for 4 weeks.³⁵ There were reductions in steady pain, paroxysmal spontaneous pain and allodynia. Oxycodone has been proven useful in the treatment of neuropathy. Interestingly, neuropathic pain usually does not respond to opioids but at least one study suggests that neuropathic pain is not opioid-resistant but only that reduced sensitivity is observed in this condition and higher doses are usually required for analgesia. Higher doses may be related to higher side effects. Oxycodone has been shown effective in studies at normal doses and this decreases or limits the possibilities of adverse effects.³⁶

Bupropion has been shown to affect non-adrenergic pathways and to reduce whole body turnover of NE in patients with depression. Semerchuk evaluated sustained-release bupropion in 41 non-depressed patients with neuropathy over a six-week period.³⁷ Neuropathic pain relief scores improved in 73% of patients. The dose administered was 150 mg of bupropion SR once daily for one week, followed by one tablet twice daily for 5 weeks. Side effects observed included dry mouth, insomnia, headache, gastrointestinal upset, constipation and dizziness. The side effects were not found to be dose-limiting.

Another option is capsaicin, a substance P depleter that been used safely in the treatment of PDN. Zhang and colleagues found that capsaicin 0.075% applied four times daily for 4-8 weeks provided a dramatic improvement in pain relief.³⁸ Seventy-three percent of patients responded to capsaicin, compared with 49% of patients given placebo. No side effects were reported.

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