Medical Management of Chronic Shoulder Pain

Dmitri Souzdalnitski

Nagy A. Mekhail

EPIDEMIOLOGY AND DEFINITIONS

Shoulder Pain: Types and Classification

Shoulder pain is second only to low back pain in the primary care setting. About 20% of the population will suffer shoulder pain during their lifetime.¹⁷,¹⁸,³⁰

Pain is classified in many ways, including acute or chronic, organic or psychogenic, and malignant or nonmalignant. Other classifications include nociceptive (associated with the detection of potentially tissue damaging stimuli), inflammatory—tissue damage (mostly acute pain), and pathologic pain (damage to the nervous system, or neuropathic).⁸⁴

Acute pain is defined as short-term pain that is related to a precipitating event as a symptom of an underlying pathology. It is associated with autonomic nervous system hyperactivity, including tachycardia, increased blood pressure, and anxiety.

Chronic pain is pain lasting more than 3 to 6 months. Objective clinical findings for chronic shoulder pain include impaired function, clinical manifestation such as withdrawal from social activities, anxiety and depression, and personality and lifestyle changes.⁴⁹

Therefore, in relation to pain, “chronic” describes not only duration but also a syndrome with specific therapeutic implications.²⁹

Chronic pain could be classified as organic versus psychogenic pain. Organic pain may be nociceptive, neuropathic, or mixed.

Nociceptive pain is found in cutaneous or deep tissue (somatic) and organs (visceral). Nociceptive pain results from direct stimulation of intact peripheral afferent nerve endings that are sensitive to noxious mechanical, thermal, or chemical
stimuli. An example of chronic nociceptive pain is rotator cuff injury.²³ This pain may be intermittent, localized, and related to position and weight-bearing or physical activity. In severe, long-standing cases, it may be persistent, diffuse, and nonrelated to position of the extremity of its mobility. Nociceptive pain is common among chronic shoulder pain.

Neuropathic pain is caused by injury or inflammation of peripheral or central nervous system elements. It may be divided into central and peripheral nervous system disturbances and is designated as differentiation pain.

Central neuropathic pain may result from nervous system injury including direct trauma, ischemia (e.g., thalamic syndrome), infection (e.g., postherpetic neuralgia [PHN]), metabolic derangement (e.g., diabetic neuropathy), or tumor invasion.

Neuropathic pain may be constant and steady or intermittent and lancinating and is described as burning, shooting, or tingling. Pain may be experienced as abnormal or altered sensation (dysesthesia), paresthesia (electrical shock sensation), hyperalgesia (extreme sensitivity to painful stimuli), or allodynia (pain with touch).

Peripheral neuropathic pain is secondary to peripheral hyperexcitability, which is due to a series of molecular changes at the level of the peripheral nociceptor, in dorsal root ganglia, in the dorsal horn of the spinal cord, and in the brain. These changes include abnormal expression of sodium channel activity at glutamate receptor sites, change in y-aminobutyric acid (GABA-ergic) inhibition, and an alteration of calcium influx into cells.³⁸

SYMPATHETICALLY MAINTAINED AND SYMPATHETICALLY INDEPENDENT PAIN

Neuropathic pain could be also divided into the categories based on its response to sympathetic neurosystem blockade, namely sympathetically maintained pain (SMP) and sympathetically independent pain (SIP).

SMP describes the pain that is dependent on and maintained by sympathetic input. Two particular features distinguish SMP: The pain is accompanied by signs of autonomic dysfunction and sympathetic blockade generally results in pain relief. Features usually include burning pain, hypersensitivity, allodynia, edema, and sometimes muscle spasms and dystonias.⁷,⁷² The response to sympathetic blockade is generally good and was the reason behind the descriptive term of SMP. Various pain disorders may have a component of SMP (Fig. 37-1).

SIP describes the pain state that occurs most often in later stages of neuropathic pain, where sympathetic blockade or sympathectomy yields no clinical improvement in pain. The pain characteristics of this clinical subgroup suggest the involvement of various mechanisms.

Psychogenic pain is defined as a somatoform pain disorder which, most of the times, is a diagnosis of exclusion.²⁹

Chronic Pain as a Disease

Independently of local source, chronic pain has been linked to distinct structural, functional, psychological, and social markers.⁵⁵,⁵⁶,⁷⁸ Certain molecular and genetic aberrations have also been related to chronic pain which pertain characteristics of a chronic disease rather than just a constellation of well-defined structural problems.

FIGURE 37-1. Relationship between sympathetically maintained pain and some selected painful conditions. This illustration is intended as a conceptual framework without indication of the quantitative relationship between the intersections. Various pain disorders may have a component of sympathetically maintained pain.

MOLECULAR MECHANISMS OF CHRONIC PAIN

An injury, acute inflammation, or neuropathic event typically precedes the development of chronic pain. It leads to the release of inflammatory mediators by activated nociceptors or nonneural cells that reside within or infiltrate into the injured area, including mast cells, basophils, platelets, macrophages, neutrophils, endothelial cells, and fibroblasts.¹,⁹,¹⁶ The “inflammatory cocktail” of signaling molecules includes, but is not limited to substance P, calcitonin-gene related peptide, bradykinin, prostaglandins, thromboxanes, leukotrienes, endocannabinoids, nerve growth factor, tumor necrosis factor α, interleukin-1β, extracellular proteases, protons, serotonin, histamine, glutamate, ATP, adenosine, and others.

These factors act directly on the nociceptor by binding to one or more cell surface receptors, including G proteincoupled receptors, transient receptor potential ion channels, acid-sensitive ion channels, two-pore potassium channels, and receptor tyrosine kinases. Nociception may be mediated by activation of B1 and B2 G- protein-coupled receptor complexes by bradykinin. This facilitates Na⁺ influx while weakening outward K⁺ currents, producing nociceptor excitation. Another mechanism of conversion of noxious stimuli into the generation of action potential is a calcium ion-mediated electrical depolarization. Various types of injuries produce diverse blends of inflammatory environment, which initiate cascades of different types of neuroplastic changes.¹,⁹,¹⁶

PERIPHERAL AND CENTRAL SENSITIZATION

A state of peripheral sensitization, produced by the abovedescribed mechanisms, serves to protect the body from further injury and promote healing. The repeated painful stimulation of peripheral nerve endings propagated to the spinal dorsal horn neurons via Aδ and C-fibers may lead to progressive activation of N-methyl-D-aspartate (NMDA) receptor. The activation of the NMDA receptor produced sustained release of glutamate, substance P, and other molecules in the dorsal horns. It leads to increased pain response from noxious stimuli (also termed hyperalgesia), or pain from previously innocuous stimuli (termed allodynia), or spontaneous pain. The process involves not only the spinal structures but also the brain, collectively termed as “central pain sensitization.” Irreversible neurochemical and neuropathologic changes may occur secondary to these and other not entirely understood mechanisms, leading to a chronic state clinically described as the chronic pain syndrome. In addition, direct damage to the spinal cord or brain, such as ischemia, spinal cord injury, tumors, trauma, multiple sclerosis, or other conditions, may lead to central pain syndrome.

SYSTEMIC EFFECTS OF CHRONIC PAIN

There are controversies over how different organ systems participate in adapting to a state of chronic pain, including the neurologic, psychiatric, endocrine, immune, cardiovascular, respiratory, metabolic, musculoskeletal, and other pathologic changes in patients with chronic pain.¹²,⁵⁹,⁷⁸ However, recent data from structural, functional, and molecular imaging studies support the concept that chronic pain has characteristics of a disease rather than just a constellation of symptoms (Fig. 37-2). This concept is likely to lead to more widespread acceptance and classification of chronic pain as a disease and promote further research and better understanding of chronic pain shoulder pain.

FIGURE 37-2. Relationship between various components of chronic pain disorder.

Most patients with a chronic shoulder disorder can initially be treated conservatively with a combination of physical therapy, rehabilitation, activity modification, medications, and injections. Satisfactory results with this approach could be achieved in a number of patients.¹⁷,⁷³

PHYSICAL THERAPY AND REHABILITATION

Activity Modification

Activity modification is an appropriate first step in reducing pain during the workup for chronic shoulder pain. The recommendations on activity modification are based on the underlying condition.⁵³ For example, cutback or avoidance of overhead activity is the main part of initial management of glenohumeral osteoarthritis and adhesive capsulitis. Staying away from loading of the shoulder may help with the pain associated with glenohumeral osteoarthritis. Avoiding the painful arc between 60 and 120 degrees is recommended for rotator cuff injuries. It is recommended to avoid certain overhead activities, which may worsen shoulder instability. Examples of particularly dangerous movements in patients with an unstable shoulder include overhand throwing and bench pressing. In patients with acromioclavicular osteoarthritis, certain movements, like those used in golf swinging or weight lifting, should be limited.

Physical Therapy

This is the fundamental step in the treatment of chronic shoulder pain.²⁷,³¹ Aggressive physical therapy and rehabilitation programs should be individually designed with the ultimate goal of regaining function of the affected extremity.⁵⁷ Exercise includes various modalities and, more specifically, stress loading and increased endurance of the affected extremity.³ Stretching and strengthening exercises are intended to relieve pain by improving overall shoulder function and providing muscle corset to support the shoulder. Exercise is typically combined with manipulation and mobilization.¹⁰

Other conservative modalities included rest, ice, or heat, electroneurostimulation, therapeutic ultrasound, iontophoresis, hyperthermia, acupuncture, low-intensity laser, repetitive motion machine use, balneotherapy, peloid therapy, etc.²,³,¹⁴,¹⁵,¹⁷,¹⁹,²⁰,²⁵,²⁶,⁴⁰ These therapeutic modalities are designed to alleviate pain directly. Limited evidence exists for the use of these therapeutic approaches alone. However, complex therapy, encompassing these modalities with other conservative measures, is more evident.³ The evidence for most of these modalities is less strong than for activity modification and exercises. The therapeutic effect of conservative therapy is higher when the underlying diagnosis is known and the patient enthusiastically participates in the rehabilitation process, and continues at home independently.⁴⁰ The type and specific application of physical therapy depends on the underlying pathology. The detailed discussion of physical therapy and rehabilitation modalities for chronic shoulder pain are out of the scope of this chapter, but are covered elsewhere in this book.

NONOPIOID ANALGESICS IN THE MANAGEMENT OF CHRONIC SHOULDER PAIN

Pharmacotherapy plays a key role in the management of chronic shoulder pain, as drug therapy may help to turn off noxious stimuli or dampen the underlying neuropathic disturbance.⁶

Nonopioid analgesics, which include acetaminophen, NSAIDs, and salicylate, provide first-line therapy for managing chronic pain.

Acetaminophen

Acetaminophen, the active metabolite of phenacetin, has been used in medicine since 1893. The mechanism of action of this drug remains a subject of debate. It appears to function as a reversible inhibitor of cyclooxygenase (participating in prostaglandin synthesis), and is believed to inhibit the synthesis of various chemical mediators in the central neural system that play a role in the central sensitization to pain. It has no or minimal effect on inhibition of peripheral prostaglandin synthesis, which accounts for the lack of anti-inflammatory effects. Metabolism occurs in the liver, primarily by cytochrome P-450 (CYP-450), 1A2, 3A4, and 2E1.⁶

Oral acetaminophen is commonly used as an adjunct to opioids in the perioperative period. Intravenous (i.v.) acetaminophen preparations combined with opioids showed a higher analgesic effect, compared to opioids acting alone in some orthopedic surgeries.

Acetaminophen has an excellent safety profile with regard to the gastroduodenal mucosa, platelet function, and nephrotoxicity but may cause hepatotoxicity. It should be cautiously used in patients with a history of ETOH abuse as these patients have a lower threshold for hepatotoxicity or nephrotoxicity secondary to depletion of glutathione associated with the accumulation of metabolites of acetaminophen. Acetaminophen has a ceiling dose effect for analgesia; beyond the recommended doses, no further pain relief occurs.⁶

Nonsteroidal Anti-inflammatory Drugs

Pharmacologic Effects

NSAIDs are among the most commonly used medications in the world. They constitute 4% of all filled prescriptions at a yearly cost in excess of $2 billion.¹¹ They are commonly used in the treatment of mild to moderate pain.

Pharmacologic effects of NSAIDs include analgesia, antiinflammatory effect, antipyresis, sodium retention followed by water retention and dilutional hyponatremia. NSAIDs may cause renal failure, heart failure, vascular tone changes, gastric irritation, platelet inhibition, hepatic dysfunction, and CNS effects such as dizziness, sedation, and confusion.⁶

The ability of NSAIDs to exert analgesic and anti-inflammatory effects is mediated by two mechanisms. The first is through suppression of proinflammatory and pain-enhancing prostaglandin synthesis at the site of inflammation. The second mechanism is through the modulation of neutrophil intracellular signaling function, which decreases the numbers of neutrophils migrating to inflammatory sites, resulting in a down regulation of the release of free radicals and destructive enzymes at these sites.

Two isoforms of COX enzyme exist: COX-1 and COX-2. COX-1 is found in most times throughout the body. It is expressed constitutively in both the gastroduodenal mucosa and platelet, and inhibition of COX-1 at these sites may predispose the patient to gastroduodenal ulceration and bleeding, respectively.

COX-2 is usually undetectable in most tissues but is expressed in response to inflammatory stimuli.

COX-1 and COX-2 are also expressed constitutively in the kidney, and inhibition of one or both of these isoforms may predispose the patient to renal adverse events, including renal insufficiency and hypertension. Traditional NSAIDs are nonselective inhibitors of both COX isoforms.⁴⁵

The salicylate group of NSAIDs includes aspirin, choline magnesium trisalicylate, and diflunisal (Table 37-1). Aspirin is commonly used not only as an anti-inflammatory agent but also for platelet-inhibiting effects in the prevention of cerebrovascular accidents and myocardial infarction.⁶

Aspirin produces irreversible inhibition of platelet aggregation. This inhibition is near complete and is sustained for at least 48 hours after a single dose. A recent study suggests that concurrent treatment with ibuprofen may limit the cardioprotective effects of aspirin by inhibiting the prolonged effect of aspirin on platelet aggregation.⁴⁵

Common side effects of aspirin include nausea and emesis, gastrointestinal (GI) hemorrhage, peptic ulcer, gastritis, and liver function abnormalities. Aspirin is the most nephrotoxic of the NSAIDs and has been associated with Rye’s syndrome in children and adolescents. Prolonged use of high doses (more than 100 mg/kg/day) may result in chronic salicylate toxicity.⁶

Indole acetic acid derivatives include indomethacin, sulindac, and etodolac.

GI side effects are quite common with indomethacin. Other adverse effects include psychosis, headache production, depression, hypertension, and fluid retention. Sulindac produces fewer side effects than indomethacin; however, a causal relationship to liver disease has been suggested. Etodolac is a mixed COX-1 and COX-2 inhibitor and therefore seems to have less toxicity.⁶

PYRROLE ACETIC ACID DERIVATIVE

Ketorolac is the only NSAID that is available as an injection in the United States. It is effective against pain of somatic origin. Concurrent use with opioids allows reduced dosing of opioids because it promotes the release of endogenous opioids. The analgesic action of ketorolac is through the CNS. It has GI and renal toxicity. To avoid such toxicity, short-term use (less than 5 days orally and less than 48 hours parenterally) is recommended.²⁴

PHENYL ACETIC ACID DERIVATIVES

Diclofenac (Voltaren) is used in the management of gout, low back and neck pain associated with degenerative joint disease, osteoarthritis, and rheumatoid arthritis. It has GI side effects, and there is a small risk of hepatic inflammation, so liver function tests must be done within 8 weeks of administration.⁶

PROPIONIC ACID DERIVATIVES

Ibuprofen, ketoprofen, and naproxen all have GI side effects. Naproxen is recognized as having more GI side effects than ibuprofen.⁶

TABLE 37-1 Pharmacologic Classifications of Nonsteroidal Anti-inflammatory Drugs

Carboxylic acids
Salicylic acids
Acetylsalicylic acid (aspirin)
Nonacetylated salicylates
	Choline magnesium trisalicylate (Trilisate)
	Salicyl salicylate (Disalcid)
	Diflunisal (Dolobid)
Acetic acids
Indole acetic acids
	Indomethacin (Indocin)
	Sulindac (Clinoril)
	Etodolac (Lodine)
Pyrrole acetic acids
	Tolmetin (Tolectin)
	Ketorolac (Toradol)
Phenyl acetic acids
	Diclofenac (Voltaren)
Naphthyl acetic acid
	Nabumetone (Relafen)
Propionic acids
Phenyl propionic acids
	Ibuprofen (Motrin)
	Fenoprofen (Nalfon)
	Flurbiprofen (Ansaid)
	Ketoprofen (Orudis)
Naphthyl propionic acids
	Naproxen (Naprosyn, Anaprox)
Anthranilic acids
Fenamates
	Meclofenamic acid (Meclomen)
	Mefenamic acid (Ponstel)
Oxicams
Piroxicam (Feldene)
Pyrazoles
Phenylbutazone (Butazolidin)

COX-2 SELECTIVE INHIBITORS

Celecoxib, valdecoxib, and rofecoxib were the first of a long line of COX-2 inhibitors to be available in the United States. Valdecoxib and rofecoxib were subsequently withdrawn from the market due to major cardiovascular side effects. These drugs have 200- to 300-fold selectivity for inhibition of COX-2 over COX-1.²⁴,⁴⁵ They are comparable to the traditional NSAIDs in their analgesic effects but have marked reduction in the GI side effects.⁴⁵ In patient not taking low-dose aspirin, the risk of confirmed upper GI events including symptomatic ulcers and the risk of confirmed complicated upper GI events is significantly reduced in patients taking COX-2 selective inhibitors compared with those taking nonselective NSAIDs, particularly ibuprofen and naproxen. Celecoxib is the only COX-2 inhibitor available now in the United States.

Routes of Administration of Nonsteroidal Anti-inflammatory Drugs

Oral administration of NSAIDs appears to be most commonly used route. Some of the NSAIDs can be administered intravenously in hospital settings. Ketorolac, for example, can provide an effective pain control. One 30 mg dose of Ketorolac may be as effective as 10 mg of morphine. It is recommended, however, to limit the treatment course to 5 days because of its side effects.

Intramuscular NSAIDs also appear to be effective in patients with shoulder pain, but have only been studied in short-term trials. A recent systematic review showed that topical NSAIDs (gel patches) can provide good levels of pain relief, without the systemic adverse events associated with oral NSAIDs, when used to treat musculoskeletal conditions. A recent meta-analysis showed that for all topical NSAIDs combined, compared with placebo, the number needed to treat to benefit (NNT) for clinical success, equivalent to 50% pain relief, was 4.5 for treatment periods of 1 to 2 weeks. Topical diclofenac, ibuprofen, ketoprofen, and piroxicam were of similar efficacy. Local skin reactions were generally mild and transient, and did not differ from placebo. There were very few systemic adverse events or withdrawals due to adverse events. There were insufficient data to reliably compare individual topical NSAIDs with each other or the same oral NSAID.⁴⁸

Cautions in the Use of Nonsteroidal Anti-inflammatory Drugs

Caution needs to be exercised in the use of NSAIDs in patients with uncontrolled hypertension, mild to moderate renal insufficiency, or congestive heart failure. The adverse effects of COX-2 selective inhibitors on organ systems other than GI appeared to be similar to those that occur with nonselective NSAIDs.

CARDIOVASCULAR SYSTEM

COX-2 selective inhibitors may increase the risk of serious cardiovascular thrombotic events, especially myocardial infarction, as these agents do not inhibit platelet aggregation.

In the VIGOR trial, the incidence of cardiovascular events was higher in patients receiving rofecoxib than in those receiving naproxen. However, in the CLASS trial, there was no increase in the incidence of cardiovascular events associated with celecoxib compared to ibuprofen and diclofenac.⁵⁴
A twofold increase in acute myocardial infarction with rofecoxib compared to placebo prompted the voluntary withdrawal of rofecoxib (Vioxx) from the U.S. and worldwide markets in 2004. The same year, the U.S. Food and Drug Administration (FDA) requested Pfizer, Inc., to voluntarily withdraw Bextra (valdecoxib) from the market. This request was based on the lack of adequate data on the cardiovascular safety of long-term use of Bextra, increased risk of adverse cardiovascular events in short-term coronary artery bypass surgery trials, and reports of serious and potentially life-threatening skin reactions. The FDA has also asked manufacturers of all prescription NSAIDs, including Celebrex (celecoxib), a COX-2 selective NSAID, to revise the labeling to include a boxed warning to highlight the potential cardiovascular and GI risks.

GASTROINTESTINAL COMPLICATIONS

In patients taking NSAIDs, the clinical ulcer rate is in the range of 1% to 4%, and a complicated ulcer rate is around 1%.³²,³⁷ The increased risk of GI complication is dose related, and there is evidence of an interaction with concomitant glucocorticoid and acetaminophen therapy. Dyspepsia is the most common side effect of NSAID therapy. It occurs in around 30% of chronic users and leads to cessation of therapy, switching therapy, and time-consuming and expensive investigations such as endoscopy.²¹

Risk factors for serious upper GI complications in patients treated with nonselective NSAIDs include older age, male sex, history of peptic ulcer disease or prior upper GI bleeding, concomitant use of oral glucocorticoids or anticoagulants, and, possibly, smoking and alcohol consumption. Ibuprofen has the lowest risk of gastrotoxicity among nonselective NSAIDs.

Celecoxib at dosages greater than those indicated clinically was associated with a lower incidence of symptomatic ulcers and ulcer complications, compared with NSAIDs at standard dosages.

Upper GI toxicity was strongest among patients not taking aspirin concomitantly. It is also better tolerated than NSAIDs.⁷¹

RENAL COMPLICATIONS

Intake of nonselective NSAIDs is associated with about a twofold increase in risk of developing renal failure, the increase being dose related. Risk factors for acute renal failure in patients treated with nonselective NSAIDs include age greater than 65 years; presence of intrinsic renal disease, usually defined as a serum creatinine greater than 2.0 mg/dL; hypertension and/or congestive heart failure; and concomitant use of diuretics and angiotensin-converting enzyme inhibitors.³³

Edema and salt and water retention are the most common adverse renal effects associated with NSAIDs, occurring in 2% to 5% of patients. Other rare renal effects include hyperkalemia, allergic interstitial nephritis, chronic interstitial nephritis, and nephrotic syndrome.⁵

HYPERTENSION

NSAIDs, with the possible exception of sulindac and aspirin, may, at least in the short term, increase blood pressure. Changes in mean arterial pressure are small, on the order of 3 to 5 mmHg. The precise mechanism by which NSAIDs raise blood pressure remains obscure, but there is evidence for both an effect on the vascular tone, through decreased angiotensindependent prostaglandin release, and volume control (sodium retention).²²

Hypertension and cardiovascular risk with the use of NSAIDs are more pronounced in elderly people and patients with preexisting hypertension. Among the NSAIDs, indomethacin, fenoprofen, and phenylbutazone are most strongly associated, while sulindac, aspirin, and ibuprofen are the least likely to be associated with this effect.²²

ADJUVANT MEDICATIONS

Pharmacologic treatment of chronic pain is notoriously difficult, and there are very few well-designed trials addressing this subject. Numerous medications including membrane stabilizers, tricyclic antidepressants (TCAs), selective serotonin release inhibitors, selective serotonin and norepinephrine release inhibitors, alpha-blockers, alpha-2 agonists, and calcium channel blockers have been used to treat chronic pain. The efficacy of such agents for chronic shoulder pain still needs to be determined.

Antiepileptics

Anticonvulsants are commonly used to treat chronic pain. They have been used for many years, since the 1960s, in the treatment of neuropathic pain. The older agents include phenytoin, carbamazepine, and valproic acid. The newer agents include gabapentin, pregabalin, lamotrigine, topiramate, zonisamide, and oxcarbazepine. The newer agents are more often used in the management of chronic pain than the older agents, because of lack of organ toxicity and lesser need to monitor therapy with blood tests⁴⁵ (Table 37-2).

Possible mechanisms of actions are enhanced gammaaminobutyric acid inhibition (valproate, clonazepam) or a stabilizing effect on neuronal cell membranes. A third possibility is action via NMDA receptor sites. By preventing bursts of action potentials, these drugs can eliminate the severe lancinating pain of trigeminal neuralgia and other neuropathic syndromes. The most common adverse effects are impaired mental and motor function, which may limit clinical use, particularly in the elderly.

Drugs with Multiple Mechanisms of Actions

FELBAMATE

Felbamate is a dicarbamate that has Na⁺ channel-blocking action, inhibits NMDA-evoked potential, and enhances GABA-evoked responses in hippocampal neurons. Clinical experience with felbamate in neuropathic pain is limited to a few case reports.⁷⁹

Given its potential for fatal toxicity of the bone marrow and the liver, the use of felbamate is restricted to some patients with refractory epilepsy. Its use in treatment of pain conditions is not warranted given the existence of many other alternatives.⁷⁹

GABAPENTIN

Of the new generation of antiepileptic drugs used for the treatment of neuropathic pain, gabapentin is perhaps the best agent studied so far. Gabapentin has an effect on alpha-2-delta types of calcium channels and acts as an antagonist of NMDA receptors. It has no direct GABAergic action and it does not affect GABA uptake or metabolism.⁷⁹

Randomized clinical trials have established the efficacy of gabapentin for relief of neuropathic pain in patients with
PHM and painful diabetic neuropathy. Gabapentin has been used in different pain syndromes, including trigeminal neuralgia and painful tonic spasms associated with multiple sclerosis, reflex sympathetic dystrophy, painful HIV-related peripheral neuropathy, and neuropathic cancer pain, postpoliomyelitis pain, central dysesthetic pain following spinal cord injury and erythromelalgia, and headache syndromes.⁴²,⁵²

TABLE 37-2 Antiepileptic Medications for the Treatment of Neuropathic Pain

• Drugs that block voltage-dependent sodium channels
	Carbamazepine
	Lamotrigine
	Phenytoin
	Oxcarbazepine
	Zonisamide
• Drugs that affect GABA metabolism
	Tiagabine
	Vigabatrin
• Drugs that affect calcium currents
	Ethosuximide
• Drugs with multiple mechanisms of actions
	Felbamate
	Gabapentin
	Levetiracetam
	Pregabalin
	Topiramate
	Valproate

Gabapentin is not metabolized in humans and is eliminated unchanged in the urine. Renal impairment will consequently decrease gabapentin elimination in a linear fashion with a good correlation with creatinine clearance. Gabapentin is removed by hemodialysis, so patients with renal failure should receive their maintenance dose of gabapentin after each treatment. The recommended starting dose in the treatment of neuropathic pain is 100 to 300 mg three times a day with titration if necessary to a maximum of 4 to 5 g as tolerated.⁶³

Analgesic, anxiolytic activity, relatively benign side effects, and minimal interactions of Gabapentin with other medications made it part of the multimodal analgesic regimens in some chronic pain management protocols. The most common side effects are somnolence (20%), dizziness (18%), ataxia (13%), and fatigue. The most serious adverse effect is convulsion (0.9%) and Steven-Johnson syndrome.⁶³ Patients who started on Gabapentin and some other newer anticonvulsants should be advised about the potential side effects, including increased suicidal risks in younger and older patients, patients with mood disorders, and patients with epilepsy or seizures.

PREGABALIN

Like gabapentin, pregabalin is a GABA analogue without proven agonistic effect on GABA receptors. Pregabalin does not appear to interact directly with Na⁺ channels, Ca²⁺ channels, or neurotransmitter responses (GABA, glutamate). A randomized controlled trial comparing three different doses of pregabalin (75, 300, and 600 mg/day orally) with placebo in 337 patients with diabetic neuropathy reported significant improvement in pain, sleep, and clinical and global impression of change scores for those who took 300 mg or more daily. Dizziness, somnolence, and peripheral edema were the most frequent adverse effects reported in this trial.⁷⁹ Pregabalin is frequently reported to be a part of the chronic pain management regimens.

TOPIRAMATE

Topiramate is a sulfamate-substituted derivative of D-fructose. It has several mechanisms of action: It blocks Na+ channelenhanced GABA activity, diminishes NMDA-mediated excitation, and blocks voltage-gated Ca²⁺ channels.⁸ Absorption is rapid with a bioavailability of about 80%. Metabolism is minimal, with 70% of a dose recovered unchanged in the urine. Elimination half-life is 18 to 23 hours.⁸

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