Pharmacotherapy of Disability

Todd P. Stitik

Robert Klecz

Brian D. Greenwald

Jiaxin J. Tran

ANALGESICS

The treatment of patients with pain is a major focus of many outpatient physiatric practices and is becoming even more important since the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) mandated pain as the fifth vital sign and Congress declared, as of January 1, 2001, that this is the Decade of Pain Control and Research. Physiatrists, therefore, should have familiarity with analgesics. This section is organized by grouping analgesic medications into classes and presenting them in simple alphabetical order (Table 65-1).

Overview of Pharmacologic Pain Management by the Physiatrist

Analgesics, particularly opioids, are being prescribed with greater frequency. Although pain can be classified as nociceptive or neuropathic, patients often present with mixed pain syndromes (1). The current optimal medication choice for neuropathic pain is unclear, even though a better understanding of the pathophysiology of neuropathic pain suggests that nonopioid agents, such as antidepressants and anticonvulsants, should be more efficacious than opioids or nonsteroidal antiinflammatory drugs (NSAIDs). Although clinical studies have not consistently demonstrated this, the many confounding factors involved in neuropathic pain states make study interpretation difficult (2).

ANALGESIC MEDICATIONS

Acetaminophen (Tylenol)

Relevance to Physiatry

Although acetaminophen is unsatisfactory as a single agent for patients requiring a powerful analgesic, it can be an effective primary or adjuvant medication for pain of mild to moderate intensity. In particular, it is considered to be the initial medication of choice for patients with osteoarthritis (OA) of the knee or hip who present without obvious signs of inflammation (3). Acetaminophen is also an alternative for some patients who experience gastrointestinal (GI) side effects with NSAIDs or celecoxib or who are at particular risk for renal toxicity associated with these agents. In addition, it is often used in combination with both opioid and nonopioid analgesics so as to decrease potential side effects (and thereby lessen interference with a rehabilitation program) by lowering the dose requirement of these other medications. In contrast to aspirin, it is often used in the pediatric rehabilitation setting due to the lack of an association with Reye’s syndrome.

Other potential uses for acetaminophen include headaches for which it can be used as a single agent or as a combination product with various narcotic analgesics as well as with butalbital and caffeine (i.e., Fioricet or Esgic). Acetaminophen is also the primary agent used to suppress fever in the inpatient rehabilitation setting.

Acetaminophen has negligible anti-inflammatory effects; it, therefore, cannot be substituted for anti-inflammatory agents when treating conditions such as rheumatoid arthritis.

Due to the potential for chronic acetaminophen overdosage leading to hepatotoxicity, patients must be counseled to not exceed dosage limitations when taking scheduled doses of acetaminophen. Patients also might not realize that over-thecounter (OTC) headache or cold/flu remedies often contain acetaminophen, and this can lead to inadvertent overdosage if they are also prescribed acetaminophen either in the form of Tylenol or in combination with analgesic medications.

Mechanism of Action and Pharmacokinetics

Despite clinical use of acetaminophen for over 120 years, its exact mechanism of action is still under investigation. Studies have confirmed a pathway whereby acetaminophen decreases production of prostaglandins by reducing prostaglandin H₂ synthase, a COX enzyme (4). This mechanism is notably distinct from NSAIDs, which physically block arachidonic acid from accessing COX enzymes active site, and is hypothesized to explain its diminished action at anti-inflammatory sites— where the activated immune system produces oxidizing agents that can reverse the reduction step.

Acetaminophen is rapidly and almost completely absorbed from the upper GI tract. It is then uniformly distributed throughout the body, partly bound by plasma proteins while the unbound portion exerts the therapeutic effects. Acetaminophen can penetrate both the placenta and bloodbrain barrier (5). It is swiftly metabolized in the liver and excreted by the kidneys at its recommended dosage.

Preparations and Dosing

The brand name Tylenol is frequently used interchangeably with the generic term acetaminophen. There are three major oral Tylenol preparations and they are shown in Table 65-2, which lists the dosing regimens that would provide a maximum dose of

4 g per 24 hours for those patients with normal hepatic function. For those with abnormal liver function, specific dosing information should be consulted prior to prescribing. Acetaminophen is also available in liquid and suppository preparations.

TABLE 65.1 Abbreviation Key

µ µg	mu microgram	LSD	lysergic acid diethylamide
ACE	angiotensin converting enzyme	MAOI(s)	monoamine oxidase inhibitor(s)
Ach	acetylcholine	mg(s)	milligram(s)
ADP	adenosine 5′ diphosphate	MI(s)	myocardial infarction(s)
AED	anti-epileptic drug	mL(s)	milliliter(s)
AF	atrial fibrillation	MT	multiple trauma
AF/flut	atrial fibrillation/flutter	Na+	sodium
APAP	acetaminophen	NE	norepinephrine
aPTT	activated partial thromboplastin time	NMDA	N-methyl-D-aspartate
ASA	aspirin	NNT	number needed to treat
AV node	atrioventricular node	NO-NSAIDs	Nitric oxide NSAIDs
bid	twice per day	NSAID(s)	nonsteroidal antiinflammatory drug(s)
BNZs	benzodiazepine(s)	OA	osteoarthritis
BP	blood pressure	OTC	over the counter
BUN	blood urea nitrogen	PO	by mouth
C_max	maximum concentration	PR	by rectum
Ca²⁺	calcium	PCP	phencyclidine
CaCB(s)	calcium channel blocker(s)	PE	pulmonary embolus
cAMP	3′,5′-cyclic adenosine monophosphate	PRN	as needed
CBC	complete blood count	PSVT	paroxysmal supraventricular tachycardia
CHF	congestive heart failure	PT	prothrombin time
CNS	central nervous system	PVC	premature ventricular contraction
COPD	chronic obstructive pulmonary disease	q	every
COX-II	cyclooxygenase-II	qd	once per day
CVA(s)	cerebrovascular accident(s)	qid	four times per day
DA	dopamine	Q wk	weekly
DP	dipyridamole	qod	every other day
DVT	deep venous thrombosis	RVR	rapid ventricular rate
ECG	electrocardiogram	SC	subcutaneous
ER	extended release	SCI	spinal cord injury
FDA	Food and Drug Administration	SL	sublingual
GERD	gastroesophageal reflux disease	SP	substance P
GI	gastrointestinal	SR	sustained release
H/S	at bedtime	SSRI(s)	selective serotonin reuptake inhibitor(s)
H2	histamine 2 receptor	SVT	supraventricular tachycardia
HDL	high-density lipoprotein	t_1/2	half-life
HIV	human immunodeficiency virus	TBI	traumatic brain injury
HTN	hypertension	TCA	tricyclic antidepressant
IM	intramuscular	TD	transdermal
INR	international normalized ratio	THA	total hip arthroplasty
IR	immediate release	tid	three times per day
IV	intravenous	TKA	total knee arthroplasty
JCAHO	Joint Commission on Accreditation of Healthcare Organizations	UFH	unfractionated heparin
LDL	low-density lipoprotein	V tach	ventricular tachycardia
LFTs	liver function tests	VLDL	very low-density lipoprotein
LMWH	low-molecular-weight heparin	WBCs	white blood cells
		VF	ventricular fibrillation

TABLE 65.2 Acetaminophen Preparations and Dosing for Adults

Tylenol Formulation	Acetaminophen Content	Dose (Maximum No. of Units)
Tylenol	325 mg	2 tabs q4h
Extra-strength Tylenol (ES-Tylenol)	500 mg	1 tab q3h or 2 tabs q6h
Tylenol arthritis	650 mg	2 tabs PO q8h

Relevant Side Effects and Drug Interactions

Acetaminophen has an extremely favorable side-effect profile when used within recommended dosage limitations (6). In those with normal hepatic function, the maximum daily recommended dose is 4 g/day. Precaution must be taken when it is used

Chronically in excess of the recommended dose
At more than approximately 2 g/day in patients who consume excessive amounts of alcohol (defined as more than three alcoholic drinks/day)
When taken as a single dose in excess of approximately 15 g. Fatalities in children due to accidental overdose were reported and OTC cold medicines in the United States were subsequently withdrawn for children under 2 years of age

Acetaminophen is metabolized into an intermediate, N-acetyl-benzoquinoneimine, that accumulates and may cause fatal hepatic necrosis (7). While the liver is the primary target of toxicity, chronic use of acetaminophen is also associated with renal failure (8). However, aside from cases of overdosage, acute nephrotoxic effects of acetaminophen are not common in the nonalcoholic population (9). The National Kidney Foundation, for this reason, has not amended its 1996 recommendation, making acetaminophen the drug of choice for analgesia in those with renal dysfunction (10).

Acetaminophen has a very favorable medication interaction profile. One potentially important exception, however, is warfarin as large acetaminophen doses can potentiate its effect by prolonging its half-life (11). Although this is believed to only be clinically significant in patients with a relatively high international normalized ratio (INR), the INR should be monitored in patients who are chronically taking acetaminophen while also on warfarin (12).

Antidepressants

Relevance to Physiatry

Because depression is a common consequence of illnesses and injuries, particularly if they are associated with functional loss, physiatrists should familiarize themselves with this medication class. Antidepressants are also used off-label to treat chronic nonmalignant pain syndromes and neuropathic pain (13, 14, 15). Not only do these agents treat the psychiatric component of chronic pain, but there is also evidence that they have independent analgesic effects (16,17). This chapter specifically addresses their use as analgesics.

Analgesic action of tricyclic antidepressant (TCA) medications for neuropathic pain has been extensively studied. Secondary-amine TCAs, nortriptyline and desipramine, are preferred to tertiary-amine TCAs (e.g., amitriptyline) because they have been shown to be equally effective and have fewer side effects (e.g., drowsiness) (18,19). Another TCA, doxepin, has shown some efficacy as a topical analgesic in managing chronic neuropathic pain (20).

A relatively newer class of antidepressants, selective serotonin reuptake inhibitors (SSRIs), is hypothesized to affect brain stem pain-modulating systems. Initial interest in using this class of medication for analgesia developed from a few promising case reports. However, a major systematic review concluded that there is very limited evidence that SSRIs are effective for management of neuropathic pain and more studies are warranted to draw definitive conclusions (21).

The serotonin-norepinephrine reuptake inhibitors (SNRIs) appear to be replacing SSRIs for neuropathic pain conditions. Venlafaxine (Effexor) and duloxetine (Cymbalta) are two SNRIs that have been studied in the treatment of pain due to postherpetic neuralgia and diabetic neuropathy. Duloxetine is currently approved for the treatment of diabetic neuropathy and venlafaxine was found to be as effective as imipramine in treatment of polyneuropathy (22,23). The popularity of SNRIs is also vested in their cost effectiveness and favorable side-effect profiles (24).

Other antidepressants that have been studied as analgesics include several that do not fall into any one particular chemical class, including trazodone and bupropion. Both of these have received somewhat less attention than the previous three classes of antidepressants but deserve further comment. Additional antidepressants in this category include mirtazapine and nefazodone. Although 5 years have passed since the last publication of this book, there is still only one case report in the peer-reviewed literature on mirtazapine and one basic science study on nefazodone in the setting of pain (25,26).

Trazodone is chemically unrelated to other antidepressants. It is rarely used for depression but is more commonly used as a hypnotic. Although there is some literature on it as an analgesic, a review of 59 randomized placebo-controlled trials of antidepressants as analgesics concluded that trazodone is not effective (27,28).

A placebo-controlled crossover trial confirmed that bupropion SR (sustained release, 150 to 300 mg daily) is effective and well tolerated in treating neuropathic pain (29). In contrast, it was found to be ineffective in treating non-neuropathic, chronic pain (30).

Mechanism of Action and Pharmacokinetics

TCAs increase aminergic transmission by inhibiting serotonin and norepinephrine (NE) reuptake to different
degrees at presynaptic nerve-ending terminals. For example, amitriptyline primarily inhibits serotonin reuptake whereas nortriptyline primarily inhibits NE reuptake. As a result, TCAs elevate pain thresholds in depressed and nondepressed patients. Analgesic doses are usually lower than those for primary depression. These agents are rapidly absorbed and bind avidly to plasma albumin. Metabolism first involves demethylation of tertiary amine to secondary amine, followed by hydroxylation, glucuronidation, and eventual renal excretion as inactive metabolites.

SSRIs selectively inhibit serotonin reuptake, with less of an effect on NE reuptake. This selectivity offers the advantage of a superior side-effect profile. End results include prolonged decreased production of serotonin and down-regulation of presynaptic and postsynaptic receptors. Paroxetine and sertraline are the most frequently used agents in this class and both have a chemical structure that is unique among the SSRIs as well as other antidepressants. As a whole, this class is well absorbed orally and then undergoes hepatic metabolism followed by renal excretion.

Bupropion’s mechanism of action is still uncertain but evidence suggests that it inhibits dopamine (DA) and NE reuptake; its effect is greater on the former than on the latter (31). Bupropion is hepatically metabolized into an active metabolite, 4-hydroxybupropion, which is excreted in the urine.

Trazodone possibly acts via serotonin reuptake inhibition and mixed serotonin agonist-antagonist effects. Although extensively metabolized in the liver, it has variable clearance that may lead to accumulation in some patients.

SNRIs act as NE reuptake inhibitors via α₂-adrenergic receptor blockade, serotonin reuptake inhibitors, and it binds to opioid receptors. This combined mechanism of action is somewhat similar to that of tramadol.

Preparations and Dosing

Dosage, side effects, and miscellaneous information about the most commonly used antidepressants for neuropathic and chronic pain are shown in Table 65-3.

Relevant Side Effects and Drug Interactions

Antidepressants in general are associated with a high incidence of sexual dysfunction that is often underreported in the product literature (32). Antidepressants that inhibit serotonin reuptake (e.g., SSRIs, SNRIs, trazodone) can cause “serotonin syndrome,” a hyperexcitable state of nervousness and insomnia.

TCA side effects are mainly anticholinergic and include dry mouth, blurred vision, tachycardia, constipation, aggravation of glaucoma, and urinary retention. They also cause antihistamine side effects such as sedation (therefore they are often prescribed as a single bedtime dose) and weight gain, related to an increased appetite for carbohydrates. TCAs also exert some quinidine-like cardiac effects, including atrioventricular (AV) conduction-time prolongation. Cognitive/behavioral alterations (e.g., agitation and memory impairment) appear at plasma TCA concentrations greater than 0.450 µg/mL (33); many TCAs, notably dothiepin, are fatal at concentrations greater than 1 µg/mL (34). Nortriptyline is generally considered superior to all TCAs because it is more potent and has a comparatively wide therapeutic range (35). Elderly and otherwise medically fragile patients should probably be started on nortriptyline rather than amitriptyline for the above reason and because side effects such as orthostatic hypotension and significant morning sedation, which can potentially interfere with rehabilitation efforts in this patient population, are relatively less common.

Since SSRIs have a relatively specific effect on serotonin reuptake without a significant effect on NE reuptake, their side-effect profile is generally superior to TCAs—especially with respect to cardiovascular issues—and they are much safer in cases of overdose. However, abrupt cessation of SSRI has been reported to cause SSRI discontinuation syndrome in some individuals. This syndrome includes dizziness, light- headedness, insomnia, fatigue, anxiety/agitation, nausea, headache, and sensory disturbance.

Bupropion has caused seizures and interference with cardiac conduction (ventricular arrhythmias and third-degree heart block). Idiosyncratic reactions including Stevens-Johnson syndrome, rhabdomyolysis, and severe hepatotoxicity have also been reported (36, 37, 38). There is evidence that bupropion is a cytochrome P450-2D6 (CYP2D6) inhibitor, but the clinical significance of this has yet to be established (39). The sustained-release (SR) bupropion is generally better tolerated than the immediate-release (IR) form.

Trazodone can be quite sedating and possesses other mild anticholinergic effects, but these are less generally than those from TCAs. It also exhibits a-adrenergic blocking properties, which can cause penile or clitoral priapism (40).

TCAs, SSRIs, and bupropion should not be used in patients taking monoamine oxidase inhibitors (MAOIs) and should be instituted cautiously in patients who have been off of MAOIs for at least 2 weeks. The only exception to this rule is nortriptyline, which can be safely combined with MAOIs or sertraline (an SSRI) (35). Concomitant use of other TCAs or any of SSRIs and MAOIs can cause hyperpyretic crises, seizures, and death. TCAs should also be used cautiously in patients taking other anticholinergic medications, neuroleptics, or central nervous system (CNS) depressants.

It is not known whether interactions occur between trazodone and MAOIs. Trazodone may increase serum digoxin and phenytoin levels and can cause either an increase or a decrease in prothrombin times (PTs) in patients on warfarin (41).

Venlafaxine’s most common side effects are from increased serotonin levels (irritability, insomnia, and sexual dysfunction) and also include constipation and nausea. There are several case reports of false-positive phencyclidine (PCP) results from ingesting high dosage of venlafaxine (42,43).

Corticosteroids

Relevance to Physiatry

Anti-inflammatory effects of corticosteroids are usually more important to the physiatrist than their mineralocorticoid and

androgenic/estrogenic effects. Physiatrists today are using corticosteroids for a range of injection procedures, including fluoroscopic-guided spinal injection procedures and peripheral joint injection procedures. They are also prescribing them in either short, tapering oral courses (e.g., Medrol Dosepak) for patients with radiculopathy and other localized musculoskeletal conditions; or chronically for systemic inflammatory diseases. Besides their oral and injectable forms, corticosteroids can additionally be delivered transdermally by iontophoresis or phonophoresis.

TABLE 65.3 Antidepressants Used in the Treatment of Neuropathic Pain^a

Generic Name		Dose (mg) Neuropathic Pain and (Depression)	Miscellaneous
[TCAs]
	Amitriptyline (Elavil/Saroten/Endep/Vanatrip)	10-100 @ H/S (150-300/d); begin @ 12.5-25 qH/S, and titrated as tolerated	Dry mouth and sedation very common Demethylated to nortriptyline
	Nortriptyline (Aventyl, Pamelor)	10-30 @ H/S (50-150/d)	First metabolite of amitriptyline; less side effects but not as potent
	Doxepin (Sinequan) topical	Topical application of 3.3% doxepin, 0.025% capsaicin, and 3.3% doxepin/0. 025% capsaicin produces analgesia of similar magnitude. The combination produces more rapid analgesia. Cream: 50 mg/g	Minor side effects
	Desipramine (Norpramin)	Start 25-100 PO once daily or in divided doses, increase to effective dose of 100-200 mg/d, MAX 300 mg/d (111 mg) used in studies	Cardiovascular: decreases of BP on rising from a sitting or a lying position, which may cause dizziness or fainting; increases of BP, rapid HR, pounding heart, altered heart rhythm Nervous system: sedation, confusion, nervousness, restlessness, sleep difficulties, numbness, tingling sensations, tremors, increased seizure tendency Autonomic: blurred vision, dry mouth, decreased sweating, difficulty urinating, constipation. Skin: rashes, sensitivity to sunlight Body as a whole: weight gain
	Imipramine (Tofranil)	Start 75 mg PO qhs. Increase to 150 mg PO qhs or in divided doses	Dry mouth, constipation, urinary retention, increased HR, sedation, irritability, dizziness, and decreased coordination
[SSRIs]
	Citalopram (Celexa)	20-40 qd (20-60 qd)	Relatively short half-life
	Fluoxetine (Prozac) (Prozac Weekly) (Sarafem)	20 qd (20-80 qd) 90 qw of Prozac Qwk 20-40 qd (20-60 qd) throughout menstrual cycle or 14 prior to menses	Very popular when first released; blamed in the press as a contributing factor to several high-profile murders
	Fluvoxamine (Luvox) Paroxetine (Paxil) (Pexeva) (Paxil CR) Sertraline (Zoloft)	100 qd (50-150 bid) 20-50 qd (20-50 qd) 25 mg PO qam max 62.5 mg/d 50-150 qd (50-200 qd)	Least studied of the SSRIs for pain Most selective of the SSRIs Tablets and oral concentrate; serotonin syndrome (hyperserotonergic state) with tramadol coadministration; also used for obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD)
[Other antidepressants]
	Bupropion SR (Wellbutrin SR)	150-300 qd (100-450 qd)	SR formulation have a better side-effect profile vs. IR preparation, esp. for sexual dysfunction and seizures; also used for smoking cessation (Zyban)
	Wellbutrin, Zyban, Buproban	Start 100 mg PO bid IR tab increase to tid
	Wellbutrin XL	150-300 qd (100-450 qd)
	Trazodone (Desyrel)	Start 50-150 mg/d PO in divided doses; @ H/S (200-300 bid), usual effective dose is 400-600 mg/d	Priapism that can be severe; less anticholinergic side effects vs. TCAs
	Mirtazapine (Remeron)	Initial dose 15 mg taken at bedtime. The dose may be increased in 15-mg increments every 1 or 2 wk as needed. Typical doses range between 15 and 45 mg. Dosages above 45 mg/d are not recommended	Side effects are sleepiness and nausea. Other common side effects are dizziness, increased appetite, and weight gain. Less common adverse effects include weakness and muscle aches, flu-like symptoms, low blood-cell counts, high cholesterol, back pain, chest pain, rapid heartbeats, dry mouth, constipation, water retention, difficulty sleeping, nightmares, abnormal thoughts, vision disturbances, ringing in the ears, abnormal taste in the mouth, tremor, confusion, upset stomach, and increased urination
	Remeron SolTab Nefazodone (Serzone)	50-, 100-, 150-, 200-, and 250-mg tablets. Initial dose of nefazodone is 100 mg taken by mouth twice daily. The dose may be increased in 100 or 200 mg increments once a week. Most commonly, final dosages range between 300 and 600 mg taken by mouth each day	Side effects: dizziness, difficulty sleeping, weakness, or agitation. Other common adverse effects are sleepiness, dry mouth, nausea, constipation, blurred vision, and confusion
[Antidepressants]SNRIs
	Venlafaxine (Effexor)	18.75-75 qd, divided bid or tid (37.5-75 divided bid or tid) 75 mg/d divided bid-tid MAX 375 mg/d 25, 37.5, 50, 75,100	An extended-release form (Effexor XR) is used for depression but not studied yet for pain
(Effexor XR)		(37.5-75 mg PO daily) MAX 225 mg/d Tabs-37.5, 75, 150
	Duloxetine (Cymbalta)	Total dose of 40 mg/d (given as 20 mg bid) to 60 mg/d (given either once a day or as 30 mg bid), no evidence that doses >60 mg/d confer any additional benefits	Side effects: impaired thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert
^aNote: Only those generally considered used for neuropathic pain are shown in the table.

Mechanism of Action and Pharmacokinetics

Corticosteroids bind to receptors within a target cell’s nucleus and cause an alteration in protein synthesis. These altered proteins then exert various mineralocorticoid, androgenic/estrogenic, and glucocorticosteroid effects. Corticosteroids are classified into one of these three categories depending upon their predominant effect. The focus of this section is the glucocorticosteroid class. At physiologic, but not pharmacologic, doses, glucocorticosteroid exerts anti-inflammatory and immunosuppressive effects via the following mechanisms:

Inhibition of prostaglandin and leukotriene synthesis (research suggests that this occurs by preventing arachidonic acid release from phospholipids; this contrasts with NSAIDs and COX-II inhibitors, both of which act at a later step in prostaglandin synthesis via inhibition of COX isoenzymes)
Inhibition of chemotactic factor release, leading to a diminished attraction of white blood cells (WBCs) to sites of inflammation
Decrease in circulating lymphocytes and monocytes
Reduction of vascular permeability by acting as vasoconstrictors or by inhibiting vasodilator release (e.g., histamines and kinins)
Stabilization of lysosomal membranes (occurs only at higher steroid doses)

Oral glucocorticoids are hepatically metabolized and renally excreted at a rate proportional to the particular agents water solubility. Hence, longer-acting glucocorticoids are less water soluble.

TABLE 65.4 Corticosteroid Preparations

Corticosteroid Generic (Trade) Name	Route	Equiv. Oral Dose (mg)	Relative Potencies: Antiinflammatory (Mineralocorticoid)	Onset	Duration
Betamethasone (Celestone)	PO/IM	0.6-0.75	20-30 (0)	Very fast	Long
Cortisone (Cortone)	PO	25	0.8 (2)	Short
Dexamethasone (Decadron, Decadron-LA)	PO/IM/IV	0.75	20-30 (0)	Fast, slow (LA)	Long
Hydrocortisone (Cortef, Solu-Cortef, Hydrocortone)	PO/IM/IV	20	1 (2)	Moderate (Cortef), fast (Solu-Cortef), slow (Hydrocortone)	Short
Methylprednisolone (Medrol, Medrol Dosepack, SoluMedrol)	PO/IM/IV	4	5 (0)	Slow	Intermediate
Prednisolone (Hydeltra)	PO/IM/IV	5	4 (1)	Moderate	Intermediate
Prednisone (Deltasone, Orasone)	PO	5	4 (1)	Fast	Intermediate
Triamcinolone (Aristocort, Kenacort, Kenalog)	PO/IM	4	5 (0)	Slow	Intermediate

Preparations and Dosing

The two most commonly used oral steroid preparations in many physiatric practices are prednisone and methylprednisolone. The latter is often prescribed as Medrol Dosepak of 4-mg tabs, which provides an initial 24 mg of Medrol (equivalent to 30 mg of prednisone) and tapers to 0 mg over 7 days. The popularity of Dosepak comes from the fact that patients’ instructions are conveniently printed on the package and it eliminates the need for patients to count out a different set of pills each day. Potential drawbacks to Medrol Dosepak are its higher expense compared to generic prednisone and a limited peak dose of merely 30-mg prednisone. Some physicians overcome the low peak dose by prescribing two Medrol Dosepak to be taken simultaneously.

TABLE 65.5 Corticosteroid Dosing Guidelines

•	Use these only after less toxic therapy has been ineffective or is not an alternative
•	Use the smallest corticosteroid amount that can control symptoms
•	Administer the corticosteroid locally rather than systemically whenever possible
•	Short-term use: Dosing qd (preferably in the a.m.) is more convenient and causes less adrenal suppression than qid dosing at quarter the total dose
•	Chronic use: Dosing qod is less likely to suppress adrenal function
•	Do not use the term steroids because of this word’s negative connotations. Although the terms cortisone and prednisone may also have negative connotations, explain that osteoporosis and truncal obesity only occur with chronic use
•	Forewarn patients that oral steroids typically cause a metallic taste
•	Adrenal suppression is likely for dose, potency, and duration as follows: Doses ≥100 mg hydrocortisone (25 mg prednisone) daily × 3 d Doses ≥30 mg hydrocortisone (7.5 mg prednisone) daily × 30 d
•	Wean patients off over weeks or months if taking steroids for more than several weeks
•	If unsure that patient has become adrenally suppressed, refer to endocrinologist for metyrapone or insulin-tolerance testing. Recovery of adrenal function is variable
•	For corticosteroid injections: Can decrease chance of corticosteroid arthropathy with limit of: 3/y; 20/lifetime Never inject directly into a tendon and avoid weight-bearing peritendinous injections (e.g., Achilles, patellar, posterior tibial) or risk tendon rupture

Corticosteroid selection can be made on the basis of equivalent cortisone dose, relative anti-inflammatory potency, relative mineralocorticoid potency, and onset and duration of action (44,45) (Table 65-4). For comparison, physiologic steroid doses are equivalent to 30 mg/day of hydrocortisone (7.5 mg/day of prednisone), whereas stress doses are equivalent to 300 mg/day of hydrocortisone (75 mg/day of prednisone). General dosing guidelines have also been developed (see Tables 65-4 and 65-5), but recent popularity of injectable
corticosteroids has raised concern that there is a lack of uniform guidelines for treating intra-articular joint conditions (46,47).

Relevant Side Effects and Drug Interactions

Most side effects occur after prolonged administration and many are simply manifestations of Cushing’s syndrome as shown in Table 65-6. Among these conditions, steroid myopathy and avascular necrosis are particularly pertinent to physiatry. The first, necrosis of the femoral or humeral head, is a rare idiosyncratic event that can occur after a short course of prednisone. Physiatrists who routinely perform electrodiagnostic studies are likely to be familiar with the need to “rule out steroid myopathy.”

Skin depigmentation and subcutaneous atrophy are dermatological complications that can occur with corticosteroid injections but can be minimized by adding local anesthetic or normal saline vehicle into the injectate and flushing the needle of residual corticosteroid with saline or local anesthetic injection before removal from the skin. Skin changes from chronic oral corticosteroids can lead to pressure ulcers and easy bruising.

Acceleration of corticosteroid metabolism occurs with medications that induce hepatic microsomal enzymes, especially phenobarbital, phenytoin, carbamazepine, and rifampin. In contrast, corticosteroid potency is increased by NSAIDs and exogenous estrogens (47). Clinicians should consider discontinuing NSAIDs or switching to a COX-II inhibitor if concomitant corticosteroid use is needed as corticosteroids are risk factors for NSAID-induced GI bleeding.

Lastly, although not a true side effect, a potential problem with corticosteroids is that they mask forewarning inflammation of various disorders. Thus, there is a tendency for patients to overvalue temporary relief and ignore the underlying disorder. An example is a patient who has received a subacromial steroid injection and soon resumes repetitive overhead activities that initially led to impingement.

TABLE 65.6 Corticosteroid Side Effects

Organ System	Side Effect
Central nervous system	Behavior and mood alteration
Cardiovascular	Fluid retention; HTN
Endocrine/metabolism	Adrenal atrophy; amenorrhea; appetite increase; glucose tolerance impairment; hypernatremia and hypokalemia; weight gain leading to “moon facies”
Gastrointestinal	Aggravation of peptic ulcer disease
Musculoskeletal	Avascular necrosis; bone demineralization; steroid myopathy
Skin	Acne, depigmentation, and subcutaneous atrophy with injection, fatty deposition leading to “buffalo hump”, hirsutism, skin thinning

Membrane-Stabilizing Medications: Antiarrhythmics

Relevance to Physiatry

There are three circumstances under which a physiatrist might prescribe antiarrhythmics: first, in the inpatient rehabilitation setting, for patient who needs ongoing treatment for existing cardiac conditions; second, for a patient with neuropathic pain who responds to off-label use of type I antiarrhythmics (i.e., mexiletine, tocainide, lidocaine, and phenytoin); third, for a patient with myotonia-associated pain from certain neuromuscular disorders. Intravenous (IV) lidocaine, as an analgesic agent, is not discussed in detail in this chapter because it is infrequently used other than as a predictive test for mexiletine treatment in highly specialized pain management clinics (48). In contrast, the low sensitivity of IV lidocaine infusion renders the test inappropriate for definitive diagnosis of neuropathic pain (49).

Literature pertaining to oral antiarrhythmics for neuropathic pain is still limited to mexiletine because other oral analogues (e.g., flecainide and tocainide) have some potentially lethal adverse effects (50). It is noteworthy that, prior to tocainide’s withdrawal from U.S. market over safety concerns, there were successful reports on using the agent as treatment for myotonic pain in paramyotonia congenita and Thomsen-Becker myotonia (51).

Earlier case reports and prospective studies suggested that mexiletine is efficacious and safe in various neuropathic pain states including pain from peripheral nerve damage, diabetic neuropathy, alcoholic neuropathy, phantom limb pain, multiple sclerosis complicated by painful dysesthesias, and thalamic pain syndrome (50,52, 53, 54, 55, 56, 57). A 2005 systematic review of local anesthetics found mexiletine (at a median dose of 600 mg/day) to be “superior to placebo in relieving neuropathic pain and… as effective as other analgesics used for this condition” (58). Critics, nonetheless, persist to this day because most studies were of relatively short duration and fewer than 400 patients have been studied altogether (59).

Mechanism of Action and Pharmacokinetics

Type I antiarrhythmics (e.g., lidocaine, mexiletine, and tocainide) block Na+ channels in nerve and muscle cell membranes with a subsequent reduction in the number of abnormal ectopic impulse generated by dysfunctional peripheral nerves. Lidocaine and oral analogues differ in that the latter have low first-pass metabolism, which enhances their oral bioavailability.

Preparations and Dosing

Mexiletine is available in 150-, 200-, and 250-mg caplets. Neuropathic pain doses are lower (150 to 300 mg tid) than those used for arrhythmias (200 to 400 mg tid). It can be initiated as a 150-mg-per-day regimen, titrated weekly.

Relevant Side Effects and Drug Interactions

Mexiletine’s potential side effects are acute in onset and can involve the GI, neurologic, and cardiovascular systems. One mexiletine study of experimentally induced pain found that
analgesic dosing caused side effects at an average of 993 mg/day, whereas another study found negligible side effects at doses up to 900 mg/day (60). GI side effects include nausea, anorexia, and gastric irritation in up to 40% of patients. Another 10% of patients experience neurologic side effects similar to those of other class I antiarrhythmics, including dizziness, visual disturbances, anxiety in patients with history of anxiety disorder, tremor, and altered coordination. Individuals with abnormal cardiac conduction are also at risk of mexiletine-induced exacerbation; mexiletine is absolutely contraindicated in second-and third-degree heart block uncontrolled by a pacemaker. Patients in fact should obtain an electrocardiogram (ECG) prior to starting this medication.

Mexilitene’s pharmacologic disposition is susceptible to multiple alterations. For example, opioid analgesics, atropine, and antacids slow its absorption while metoclopramide enhances it. Phenytoin, rifampin, and smoking increase its metabolism. Mexiletine, in turn, may significantly reduce the clearance of theophylline and caffeine (61).

Membrane-Stabilizing Medications: Anticonvulsants

Relevance to Physiatry

When anticonvulsants are used to treat neuropathic pain, they are generally referred to as membrane-stabilizing medications. Their initial use as antineuralgic drugs in the 1960s was derived merely from positive clinical observations. Current research efforts are dedicated to understanding this phenomenon. A popular theory now attributes similarities between neuropathic pain and epilepsy pathophysiology models to the efficacy of anticonvulsants in treating both conditions (62). As supportive evidence continues to accumulate, anticonvulsants have marked a new era in the treatment of pain.

Various anticonvulsants have yielded good results thus far and pregabalin is the latest addition to the list. Specific drugs will be discussed individually as there are some significant differences among them with respect to side effects and mechanisms of action (Tables 65-7 and 65-8).

Gabapentin (Neurontin)

Relevance to Physiatry

Gabapentin is still among the first-line treatments for neuropathic pain. It has been shown to be as effective as TCAs and carbamazepine and has a highly favorable side-effect profile and reputation for minimal drug interactions (63). Although evidence is lacking for its efficacy in acute pain states (64), there is now growing evidence supporting its efficacy in treating painful diabetic neuropathy (65, 66, 67, 68). It has also been investigated for spasticity reduction in spinal cord injury (SCI) patients (69,70).

Mechanism of Action and Pharmacokinetics

See Tables 65-7 and 65-8.

Gabapentin’s mechanism of action is still poorly understood. It was originally thought to inhibit gamma-aminobutyric acid (GABA) receptors because of its structural similarity to GABA, a major CNS excitatory neurotransmitter. While there is evidence suggesting that it does indeed interact with presynaptic GABA-B receptors to reduce glutamate release, other studies point to more possibilities. Specifically, gabapentin has been implicated as a calcium channel blocker (CaCB) and hippocampal CA1 neural enhancer. There is also evidence that it may raise the interneuron pool excitability threshold of polysynaptic reflexes (71).

Gabapentin is transported from the GI tract into the bloodstream by the amino acid transport system. It does not bind to plasma protein, is not metabolized, and is ultimately excreted by the kidneys at the rate of creatinine clearance.

Preparations and Dosing

The reported dosage that provides adequate relief from neuropathic pain ranges from 900 to 2,400 mg per day, divided tid. When initiating therapy, a 300-mg dose at bedtime on the first day, then bid dosing on the second day, and tid dosing thereafter can be used as a way of helping patients accommodate to its CNS depressive effects. A maximum of 3,600-mg daily dose has been well tolerated in a small number of patients for short duration.

Relevant Side Effects and Drug Interactions

CNS depression (e.g., somnolence, dizziness, ataxia, and fatigue) is the main side effect. Nystagmus has also been reported. Side effects are generally transient with resolution in 2 weeks. There have been only rare reports of adverse events (e.g., rash, leukopenia, increased blood urea nitrogen (BUN), thrombocytopenia, and nonlethal ECG abnormalities) that required its discontinuation. Given the rarity of serious adverse events, routine laboratory monitoring and monitoring of serum gabapentin levels are not indicated.

There are two documented drug interactions, but both are deemed to be clinically insignificant. Cimetidine minimally decreases renal gabapentin excretion, and Maalox reduces gabapentin’s bioavailability by 20%. This lack of significant drug interactions is expected given its pharmacokinetics profile.

Carbamazepine (Tegretol)

Relevance to Physiatry

Carbamazepine was the first anticonvulsant to be studied in neuropathic pain clinical trials. Results from these trials confirmed its indication in treating trigeminal neuralgia (Food and Drug Administration [FDA] approved), glossopharyngeal neuralgia, painful diabetic neuropathy, and postherpetic neuralgia. It has not been as extensively studied in other neuropathic conditions. Traditional belief is that carbamazepine is especially effective for neuropathic pain that is acute and lancinating, as is often found in postamputation neuroma. Its relative lack of CNS side effects compared to other anticonvulsants offers an obvious advantage with respect to functional activities. The unfortunate combination of potential hematologic toxicity, the need for periodic blood work, baseline and periodic eye examinations, and numerous medication interactions renders carbamazepine a less attractive choice.

TABLE 65.7 Anticonvulsant Efficacy and Pharmacokinetics in Neuropathic Pain

Efficacy	Medication	Specific Neuropathic Pain Uses	Pharmacokinetics
Efficacious
	Gabapentin (Neurontin)	Especially diabetic neuropathy and postherpetic neuralgia (FDA approved)	Not protein bound or metabolized; renal excretion
	Carbamazepine (Tegretol)	Trigeminal neuralgia (FDA-approved), glossopharyngeal neuralgia, painful diabetic neuropathy, and postherpetic neuralgia	Binds and prolongs inactivation of voltagedependent sodium channels. The number of action potentials is consequently decreased. Highly plasma proteinbound, variable t_1/2 as it induces its own metabolism
	Pregabalin (Lyrica)	FDA approved in treating diabetic neuropathy pain, postherpetic neuralgia pain. Used off-label for other neuropathic pain conditions. Mounting evidence it can manage pain due to fibromyalgia	Does not bind to plasma proteins and nearly the entire dose is excreted unchanged in the urine, with elimination following first-order kinetics
Unclear
	Clonazepam (Klonopin)	Some efficacy in trigeminal neuralgia	Good absorption; highly plasma protein-bound, lipid soluble, and hepatically metabolized
	Lamotrigine (Lamictal)	Primarily indicated in treatment for epilepsy and bipolar disorder. Provides minimal, if any, therapeutic effects in acute and chronic pain. Some efficacy in trigeminal neuralgia; peripheral neuropathy poststroke syndromes	Good oral absorption; hepatic conjugation; renal excretion
	Oxcarbazepine (Trileptal)	Efficacy in newly diagnosed and refractory trigeminal neuralgia and possible merit in areas of neuropathic pain and bipolar disorder other neuropathic pain conditions	Hepatically metabolized to its active metabolite; renal excretion
	Phenobarbital (Solfoton)	No clinical studies in humans in peer-reviewed literature	Moderate protein binding; hepatic metabolism; pH-dependent renal excretion
	Phenytoin (Dilantin)	Conflicting results in trigeminal neuralgia and diabetic neuropathy	Metabolism saturable at high plasma levels, thus large concentration increases from additional small doses
	Tiagabine (Gabitril)	Two small trials showed beneficial outcome in painful sensory neuropathy	Highly protein bound; at least 2 metabolic pathways
	Topiramate (Topamax)	Conflicting results in studies of neuropathic pain and diabetic neuropathy. Some evidence in refractory intercostal neuralgia, trigeminal neuralgia, and trigeminal autonomic cephalgias	Rapidly absorbed orally, a third of the drug is metabolized by the hepatic CYP450 system into inactive metabolites, remainder excreted renally unchanged
	Valproate (valproic acid, Depakene)	Efficacy in neuropathic cancer pain but not paraplegia central pain. Mixed results in neuropathic pain, postherpetic neuralgia, and polyneuropathy	A lipid-soluble compound, rapidly absorbed and becomes tightly protein bound. Metabolized in the liver through oxidation and glucuronidation pathways. Active metabolites and a small, unchanged portion are renally eliminated.
	Zonisamide (Zonegran)	Studies in neuropathic pain are lacking	Renally excreted intact and as a glucuronide metabolite

Mechanism of Action and Pharmacokinetics

See Tables 65-7 and 65-8.

Carbamazepine binds and prolongs inactivation of voltage-dependent sodium channels. The number of action potentials is consequently decreased.

Because of its high lipid solubility, it is slowly absorbed into the body following oral administration and becomes highly protein bound. It induces the hepatic CYP450 enzymes and this increases the metabolism of multiple medications— including its own.

TABLE 65.8 Proposed Mechanism of Action of Anticonvulsants in Neuropathic Pain

Proposed Mechanism	Medications
Na+ channel blocker	Carbamazepine; lamotrigine; oxcarbazepine; phenytoin; valproate; zonisamide
Ca⁺⁺ channel blocker	Gabapentin; oxcarbazepine; zonisamide
GABA receptor activity	Barbiturates; BNZs
GABA metabolism	Gabapentin; tiagabine; valproate
Glutamate receptor activity	Carbamazepine; lamotrigine; topiramate
Glutamate metabolism	Gabapentin

Preparations and Dosing

Carbamazepine is available in tablets, chewable tablets, extended-release capsules, syrup, suspensions, and rectal suppositories preparations. Although there are no dosing guidelines for trigeminal neuralgia, it is commonly used to treat this condition with 100 mg bid initially, and then the dose is gradually increased to a maximum of 400 mg tid. Given the potential for hematologic toxicity, the maintenance dose should be reduced to the minimum effective level. The extended-release form, Tegretol-XR, can be given bid to achieve the same total daily doses as described above.

Relevant Side Effects and Drug Interactions

Severe toxicity can occur with carbamazepine including leukopenia and thrombocytopenia, aplastic anemia and agranulocytosis (rare), hepatotoxicity, skin reactions (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis), and (72), to a lesser degree, renal dysfunction. Prior to initiating carbamazepine, a complete blood count (CBC), liver function tests (LFTs), BUN and urinalysis, reticulocyte count, and serum iron levels are recommended. CBC and LFTs should be reviewed periodically and, if toxicity is suspected, consideration should be given for medication discontinuation.

TABLE 65.9 Potential Drug-Drug Interactions with Carbamazepine

Interaction	Decreased Serum Level	Increased Serum Level
Medications whose serum levels are affected by carbamazepine	Acetaminophen, alprazolam, amitriptyline, bupropion,busprione, citalopram, clobazam, clonazepam, clozapine, cyclosporine, delavirdine, desipramine, diazepam, dicumarol, doxycycline, ethosuximide, felbamate, felodipine, glucocorticosteroids, haloperidol, itraconazole, lamotrigine, levothyroxine, lorazepam, methadone, midazolam, mirtazapine, nortriptyline, olanzapine oral and other hormonal contraceptives, oxcarbazepine, phenytoin, praziquantel, protease inhibitors, quetiapine, risperidone, theophylline, tiagabine, topiramate, tramadol, triazolam, trazodone, valproate, warfarin, ziprasidone, zonisamide	Clomipramine, phenytoin, primidone
Medications that affect serum carbamazepine levels	Cisplatin, doxorubicin HCL, felbamate, methsuximide phenobarbital, phenytoin, primidone, rifampin, theophylline	Acetazolamide, azole antifungals, CaCBs, cimetidine, clarithromycin, dalfopristin, danazol, delavirdine, diltiazem erythromycin, fluoxetine, fluvoxamine, grapefruit juice, isoniazid, itraconazole, ketoconazole, loratadine, nefazadone niacinamide, nicotinamide, protease inhibitors, propoxyphene, quinine, quinupristin, troleandomycin, valproate, verapamil, zileuton

Due to the pharmacokinetics described previously, carbamazepine interacts with many medications (Table 65-9). In addition, it should not be given to individuals with TCA hypersensitivity due to potential crossreactivity, nor should it be used within 2 weeks of an MAOI.

Clonazepam (Klonopin)

Relevance to Physiatry

This benzodiazepine (BNZ) has been used to provide relief in neuropathic pain states (especially in patients with trigeminal neuralgia who are either intolerant to or have failed carbamazepine, baclofen, or phenytoin) and movement disorders (e.g., sleep-related nocturnal myoclonus, restless legs syndrome, tar dive dyskinesia, phantom limb pain, and opioid-related myoclonic jerks).

Mechanism of Action and Pharmacokinetics

See Tables 65-7 and 65-8.

Clonazepam is avidly bound to plasma protein and is highly lipid soluble. It is acetylated into nonactive metabolites in the liver and is gradually excreted by the kidneys. Low level of metabolites is also excreted in breast milk. In spite of this, there have not been reports of adverse outcome in newborns; lactation is therefore not a contraindication (73).

Preparations and Dosing

Clonazepam is available as 0.5-mg, 1-mg, and 2-mg tablets. These tablets distinguish themselves with a unique K-shaped perforation in the middle of the pill. For movement disorders, clonazepam is begun at either 0.5 mg at bedtime or 0.5 mg tid, and it can be titrated up to 2 mg tid. A daily dose of 0.5 to 1.0 mg is recommended to treat trigeminal neuralgia (74).

Relevant Side Effects and Drug Interactions

Ataxia and personality changes can develop early in the treatment course but may subside with long-term use. At the other end of the spectrum, withdrawal often causes a flu-like syndrome, and abrupt discontinuation of a chronic, highdose regimen can even lead to seizures. Moreover, common to all BNZs, chronic clonazepam use can result in psychological addiction and physical tolerance. Caution should be exercised when clonazepam is given along with another CNS depressant.

Lamotrigine (Lamictal, Lamictal CD)

Relevance to Physiatry

Lamotrigine is primarily indicated in treatment for epilepsy and bipolar disorder. Multiple, well-designed clinical trials have investigated its efficacy in neuropathic pain, but a recent systematic review concluded that lamotrigine provides minimal, if any, therapeutic effects in acute and chronic pain (75). In addition, fatal skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

Oxcarbazepine (Trileptal)

Relevance to Physiatry

Oxcarbazepine is a structural analog of carbamazepine. It has been used in the treatment of epilepsy since 1990. There is convincing evidence of its efficacy in newly diagnosed and refractory trigeminal neuralgia (76). In addition, it has emerging merit in areas of neuropathic pain and bipolar disorder (77).

Mechanism of Action and Pharmacokinetics

See Tables 65-7 and 65-8.

Liver microsomes metabolize oxcarbazepine into an active metabolite, 10-monohydroxy metabolite (MHD), which exerts the desired pharmacologic effects. This process minimally induces hepatic CYP450 enzymes. MHD is excreted by the kidneys.

Preparations and Dosing

Oxcarbazepine is available as 150-, 300-, and 600-mg scored tablets; and as a 60 mg/mL suspension. Rapid titration (over 7 to 10 days) from the initial dose (ranging from 75 to 300 mg bid) to a maximum of 1,200 mg bid is recommended. Therapeutic range for trigeminal neuralgia extends from 600 to 1,800 mg per day.

Relevant Side Effects and Drug Interactions

Although a carbamazepine analogue, oxcarbazepine is not associated with serious hematologic toxicity. CNS and GI disturbances are instead reported; between 20% and 25% of patients discontinue oxcarbazepine due to its side effects.

The coadministration of felodipine with CaCBs and/or oral contraceptives should be avoided. The specific mechanism is undetermined, but verapamil (a CaCB) is known to decrease oxcarbazepine concentration by 20% and oxcarbazepine, in turn, decreases CaCB felodipine concentration by 30%. As for contraceptives, oxcarbazepine stimulates their metabolism and, in effect, diminishes their efficacy (78). Antiepileptic drug (AED) coadministration, a regular practice in the setting of epilepsy but not neuropathic pain, also warrants caution because CYP450 enzymes inducers (e.g., carbamazepine, phenobarbital, and phenytoin) decrease mean plasma oxcarbazepine concentrations by 40%.

Phenobarbital (Luminal, Solfoton)

There is limited evidence for the effectiveness of phenobarbital in pain management (79). As is true of all barbiturates, human neuropathic pain studies are lacking and sedative properties limit their usage. Phenobarbital thus has a very limited role in neuropathic pain management.

Phenytoin (Dilantin)

Relevance to Physiatry

Besides its well-known anticonvulsant use, phenytoin is also used off-label as a neuropathic pain agent. It was the first anticonvulsant used as an antinociceptive agent and was confirmed (via controlled clinical trials) to be effective in managing trigeminal neuralgia and diabetic neuropathy more than 20 years ago. Recent clinical trials have ironically shown conflicting evidence (80). In addition to this ambiguity, there is a significant potential for medication interactions. In contrast, phenytoin offers the advantage of relative low cost and once a day dosing.

Mechanism of Action and Pharmacokinetics

See Tables 65-7 and 65-8.

Oral absorption of phenytoin in the stomach is slow because it is weakly acidic. The drug is mainly bound to plasma proteins and it readily traverses the blood-brain barrier. Liver hydroxylates phenytoin into nonactive metabolites, which are excreted by the kidneys; this metabolic pathway is progressively saturated as the concentration of phenytoin increases.

Preparations and Dosing

Phenytoin is available as tablets, extended-release capsules, chewable tablets, injectable solution, and oral suspension. Neuropathic pain doses are often less than those used for seizures, but a specific therapeutic range has not yet been defined. Given the complex pharmacokinetics, it is important to monitor serum phenytoin levels because small increases in the dose can produce unexpectedly large increase in plasma concentrations.

TABLE 65.10 Potential Phenytoin Drug Interactions

Can interfere with phenytoin absorption	Antacids (calcium-containing), Moban brand of molindone HCI
Can raise phenytoin levels	Alcohol (acute intake), amiodarone, chloramphenicol, chlordiazepoxide, diazepam, dicumarol, disulfiram, estrogens, ethosuximide, H2-antagonists halothane, isoniazid, methylphenidate, phenothiazines, phenylbutazone, phenylbutazone, salicylates, succinimide, sulfonamides, tolbutamide, trazodone
Can decrease phenytoin levels	Alcohol (chronic abuse), carbamazepine, reserpine, sucralfate
Can raise or decrease phenytoin levels (or its level can be raised or decreased by phenytoin)	Phenobarbital, sodium valproate, valproic acid
Efficacy is impaired by phenytoin	Corticosteroids, coumarin anticoagulants, digitoxin, doxycycline, estrogens, furosemide, oral contraceptives, quinidine, rifampin, theophylline, vitamin D

Relevant Side Effects and Drug Interactions

Side effects can be classified into three different categories: dose-related toxic effects, true side effects, and idiosyncratic reactions:

Toxic effects generally occur between plasma levels of 20 and 40 µg/mL, but there is marked individual variation. The effects include sedation, ataxia, and nystagmus. Ingesting high doses over a prolonged period can result in painful peripheral neuropathy.
True side effects from long-term use include hirsutism, osteomalacia, and hypocalcemia (secondary to interference with vitamin D metabolism), megaloblastic anemia (secondary to interference with vitamin B₁₂ metabolism), and gingival hyperplasia (secondary to interference with fibroblastic activity).
Idiosyncratic reactions include blood dyscrasias and a rare clinical picture, which resembles malignant lymphoma.

Phenytoin should not be prescribed to pregnant women as there are conflicting reports on its teratogenic effects, including the fetal hydantoin syndrome. Cerebellar ataxia can occur at seizure management doses and may interfere with rehabilitation efforts.

Refer to Table 65-10 for drug interactions related to serum protein binding and hepatic metabolism.

Pregabalin (Lyrica)

Relevance to Physiatry

A second analogue of GABA, pregabalin, is FDA approved for use in treating diabetic neuropathy pain, postherpetic neuralgia pain, and epilepsy. It is also being used off label for other neuropathic pain conditions. Furthermore, there is mounting evidence that this potent “sibling” of gabapentin can help to manage pain due to fibromyalgia and symptoms of anxiety disorder (81, 82, 83).

Mechanism of Action and Pharmacokinetics

Based on its structure, pregabalin is expected to be a CaCB (84). However, it is also theorized to have other mechanisms of action, including modulating the release of various neurotransmitters (i.e., glutamate, noradrenaline, and substance P [SP]) (85) to produce its net inhibitory effect on neurons.

Pregabalin has an oral bioavailability of greater than 90%. Concomitant food intake reduces the absorption rate but the total amount absorbed remains constant. Pregabalin does not bind to plasma proteins and nearly the entire dose is excreted unchanged in the urine, with elimination following first-order kinetics.

Preparations and Dosing

Pregabalin is available as capsules in the following strengths: 25, 50, 75, 100, 150, 200, 225, and 300 mg. For the treatment of painful diabetic neuropathy, it is generally started at 50 mg tid for 1 week then increased to a maximum of 1,000 mg tid. Therapeutic level of pregabalin for postherpetic neuralgia can be achieved with an initial dose of 75 mg bid or 50 mg tid, and increased to 150 mg bid or 100 mg tid after 1 week; the maximum dose for this purpose is 600 mg/day.

Relevant Side Effects and Drug Interactions

Dizziness, somnolence, and dry mouth have been frequently reported (86). Complaints of headache, weight gain, edema, blurred vision, and difficulty with concentration are also sometimes reported. Pregabalin is classified as a schedule V controlled substance because it leads to euphoria in selected individuals (87). As is true for gabapentin, pregabalin has no known drug interactions.

Tiagabine (Gabitril)

Relevance to Physiatry

Tiagabine became available at the turn of the century. Although it demonstrated antihyperalgesic and antinociceptive activity for neuropathic pain in animal models, placebo-controlled trial data are lacking; there are only two small clinical trials to date documenting its beneficial outcome (88, 89, 90). New research also proposes that tiagabine is indicated for Stiffman syndrome, bruxism, and tonic spasms in multiple sclerosis; however, more studies are needed to draw definite conclusions (91, 92, 93).

Mechanism of Action and Pharmacokinetics

See Tables 65-7 and 65-8.

Tiagabine is well absorbed orally; concomitant consumption of food decreases the absorption rate but the fraction absorbed remains constant. It is highly bound to plasma proteins. Metabolism of tiagabine involves oxidation and glucuronidation. Both pathways produce inactive metabolites, which are excreted by the biliary system (major) and the kidneys (minor).

Preparations and Dosing

Tiagabine is available in multiple strength tablets (2, 4, 12, 16, and 20 mg). Its neuropathic pain dosing schedule has not been established. The two published clinical trials investigated its efficacy in the range from 4 to 24 mg daily. When used as an anticonvulsant, however, it should be initiated at 4 mg every day, then increased to 8 mg at the beginning of week 2, and increased by 4 to 8 mg at weekly intervals thereafter, until clinical response is achieved or up to 32 mg/day.

Relevant Side Effects and Drug Interactions

Side effects are mild. CNS and GI disturbances (e.g., tiredness, somnolence, nausea, and abdominal pain) are the primary reasons that participants withdraw from tiagabine-related clinical trials. Tiagabine is also free of significant drug interactions.

Topiramate (Topamax)

Relevance to Physiatry

Structurally derived from D-fructose, topiramate is FDA approved for seizure management and migraine prophylaxis, but is also used off-label for neuropathic pain and myoclonic jerks (94). Though several small studies support its efficacy in neuropathic pain, including diabetic neuropathy, larger studies have been disappointing (95,96). Minor studies also found that topiramate provides pain relief in refractory intercostal neuralgia, trigeminal neuralgia, and trigeminal autonomic cephalgias; these findings will likely invite additional future research (97,98). Other possible indications of less physiatric relevance include obesity and bipolar disorder (99).

Mechanism of Action and Pharmacokinetics

See Tables 65-7 and 65-8.

Topiramate is rapidly absorbed into the body and does not bind well to plasma proteins (<20%). Only a third of the drug is metabolized by the hepatic CYP450 system into inactive metabolites. The remainder is excreted unchanged in the urine.

Preparations and Dosing

Topiramate is available as tablets (25, 50, 100, and 200 mg) and sprinkle capsules (15 and 25 mg). Its recommended daily dose as an adjunctive therapy for seizure prophylaxis is 200 mg bid and gradual titration from an initial daily dose of 25 mg over 8 weeks can reduce adverse cognitive effects. There are no dosing guidelines in neuropathic pain, but topiramate has been used between 200 and 400 mg per day.

Relevant Side Effects and Drug Interactions

Topiramate causes two general CNS-related side effects: delayed psychomotor actions (e.g., difficulty concentrating and sluggish speech) and somnolence. Weight loss (secondary to appetite suppression) and paresthesia can develop with chronic intake. The reversible effects discussed above are generally more common at seizure prophylaxis doses (100). Occasional cases of acute myopia and angle closure glaucoma have recently associated with topiramate use as well (101). Last but not least, animal models suggest that it may be teratogenic.

Topiramate is a carbonic anhydrase inhibitor; concomitant use with another carbonic anhydrase inhibitor should be avoided to prevent increased risk of renal stone formation. It also has a mild inductive effect on hepatic CYP450 enzymes and can hence increase metabolism of digoxin and oral contraceptive.

Valproate (Valproic Acid, Depakene)

Relevance to Physiatry

Valproate has been used as a third-line agent for epilepsy and migraine prophylaxis. It is more recently being studied for use in neuropathic pain, postherpetic neuralgia, and polyneuropathy (102, 103, 104, 105, 106). Similar to several other anticonvulsants though, evidence of its efficacy is weak. Previously, it was the subject of a small randomized clinical trial in paraplegic central pain and was not effective (107). It has yield variable results in experimentally induced central pain (108).

Mechanism of Action and Pharmacokinetics

See Tables 65-7 and 65-8.

Valproate, a lipid-soluble compound, is rapidly absorbed and becomes tightly protein bound. It is then metabolized in the liver through oxidation and glucuronidation pathways. Active metabolites and a small, unchanged portion are then renally eliminated.

Preparations and Dosing

Valproate is widely available in the following forms: caplet, sprinkle capsule, delayed-release tablet, extended-release tablet, syrup, and parenteral preparation. It is often initiated at 250 mg/day and is then titrated to a maximum dose of 1,000 mg bid.

Side Effects and Drug Interactions

Nausea, tremors, drowsiness, and weight gain are commonly encountered in the clinical setting. More serious complications include hepatotoxicity among the children population, pancreatitis, and prolonged bleeding time. Frequent monitoring of the previous parameters is recommended. Rare instances of valproate-induced encephalopathy are presumed to be caused by inhibition of ammonia metabolism (109). However, there are recent reports of encephalopathy in the absence of hyperammonia (110).

Valproate is an inhibitor of the oxidation and glucuronidation pathways; it inhibits the metabolism of phenytoin,
carbamazepine, and lamotrigine. It also decreases the clearance of amitriptyline and nortriptyline.

Zonisamide (Zonegran)

Relevance to Physiatry

Zonisamide is FDA approved as an adjunctive therapy in partial seizures. A small, randomized clinical trial in 2005 concluded that it produces statistically insignificant effects when used in diabetic neuropathy (111). There has been renewed interest lately and at least one ongoing research dedicated zonisamide’s analgesic mechanism in animal models (112).

Mechanism of Action and Pharmacokinetics

See Tables 65-7 and 65-8.

Preparations and Dosing

Zonisamide (100 mg) capsules are given daily for the first 2 weeks, after which the dose may be increased to 200 mg/day for at least 2 weeks. It can be increased to 300 and 400 mg per day, with the dose stable for at least 2 weeks to achieve steady state at each level. Evidence from controlled trials as an anticonvulsant suggests that 100 to 600 mg per day doses are effective, but there is no suggestion of increasing efficacy above 400 mg/day.

Relevant Side Effects and Drug Interactions

Zonisamide is contraindicated in sulfonamide allergy. Rare cases of aplastic anemia and agranulocytosis have been reported. It can also cause adverse psychiatric CNS events (depression and psychosis), psychomotor slowing (concentration difficulties and speech/language problems, especially word-finding difficulties), and somnolence and fatigue. Concomitant phenytoin or carbamazepine use increases zonisamide clearance.

LOCAL ANESTHETICS—INJECTABLE ANESTHETICS

Relevance to Physiatry

In the outpatient physiatric setting, injectable and sometimes topical anesthetics are frequently used to provide local anesthesia for a variety of procedures and as a diagnostic tool during intra-articular, soft tissue, and nerve block procedures. They can also be combined with corticosteroids in intra-articular and soft tissue injections to attain immediate pain relief. Injectable anesthetic can also be found as a component of proliferant solutions used in prolotherapy.

Local anesthetics are classified as esters (e.g., procaine) or amides (e.g., bupivacaine and lidocaine) based upon their chemical structure. Amide anesthetics are preferred over ester anesthetics because the latter are associated with a higher incidence of allergic reactions. Cross-sensitivity between the two classes does not occur (113). The amide class is further subdivided according to each drug’s duration of action. Lidocaine, a short-acting injectable anesthetic, is commonly used in percutaneous infiltration anesthesia. Long-acting injectable anesthetics (e.g., bupivacaine) are often reserved for procedures in which a longer degree of postprocedure pain relief is desirable. For example, after a positive lidocaine diagnostic shoulder impingement test, bupivacaine can be added to the corticosteroid to provide prolonged pain relief while corticosteroid gradually takes effect. This section will examine the amide anesthetics in greater detail.

Bupivacaine (Marcaine, Sensorcaine)

Bupivacaine has been widely used for half a century now. Two comparable variants, levobupivacaine and ropivacaine, were subsequently introduced to circumvent the drawbacks of bupivacaine-related side effects, but bupivacaine remains a viable, inexpensive choice (114). Though spinal anesthesia for surgical procedures is considered to be the best indication for bupivacaine, a blend of bupivacaine and corticosteroid can also be injected as part of intra-articular, soft tissue, and some spinal injection procedures to provide long-term relief; candidates for this procedure are typically individuals who responded to prior lidocaine injection (115). Bupivacaine is also used as part of comparative local anesthetic medial branch blocks as a precursor to possible radiofrequency ablation, as is discussed in Chapter 68.

Lidocaine (Xylocaine)

Lidocaine has been used as an anesthetic for over half a century. It has long replaced the first synthetic anesthetic, procaine, as the short-acting injectable anesthetic of choice because of its favorable side-effect profile. Lidocaine is regularly used in outpatient offices for procedures such as abscess drainage and laceration repair, but indications most relevant to physiatry include regional anesthesia for musculoskeletal procedures and nerve blocks.

Mechanism of Action and Pharmacokinetics

All amide anesthetics are speculated to be sodium channel blockers. They selectively inhibit tetrodotoxin-resistant sodium channels on dorsal root ganglia. These axonal structures are involved in generating nociceptive and temperature sensation. Local anesthetics cause a differential neural block— that is, sensory block with minimal loss of motor function (116,117).

Many factors influence an injectable anesthetic’s activity including lipid solubility, level of ionization, molecular size, and vasodilation capacity that are proportional to its potency, onset, and duration of action. Amides undergo extensive hepatic metabolization to become active metabolites—whereas esters are hydrolyzed by plasma enzymes to para-aminobenzoic acid (a potential allergen). Serum levels peak between 5 and 25 minutes postinjection, depending on route of administration and rate of renal excretion.

Preparations and Dosing

Table 65-11 summarizes the dosing guidelines for using lidocaine and bupivacaine in percutaneous infiltration anesthesia.
There are more concentrated preparations available (e.g., a 2% lidocaine solution) for use in procedures where minimal injectable volume is desirable, for example, digital nerve blocks and acromioclavicular joint injections.

TABLE 65.11 Commonly Used Local Anesthetics

Generic (Trade) Name	Applicable Preparations and Concentrations	Onset of Action (Duration)	Usual Dosage (mL): Bursal Injection (A); (IP); (Ish); (SA); (T)^a	Usual Dosage (mL): Joint Injection Small (Large)	Dosage: Percutaneous Infiltration (Maximum Amount)
Bupivacaine (Marcaine, Sensorcaine)	0.25%, 0.5%, and 0.75%	5 min (2-4 h)	(A) 2½-4½; (IP) 4-4½ (Ish) 2½-4; (SA) 4-6; (T) 4½-9	1-2 mL (2-4 mL)	Up to 70 mL
Lidocaine (Xylocaine)	0.5%, 1%, 1.5%, and 2%	½-1 min (½ h)	(A) 2½-4½; (IP) 4-4½ (Ish) 2½-4; (SA) 4-6; (T) 4½-9	1-2 (2-4 mL)	Up to 60 mL
Ropivacaine (Naropin)	0.5%, 0.75, and 1%	5 min (2-4 h)	Not yet described	Not yet described	Up to 100 mL
^a(A), anserine bursa; (IP), iliopectineal bursa; (Ish), ischial bursa; (SA), subacromial bursa; (T), trochanteric bursa.

The smallest effective should always be used. Dosages should be adjusted for factors such as a patient’s age and general health, because children, the elderly, debilitated, and acutely ill patients are at greater risk for anesthetic toxicity; individuals with hepatic dysfunction or reduced hepatic blood flow (e.g., those taking β-blockers or those with congestive heart failure [CHF]) are at risk as well. Anesthetic doses should also be adjusted according to the systemic absorption rate at the site of injection. Injection into the intercostal and epidural regions warrants lower doses because these areas are highly vascular and hence produce a large increase in the serum concentration. Subcutaneous tissues, in contrast, have low perfusion and require higher doses.

Other Medications Sometimes Used in Conjunction with Local Anesthetics

Epinephrine

Epinephrine counteracts the anesthetic’s vasodilation property and therefore slows systemic absorption rate at the site of injection. Coadministration of this agent with anesthetics can potentiate and prolong analgesic effects, as the effective dose is maintained longer. Epinephrine is also used to dilute highdose preparations to prevent anesthetics-associated systemic side effects. Concentrations between 2 and 10 µg/mL (i.e., ratio from 1:500,000 and 1:100,000) are generally used.

Despite its benefits, epinephrine may expose patients to additional side effects such as wound infection, tachycardia, and hypertension (HTN). It is generally believed that tissue ischemia can occur when the mixture is injected into body regions, the digits in particular, that have compromised or limited blood supply. The other concern is that epinephrine solutions contain sodium metabisulfite, which can cause an allergic reaction in certain individuals (118).

7.5% Sodium Bicarbonate

Lidocaine leaves a memorable burning sensation upon intradermal and subcutaneous injection because lidocaine solutions are acidic in part due to the preservative contained in multidose bottles. The addition of epinephrine worsens the sting by further decreasing the pH. This unpleasant feeling can be minimized by buffering a lidocaine solution with 7.5% sodium bicarbonate at a 9:1 ratio (e.g., 2 mL sodium bicarbonate added to 20 mL of 1% lidocaine) (119,120). The mixture should be within 24 hours to avoid risk of contamination due to the unclear effect upon the preservative when the solution has been buffered.

Relevant Side Effects and Drug Interactions

Amide anesthetics have a wide therapeutic index. Although toxicity can occur and it is dose related, when used alone, lidocaine and bupivacaine have maximal recommended doses of 5 and 2 mg/kg, respectively (121,122). Spinal injections carry higher likelihood of significant toxicity from possible inadvertent intrathecal administration. Toxicity manifestation can be divided into two categories: local and systemic. Local toxicity encompasses a variety of irreversible neurovascular changes (e.g., paresthesia). Systemic toxicity, albeit uncommon, can affect the CNS followed by the cardiovascular system (114). The patient may initially complaint of drowsiness, tremors, and altered special senses; but, as serum level of the offending agent increases, arrhythmia, seizure, and respiratory/cardiac arrest can develop (123). Lipid infusion can reportedly treat latephase systemic toxicity (124).

Because local anesthetics are CNS depressants, they should not be combined with another CNS depressant. Anesthetics can enhance the action of neuromuscular-blocking agents. Preparations containing epinephrine should not be given concomitantly with MAOIs or TCAs due to risk for severe HTN.

LOCAL ANESTHETICS—TOPICAL ANESTHETICS

In addition to the injectable preparations, local anesthetics are available as a cream and as a transdermal (TD) patch that are sometimes employed for preprocedural soft tissue anesthesia. Topical lidocaine patch has also become a recommended first-line treatment for postherpetic neuralgia and is becoming increasingly used off-label for various neuropathic and musculoskeletal pain conditions (125,126).

Eutectic Mixture of Local Anesthetics

Eutectic mixture of local anesthetics (EMLA) cream is an emulsion composed of 2.5% prilocaine and 2.5% lidocaine droplets. This topical compound has a lasting anesthetic effect for up to 4 hours (127). It can be applied to intact skin an hour prior to painful outpatient procedures. Numerous studies confirmed its efficacy over placebo cream, ethyl chloride, subcutaneous lidocaine, and iontophoresis (128). Although EMLA was deemed less effective than intradermal lidocaine, it is nonetheless preferred by patients (129).

Lidocaine Cream and Patch

Lidocaine cream (LMX) is regarded as an equivalent of EMLA but with faster onset of action (i.e., half an hour vs. 1 hour) (130). The patch form, with a dual mechanism of nociceptive sensation blockade and a mechanical barrier from friction against injured skin, is FDA approved for treatment of postherpetic neuralgia pain. There is also new evidence that lidocaine patches are effective for other neuropathic pain, low back pain, and OA of the knee (125,131,132). Two small, uncontrolled studies reported significant pain relief in reflex sympathetic dystrophy (RSD)/complex regional pain syndrome, stump neuroma pain, intercostal neuralgia, post-thoracotomy pain, and meralgia paresthetica as well (133,134).

The branded lidocaine patch, Lidoderm, contains 700 mg of 5% lidocaine. The recommended guideline to treat postherpetic neuralgia is to apply a maximum of three simultaneous patches on intact skin for 12 hours a day. Clothing may be worn over the application area. Weaker preparations of both the cream and patch can be found OTC.

LET

Both LET solution and gel are formulated with 4% lidocaine, 0.1% epinephrine, and 0.5% tetracaine. The gel has obvious advantages over the liquid form and is widely used half an hour before suturing uncomplicated facial and scalp lacerations (135). LET can also ameliorate pain from infiltrative anesthesia. Doses between 1 and 3 mL are effective in the aforementioned procedures. LET is not effective when used to anesthetize large wounds on the trunk or extremities at recommended doses.

LT Peel

A 7% lidocaine and 7% tetracaine cream dries within half an hour of application and is then peeled off. There is evidence that it is superior to EMLA in adults undergoing cutaneous procedures (136).

Relevant Side Effects and Drug Interactions

Topical agents are associated with potential side effects that are similar to their injectable counterparts except that the TD mode of delivery has a predilection to cause local skin irritation. This generally consists of mild redness and irritation at the application site. Importantly, these local reactions are usually not due to anesthetic allergy. Overall, topical anesthetics are safe. No serious adverse events have been observed in more than 120,000 patch hours in patients who used the patch for up to 8.7 years (137,138).

However, topical anesthetics should be used cautiously in patients who are taking class I antiarrhythmics (e.g., tocainide and mexiletine) as the toxic effects of both drugs are potentially synergistic.

MUSCLE RELAXANTS

Relevance to Physiatry

Unlike antispasticity agents, muscle relaxants are not indicated for true skeletal muscle spasticity. They are instead intended for short-term use in musculoskeletal conditions where muscle “tightness” is one of the primary pain generators. A recent meta-analysis supports this indication and showed that muscle relaxants provided modest short-term pain relief in the treatment for patients with back pain (139). Although there are no published studies comparing the relative efficacy of acetaminophen, NSAIDs and muscle relaxants appear to offer some benefits in patients with nonspecific back pain.

Muscle relaxants act by decreasing muscle excitability and thus diminishing tension-induced pain. Unlike antispasticity agents, muscle relaxants offer the advantage of not compromising muscle strength. Unfortunately, sedation limits their application and sometimes obliges physicians to prescribe them for bedtime use only. Cyclobenzaprine, methocarbamol, and carisoprodol are some of the most commonly prescribed muscle relaxants.

Mechanism of Action and Pharmacokinetics

Muscle relaxants are a unique group of medications as they have different mechanisms and pharmacokinetics (Table 65-12). The only common denominator among them is that they all act in some fashion on the CNS, rather than at the muscle fibers level, to interrupt nociceptive signals.

Preparations, Dosing, Relevant Side Effects, and Drug Interactions

See Table 65-12.

TABLE 65.12 Muscle Relaxants

Drug Name	Structural Analog	Dose (mg)	Other Properties and Side Effects
[Single agents]			Sedation often occurs from muscle relaxants
Carisoprodol (Soma)	Meprobamate (Equanil) Miltown	350 PO tid-qid	? mechanism but centrally acting; sedation; first dose idiosyncratic reactions; contraindicated in acute intermittent porphyria; addictive
Cyclobenzaprine (Flexeril)	Tricyclic antidepressants	5-10 PO tid initial; max: 60 PO	? mechanism but centrally acting; widely used; plasma levels vary widely; sedation and other anticholinergic side effects; avoid use in elderly
Diazepam (Valium, Diastat)	BNZs	2-10 PO/PR bid-qid 5-10 IV/IM q3-4h	Enhances GABA effect by binding to BNZ receptors; also used as an antispasticity agent
Metaxalone (Skelaxin)	None	800 PO tid-qid	? mechanism but centrally acting; drowsiness or CNS paradoxical excitation; hematologic toxicity, esp. hemolytic anemia or leukopenia; avoid if hepatic dysfunction
Methocarbamol (Robaxin)	Mephenesin (first muscle relaxant)	1,500 qid load × 48-72 h, then 1,000 PO/IM/IV qid	? mechanism but centrally acting; IM form inconvenient since should inject into each buttock rather than entire dose into one; lowers seizure threshold
Orphenadrine (Norflex)	Antihistamines	100 PO bid 60 IV/IM bid	? mechanism but centrally acting; sedation; reports of anaphylaxis in some asthmatics with IM/IV dosing
[Muscle relaxant/analgesic]
Norgesic	2 tabs PO tid-qid	Contents (mg): orphenadrine 25/ASA 385/caffeine 30
Norgesic forte	1 tab PO tid-qid	Contents (mg): orphenadrine 50/ASA 770/caffeine 60 addition of ASA and caffeine is based upon a presumed synergistic effect with the muscle relaxant and decreased sedation
Soma compound	1-2 tabs PO qid	Contents (mg): carisoprodol 200/ASA 325; addictive
Soma compound with codeine	1-2 tabs PO qid	Contents (mg): carisoprodol 200/ASA 325/codeine 16; potentially quite sedative; highly addictive
Robaxisal	2 tabs PO qid	Contents (mg): methocarbamol 400/ASA 325

N-METHYL-D-ASPARTATE-RECEPTOR ANTAGONISTS

Relevance to Physiatry

Tissue and nerve injury enhance the release of glutamate. This excitatory amino acid then binds to N-methyl-D-aspartate (NMDA) receptors in the spinal cord and, in turn, modulates pain sensation. NMDA receptor antagonists (also known as NMDA glutamatergic antagonists) act to inhibit this pathway. There is some preliminary evidence of success in using the oral form of these agents to treat neuropathic and cancer pain (140). Other potential applications include oral/epidural preemptive analgesia prior to surgery and coadministration with opioids to improve postoperative pain relief (141, 142, 143, 144). In addition to their independent analgesic effect, NMDA receptor antagonists are also synergists with opioids and can prevent tolerance to opioids (145).

Ketamine, dextromethorphan, memantine, and amantadine are examples from this category of medication. Two opioids (i.e., methadone and dextropropoxyphene) also possess NMDA antagonistic properties. These agents are discussed below. Other NMDA-receptor antagonists exist, but their use is significantly limited by side effects.

Several NMDA-receptor antagonist clinical trials have been discontinued due to psychomimetic adverse effects as well as ataxia and coordination impairment (146). This has led to the development of moderate affinity channel blockers (e.g., glycine B) and NR2B selective antagonists, which selectively block peripheral NMDA receptors (147). This new generation of drugs currently displays a better side-effect profile in animal models.

Ketamine (Ketalar)

Ketamine hydrochloride is primarily used in veterinary practices as a tranquilizer. It is approved for use in children and individuals with poor health as a general anesthetic (IV or intramuscular [IM]) and as a preoperative sedative (PO or parenteral). It causes a state of consciousness known as dissociative anesthesia. It does not have an official pain indication. There is no predetermined dosing guideline for its analgesic use, but a dose ranging from 6.5 to 13 mg/kg IM is administered for 12 to 25 minutes of surgical anesthesia. One study used 0.4 mg/kg IM doses to treat trigeminal neuralgia (148). There is also a case report on its successful use in complex regional pain syndrome (aka RDS) (149). Ketamine gel has been reported in a case series involving several different neuropathic pain conditions (150). Ketamine is classified as a schedule III controlled substance because its psychomimetic effects are comparable to snorting PCP.

Dextromethorphan

Dextromethorphan attenuates acute pain at doses of 30 to 90 mg, divided every 4 to 6 hours (5-10 mg/mL), and reduces analgesic requirements in postoperative patients without major side effects, but it has a suboptimal analgesic effect in treatment of chronic pain (151). There is some preclinical evidence of neuroprotective properties in the setting of perioperative brain injury, amyotrophic lateral sclerosis, and methotrexate neurotoxicity (152).

Amantadine

Amantadine is an antiviral agent with NMDA receptor antagonist properties. It is also used in Parkinson’s disease and traumatic brain injury (TBI). Amantadine was unsuccessful as an agent used to prevent postmastectomy pain neuropathic syndrome (153).

Memantine

Memantine is a moderate affinity NMDA-receptor antagonist. It is indicated for moderate Alzheimer’s disease. There is some evidence from case reports and small, controlled trials on its application in neuropathic pain (154,155).

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

Relevance to Physiatry

Oral NSAIDs are frequently used in the outpatient musculoskeletal medicine setting. At high doses, NSAIDs display both anti-inflammatory and analgesic properties, generally without causing sedation. All NSAIDs share the same mechanism of action and overall side-effect profile, but they also have individual characteristics that distinguish them from each other. No one NSAID has been demonstrated as being superior in terms of efficacy to others. Ideally, physiatrists should be familiar with at least one agent from each NSAID class. This will allow the physician to comfortably switch a patient off an agent from one NSAID class to an agent from a different class. This strategy can be emplaced if they do not respond and/or have side effects with use of an NSAID from one class.

Mechanism of Action and Pharmacokinetics

NSAIDs exert their primary effects by inhibiting the synthesis of prostaglandins and other related inflammatory compounds (e.g., thromboxanes and leukotrienes). The four primary properties of NSAIDs are analgesia for mild to moderate pain, anti-inflammatory effects, antipyresis, and reversible platelet inhibition. Anti-inflammatory effects also contribute to analgesia by preventing inflammatory-mediated sensitization of nociceptors.

Oral NSAIDs are absorbed in the upper GI tract. A large percent of the drug becomes bound to plasma protein while the unbound portion exerts its pharmacological effects. NSAIDs undergo hepatic metabolism and renal excretion. NSAIDs are available as short-acting and long-acting preparations with a half-life ranging from 30 to 50 hours at steady state. The consequence of accumulating long-acting agents (e.g., oxaprozin [Daypro] and piroxicam [Feldene]) in the human body is unclear, but to date, there are no reports of any additional significant adverse events beyond those typically seen with NSAIDs (156).

Preparations and Dosing

Table 65-13 shows a classification scheme of NSAIDs based on their chemical structure. Additional information on the individual classes is as follows:

Salicylates: These include aspirin and three nonacetylated salicylates. Compared to other NSAIDs, nonacetylated salicylates are less potent but cause less GI and platelet inhibition. It is unclear if any one particular nonacetylated salicylate in this category is more advantageous than the other two.
Propionic acids: This is the most popular NSAID class due to the OTC availability of ibuprofen and naproxen, and the direct marketing of the agent to the general public.
Acetic acids: This class is the most potent and most potentially toxic of all NSAIDs. It includes two drugs that can be administered via IM and parenteral routes (i.e., ketorolac and indomethacin) and two prodrugs (i.e., sulindac and nabumetone) are converted into their active counterparts.
Fenemates: Meclofenamate and mefenamic acid offers no advantage over other NSAIDs but can cause significant GI toxicity and dysmenorrhea pain, respectively.
Oxicams: Only piroxicam and meloxicam are currently available in the United States. Piroxicam has convenient once-daily dosing but is associated with severe dermatologic reactions such as exfoliative dermatitis and pemphigus vulgaris. The risk of adverse effects is lower for meloxicam. It was FDA approved for treatment of pain due to OA in 2004.

Relevant Side Effects and Drug Interactions

Individuals regularly using NSAIDs have up to five times the risk of developing GI complications (157). NSAIDs act directly to increase gastric acid secretion and indirectly to inhibit prostaglandin, which protects the GI tract lining. The direct effect varies among NSAIDs and only occurs with oral administration. The direct effect, on the contrary, remains constant regardless of the rate of administration. The elderly and patients with a history of peptic ulcer disease are particularly vulnerable to epigastric discomfort and ulceration. Recent studies indicate that piroxicam and ketorolac confer the highest GI risks at low dose and ibuprofen confers the least (158). The theory behind relative GI risks is that certain NSAIDs undergo extensive biliary excretion of their active metabolites and this, in turn, prolongs mucosal contact.

Simple strategies to decrease risk of GI complications include taking NSAIDs with meals and selecting enteric-coated

preparations. Prophylactic medications can be given if the patient has concomitant use of corticosteroids, warfarin, or a history of GI bleeding or peptic ulcer disease (Table 65-14). The classes of available medications include antacids, H₂ blockers, misoprostol, proton pump inhibitors (PPIs), and sucralfate (Table 65-14). Only misoprostol and PPIs are FDA approved for gastric ulcer prevention and H₂ blocker has not been shown to be effective in chronic NSAID users (159). Misoprostol is recommended over PPIs in patients without active Helicobacter pylori infection (160). Ideally, the selected prophylactic medication should be taken for the duration of NSAID therapy in order to provide maximum protection.

TABLE 65.13 Nonsteroidal Antiinflammatory Drugs (NSAIDs)

Drug Name	Dose (Oral in mg)	Other Properties and Side Effects
[Salicylates: acetylated]
Aspirin (Ecotrin, Anacin, Bayer)	325-650 q4-6h 81-325 daily cardioprotective	Used: especially for antipyretic and cardioprotective effects Other formulations available: 800 mg controlled release (prescription only) 975 mg enteric-coated (prescription only) suppositories: 120, 200, 300, 600 120, 200, 300, 600 600 mg combined with narcotics and muscle relaxants Side effects: allergy esp. if triad of nasal polyps, hay fever, asthma; GI toxicity but enteric-coated and buffered forms exist; tinnitus; Reye syndrome in children
[Salicylates: nonacetylated] Diflunisal (Dolobid)	500-1,000 load then 250-500 q8-12h	Relatively weak anti-inflammatory effect; lacks antipyretic activity
Salsalate (Disalcid, Salflex)	3,000 divided q8-12h	Relatively weak anti-inflammatory effect; no platelet inhibition
Salicylate combination (Trilisate)	1,500 bid	Relatively weak anti-inflammatory effect;? no ASA-allergic reactions; liquid preparation available (500 mg/5 mt)
[Propionic acids] Flurbiprofen (Ansaid) Ibuprofen (Motrin)	200-300 divided bid-qid 200-800 tid-qid	Available in ophthalmic solution (Ocufen); TO form available Inexpensive and widely used; frequent dosing; (OTC): Advil, Motrin IB; Nuprin, Rufen;TD form available
Ketoprofen (Ordis, Actron)	25-75 tid-qid	Accumulates if poor renal function
Naproxen (Naprosyn, Aleve) (EC-Naprosyn)	250-500 bid 375-500 bid	High-incidence GI side effects; advantage of enteric-coated form?, although expensive; (OTC): Aleve;
Naproxen-Na (Naprelan)	750-1,000 qd	Naprelan has Intestinal Protective Drug Absorption System (IPDAS);
(Anaprox)	275-550 bid	IR- and SR components
Oxaprozin (Daypro)	600 mg bid; 1,200 qd	qd or bid dosing
[Acetic acids]
Diclofenac (Cataflam, Voltaren) (Voltaren-XR)	50 bid- tid or 75 bid 100-200 qd	LFT monitoring if prolonged use; side effects in up to 20%; Arthrotec = diclofenac (50 or 75 mg) + misoprostol (200 µg)
Etodolac (Lodine) (Lodine XL)	200-400 bid-tid 400-1,200 qd	Gastric-sparing properties?
Indomethacin (Indocin) (Indocin-SR)	25-50 tid 75 qd	Most potent and toxic NSAID; PR preparation (Indotec); drug of choice in ankylosing spondylitis; indicated in other highly inflammatory conditions (e.g., acute gouty arthritis); Prevents heterotopic ossification s/p total hip replacement (THR) and used for myositis ossificans; dose- related CNS/hematologic side effects in up to 25-50%; GI toxicity
Ketorolac (Toradol)	15-30 IV/IM q6h or 10 q4-6h prn Lower doses if age >65 or renal dysfunction	FDA-approved only for 5 consecutive days; GI bleeding at higher doses; rapid analgesia with IM form—decrease dose for age ≥ 65, renal dysfunction, weight <110; IV preparation also available
Nabumetone (Relafen)	1,000 initially then 1,500-2,000 qd or divided bid	qd or bid dosing; nonacidic prodrug that undergoes hepatic biotransformation into active metabolite; preliminary studies suggest that unlike other NSAIDs, no evidence of enterohepatic recirculation of active metabolite— this may be an advantage
Sulindac (Clinoril)	150-200 bid	Prodrug; possibly renal-sparing because urinary excretion, primarily as biologically inactive forms, may be more GI toxic
Tolmetin (Tolectin)	200-600 tid	Frequent dosing; frequent GI toxicity
[Fenemates]
Meclofenamate Mefenamic acid (Ponstel)	50-100 tid-qid or 500 initially, then 250 mg q6h prn for ≤1 wk	Frequent dosing; diarrhea common Frequent dosing; used for dysmenorrheic pain
[Oxicams]
Piroxicam (Feldene) Meloxicam (Mobic)	20 qd 7.5 qd	qd dosing; accumulation in older adults possibly due to enterohepatic recirculation; dermatologic side effects and cases of serum sickness; PR form (Fexicam)

TABLE 65.14 Agents Used in NSAID-Induced Upper GI Toxicity Prophylaxis/Treatment

Medication	Dose Range	Gastric Ulcer (NSAID-Induced)	Duodenal Ulcer (NSAID-Induced)
Antacids	Standard	Not preventative	Not preventative
H₂ blockers	Standard	Not preventative	Preventative
	High dose	Preventative?	Preventative
Misoprostol (Cytotec)	Standard (200 µm qid)	Preventative (FDA approved)	Not preventative
	Low (200 µg bid-tid)	Preventative?	Not preventative
PPIs	Standard	Not preventative	Preventative?
Sucralfate (Carafate)	Standard (1 g qid)	Not preventative	Healing (if stop NSAIDs)

Less common GI side effects involve the esophagus, the nonduodenal portion of small bowel, colon, and liver. Esophageal side effects include esophagitis and benign esophageal strictures. Irritable bowel disease can be unmasked while the small bowel and colon can develop ulcers, erosions, and web-like strictures. NSAID enteropathy is not believed to occur via an acid mechanism and is therefore not prevented by antacids, H₂ blockers, or PPIs.

A large study in 2005 found that NSAIDs are the second main cause of drug-induced liver injury. Despite this, hepatotoxicity is rare except in individuals with a history of liver disease (161). Clinically, significant hepatic enzymes elevation does occur with certain NSAIDs, particularly diclofenac. When employing these NSAIDs, LFTs are recommended throughout the course of treatment. There is however currently no established specifically recommended schedule for liver function testing.

In large part due to studies of coxibs (see below), all NSAIDs now carry a black box warning that warns against potential cardiovascular and GI side effects. This is discussed in more detail in the coxib section below.

Individuals with preexisting kidney disease or comorbid medical conditions that impair renal blood flow (e.g., CHF and hypovolemia) are prone to acquire NSAID-induced renal toxicity. Acute renal failure, nephrotic syndrome, and interstitial nephritis are examples. It has been suggested but not proven that sulindac is somewhat renal sparing compared to other NSAIDs (162).

In light of all adverse effects discussed above, a significant amount of research has been dedicated to find an alternative to traditional NSAIDs. The effort yielded only one product, the COX-II inhibitor celecoxib, that is still available on the market and it will be further explored in the following section. More options are currently under investigation. They include dual COX and 5-lipooxygenase (5-LOX) inhibitors, synthetic lipoxins, nitric oxide-releasing NSAIDs, and hydrogen sulfide-releasing NSAIDs (163). The mechanism of action for these drugs involves either combining current NSAIDs with a moiety (i.e., nitric oxide and hydrogen sulfide) that releases gastroprotective mediators or targeting new processes of the inflammatory process.

True NSAID allergic reactions occur in 1% of the population and range from simple skin rashes and rhinitis to anaphylaxis. NSAIDs should not be used in patients allergic to aspirin.

CYCLOOXYGENASE-II INHIBITORS

Relevance to Physiatry

COX-II inhibitors (also known as coxibs) represent an alternative to NSAIDs. Coxibs in general were generally thought to confer the advantage of less GI toxicity compared to traditional NSAIDs. This appeal led to them becoming the most frequently prescribed new medication within the first year of being introduced in 1999. However, much has changed since the turn of the century. For example, the two other previously available coxibs, rofexcoxib (Vioxx) and valdecoxib (Bextra), were withdrawn from the market in 2004 due to an increased risk of cardiovascular toxicity as is discussed in more detail below. Celecoxib, the only currently available coxib at the time of this writing, is FDA approved for the treatment of pain associated with rheumatoid and OA, and for acute pain. Celecoxib is especially used in those individuals who require oral anti-inflammatories but are on concomitant anticoagulation therapy, are at high risk for GI side effects, or are to undergo certain injection procedures such as fluoroscopicguided spinal injection procedures or injection procedures into deep joint structures, where the risk of inadvertent bleeding makes the use of traditional NSAIDs potentially dangerous (164,165). There also continues to be interest in coxibs because COX-II expression is implicated in colon cancer and Alzheimer’s disease (165).

TABLE 65.15 Celecoxib: Recommended Doses for Approved Indications

Indication	Celecoxib (Celebrex): Capsules (mg) 50; 100; 200
Acute pain or primary dysmenorrhea	400 mg first dose, then another 200 mg on day 1 prn, then 200 mg bid prn thereafter
Ankylosing spondylitis	200 mg qd or 100 mg bid, then 400 mg qd if no effect after 6 wk
Osteoarthritis	200 mg qd or 100 mg bid
Familial adenomatous polyposis	400 mg bid
Rheumatoid arthritis—adults	100-200 mg bid
Rheumatoid arthritis—juvenile (≥2 years old)	≥10 kg to ≤25 kg: 50 mg bid; >25 kg: 100 mg bid

Mechanism of Action and Pharmacokinetics

Coxibs reduce prostaglandin synthesis by selectively inhibiting one isoform of cyclooxygenase enzyme over another—namely, COX-II over COX-I. This mechanism contrasts with that of NSAIDs, which inhibit COX-II and COX-I equally. COX-I is constitutively expressed in all human tissues including the GI tract. Only a low level of COX-II is constitutively expressed in brain, kidney, bone, and female reproductive tissues; however, the expression of COX-II can be induced at sites of inflammation. By sparing COX-I, coxibs achieve comparable anti-inflammatory and analgesic effects, with less adverse GI toxicity. The lack of effect on thromboxane synthesis explains the absence of antiplatelet effect.

Food has no significant effect on either peak plasma concentration or absorption at therapeutic doses. Higher doses (≥400 mg bid) should, however, be taken with food to improve absorption.

Preparations and Dosing

Celecoxib is available as 100-mg, 200-mg, and 400-mg capsules. It is currently only approved for the indications as shown in Table 65-15. The lowest effective dose should be used, especially in patients with HTN or CHF because coxibs may cause renal prostaglandin-mediated fluid retention. In patients with moderate hepatic impairment, doses should be decreased by approximately 50%.

Relevant Side Effects and Drug Interactions

Clinical trials found that coxibs caused less gastropathy than traditional NSAIDs; the most notable trials included the VIGOR (Vioxx GI Outcomes Research), TARGET (Therapeutic Arthritis Research and GI Event Trial), and CLASS studies (Celebrex Long-term Arthritis Safety Study) (166, 167, 168). There is however growing evidence that coxibs impair healing of damaged gastric mucosa and may negatively affect both the small and the large intestines (169, 170, 171). These findings have led to further questioning as to whether there really is an advantage of less GI toxicity from coxibs over traditional NSAIDs (163).

Coxibs can cause a dose-dependent risk of adverse cardiovascular events, including myocardial infarction and stroke (172,173). Rofecoxib was withdrawn upon completion of the 3-year APPROVe study, which showed that daily intake of 25 mg of this coxib doubled the risk of thrombotic events (174). It was also shown that doubling the dose of celecoxib increased adverse cardiovascular events by (risk ratio, 3.4; 95% confidence interval, 1.5 to 7.9) above that of the 200 mg qd Celebrex dose (2.6; 95% CI, 1.1 to 6.1) (175,177). The pathophysiology behind this effect is that coxibs inhibit vascular endothelium production of prostaglandin I₂, a lipid that counteracts thromboxane A₂ to prevent platelet aggregation leading to atherosclerosis, and cause a similar blood pressure (BP) elevation as NSAIDs (176). It is not known if cardioprotective aspirin or low-salt diet can mitigate coxibs’ cardiovascular risks (177).

This issue of increased cardiovascular risk led to a black box warning that is now part of the package inserts of celecoxib and all NSAIDs as follows:

Cardiovascular Risk