145,146

Side effects of prazosin are significant at maximal doses and include dizziness,

edema, fatigue, and orthostasis. The longer acting α1

-adrenergic antagonist terazosin

was evaluated in one small study, and it improved symptomatology as well as

objective measures of blood flow.

147

Insufficient data with this class of drugs exist to

routinely recommend their initial use in patients with RP. Topical nitrates have been

used clinically for several years and newer formulations have recently been studied,

but data showing efficacy is limited.

119

Several therapeutic approaches are being vigorously investigated and show

promise as future therapies for RP. These include the intravenous prostaglandin

analogs iloprost and alprostadil, which enhance nitric oxide–mediated

vasodilation

148

; endothelin antagonists, such as bosentan

149

; and oral

phosphodiesterase inhibitors

150–152 which also promote vasodilation. A meta-analysis

of phosphodiesterase inhibitors for the treatment of secondary RP showed a modest

decrease in frequency and duration of attacks, although further larger trials are

needed.

152 Botulinum toxin-A has also been studied.

153 Because of side effects, cost,

and administration difficulties, these agents are primarily being studied in the most

severe cases of secondary RP with digital ulcers or other systemic complications

associated with connective tissue diseases. If benefit is proved, however, it will

shed light on the pathogenesis of the disorder, and perhaps lead to therapies

appropriate for the larger population with RP.

Statins may have promise in severe cases resulting in digital ulcers secondary to

systemic sclerosis (SSc). Pleiotropic effects of atorvastatin 40 mg/day on endothelial

function compared with placebo were investigated in 84 SSc patients who fulfilled

the American College of Rheumatology criteria for classification of SSc with

secondary RP despite ongoing vasodilator therapy. The study found a significant

decrease in both new and the total number of digital ulcers in the atorvastatin group

compared with placebo.

154

The renin–angiotensin system mediators act as vasodilators and have been

investigated in several small studies. ACE inhibitors and angiotensin receptor

blockers, however, have yielded conflicting results with respect to beneficial effects

in patients with RP.

155–158 Small beneficial effects have been realized, specifically

with captopril 25 mg 3 times a day and losartan 12.5 to 25 mg/day; however, no

benefit has been found with enalapril 20 mg once daily.

155 Fluoxetine, a selective

serotonin reuptake inhibitor, was shown in one study to reduce the symptoms of

RP.

159

It is hypothesized to exert its effect by depleting platelet serotonin, rendering

the platelet unable to release a significant amount of the vasoconstrictive serotonin

during activation and aggregation.

Alternative therapies, such as Ginkgo biloba and L-arginine, have also been

studied in small trials with positive results; however, larger trials are needed to

confirm the findings before these therapies can be recommended.

160–162

All patients with RP should be counseled regarding cold avoidance and other

protective measures. A CCB, extended-release nifedipine if tolerated, should be

initiated if conservative measures are ineffective and titrated to the highest tolerated

dose and symptom resolution. Combination therapies have not been investigated, but

another agent, such as an α1

-adrenergic antagonist, may be considered in addition to

the CCB if symptom resolution is not satisfactory and side effects permit.

NOCTURNAL LEG MUSCLE CRAMPS

Nocturnal leg muscle cramps are idiopathic, involuntary contractions occurring at

rest that cause a visible and palpable knot in the affected muscle. This type of muscle

cramp usually afflicts middle-aged to elderly persons and is a distressing and painful

condition. Its cause is unknown. The two primary hypotheses that attempt to explain

the pathophysiology propose neurologic impairments. One involves a central nervous

system impairment of γ-aminobutyric acid,

163 and the other, an impaired peripheral

response to muscle lengthening.

164 Although the incidence of

p. 171

p. 172

nocturnal cramps is unknown, some data indicate it is very common. In a survey of

veterans (95% men averaging 60 years of age), 56% complained of leg cramps, with

12% having cramping nearly every night

165

; 36% of these veterans were also

attempting some type of drug treatment for their symptoms. A survey of the general

population revealed that the prevalence of nocturnal leg cramps was 37% in people

older than 50 years of age, and increased to 54% in people older than 80 years of

age. The prevalence in men and women is equal.

166 Nocturnal leg cramps are

associated with lower extremity atherosclerosis, CAD, and peripheral neurologic

deficits.

166,167

Clinical Presentation

CASE 10-3

QUESTION 1: H.C., a 62-year-old woman, complains of cramps in her left calf that began last night around

10 PM. The cramps occurred several times throughout the night and has resolved slowly this morning. These

nighttime cramping episodes occur frequently, are very painful, and cause her calf muscle to become “knotted,”

but is not associated with walking. She denies any trauma, fever, or chills, has no other medical problems, and

takes no medications. Her physical examination, extended chemistry panel, and thyroid function tests are

unremarkable, and her vital signs are stable. H.C. works at an elementary school and walks up and down stairs

throughout the day. Her physician associates the pain with nocturnal leg cramps. What characteristics

differentiate H.C.’s nocturnal leg cramps from other pain syndromes?

Benign nocturnal leg cramps usually occur in the early hours of sleeping; they are

asymmetric and primarily affect the calf muscle and small muscles of the foot. These

cramps are not associated with exercise, electrolyte or laboratory abnormalities, or

medications, although cramping requiring therapy was more likely in the first year of

patients being prescribed long-acting β-agonists, thiazide, and potassium-sparing

diuretics.

168

For diagnosis and treatment of nocturnal cramps, other causes of muscle cramping,

including drug-induced cramps, must be excluded (Table 10-8). The onset of cramps

at rest is characteristic of ordinary leg cramps and is the primary symptom used for

diagnosis. Clinical signs of sodium depletion, hyperthyroidism and hypothyroidism,

tetany, and lower motor neuron disease should be evaluated. Laboratory

measurements such as standard electrolytes and thyroid function tests can help rule

out some of these other conditions.

Table 10-8

Other Causes of Muscle Cramps

169–171

Drug-Induced Cramps Biochemical Causes Other

Alcohol

Antipsychotics (dystonia)

β-Agonists (e.g., albuterol,

terbutaline, salbutamol)

Cimetidine

Clofibrate

Diuretics

Lithium

Narcotic analgesics

Nicotinic acid

Nifedipine

Penicillamine

Statins

Steroids

Dehydration

Hemodialysis

Hypocalcemia

Hypokalemia

Hypomagnesemia

Hyponatremia

Uremia

Contractures

Diabetes

Lower motor neuron disease

Peripheral vascular disease

Tetany

Thyroid disease

Treatment

THERAPEUTIC OBJECTIVES AND NONPHARMACOLOGIC

INTERVENTIONS

CASE 10-3, QUESTION 2: What are the therapeutic objectives in treating H.C.? What nonpharmacologic

recommendations can be made?

The primary treatment goal is to prevent this uncomfortable condition. Given the

limited evidence and potential side effects with drug therapy, nonpharmacologic

therapy is the preferred initial therapy. Patients are commonly advised to stretch out

the afflicted muscle or perform dorsiflexion of the feet throughout the day and before

bedtime.

170 Patients are also warned to avoid plantar flexion while sleeping by

hanging the feet over the edge of the bed when sleeping on the stomach. Once a cramp

occurs, the goal is to relieve the cramp as quickly as possible. Acute therapy consists

of dorsiflexion (grasping the toes and pulling them upward in the opposite direction

of the cramp). This can be accomplished with the hands, by walking, or by leaning

toward a wall while standing 2 feet away from it, maintaining the feet flat on the

floor.

172

PHARMACOTHERAPY

CASE 10-3, QUESTION 3: H.C. adopted the recommended stretching practices, and reduced plantar flexion

during sleep. She returns 3 months later, and reports a minor decrease in the attack frequency, but not severity.

Her sleep is affected 2 to 3 nights/week, and she feels it is affecting her performance as a teacher. She

remembers her aunt taking a “pill” for her leg cramps. Are there any medications that may help relieve her

symptoms?

A variety of medications have been reported to help treat nocturnal leg cramps, but

all have limited, very limited, and inconclusive evidence. Vitamin B12

, vitamin E,

diphenhydramine, gabapentin, diltiazem, and verapamil have limited effectiveness

data, mostly via small single trials or case series. Quinine historically had been the

most frequently prescribed medication for nocturnal leg cramps. The FDA, however,

has clearly stated quinine should not be used for nocturnal leg cramps because of an

unfavorable risk–benefit ratio.

173

Quinine has been used to treat nocturnal leg cramps since the 1940s, when four

patients having leg cramps experienced marked improvement in symptoms after being

treated with quinine.

174 Despite its use, significant controversy exists about its

benefit. Only a few small controlled trials have been conducted, with mixed

conclusions. A meta-analysis was published in 1998 that included both published and

unpublished data addressing the efficacy of quinine in the treatment of leg cramps.

175

Pooled data from 659 patients indicated that quinine, at 200 to 325 mg/day, reduced

the severity and average number of cramps experienced in a 4-week period from

17.1 to 13.5. Of note, a recent study that randomly assigned patients to quinine

cessation reported no effect on nocturnal leg cramp frequency (e.g., no worsening of

symptoms).

176

Cinchonism, a syndrome that includes nausea, vomiting, blurred vision, tinnitus,

and deafness, is a dose-related side effect of quinine.

169 Tinnitus alone occurs in up

to 3% of patients.

177 With overdose, central nervous system manifestations, such as

headache, confusion, and delirium, can occur. Self-limiting rashes

p. 172

p. 173

that resolve with drug discontinuation have been described.

169 The unpredictable

and life-threatening side effect of thrombocytopenia was the impetus for the FDA to

ban the over-the-counter status of this preparation. Thrombocytopenia has been

estimated to occur in up to 1 of 1,000 patients taking quinine.

173 Care should also be

taken with the use of quinine because its clearance is decreased in the elderly,

178 and

several drugs decrease its clearance, such as cimetidine, verapamil, amiodarone, and

alkalinizing agents.

179 Quinine can also produce toxic levels of digoxin,

phenobarbital, and carbamazepine

180 and is contraindicated in patients with glucose6-phosphate dehydrogenase deficiency.

OTHER THERAPIES

CASE 10-3, QUESTION 4: Are there other treatment options for H.C.?

Electrolyte replacement (e.g., sodium, potassium, calcium, magnesium) may be

indicated if specific deficiencies are noted or if the onset of cramping is associated

with a recent initiation or dosage increase of diuretic therapy. Prophylactic use of

other pharmacologic agents has been attempted, but their use is mostly anecdotal.

Diphenhydramine, riboflavin, carbamazepine, methocarbamol, and phenytoin have

been used empirically,

169 but no data support their use in nocturnal leg cramps.

Vitamin E has been recommended, but one controlled study with 800 international

units/day of vitamin E showed no benefit.

180 Verapamil has been shown in an openlabel trial of eight elderly patients to relieve quinine-resistant cramps. A dose of 120

mg of verapamil at bedtime was used, and relief was seen after 6 days of

treatment.

180 Similar results were reported from a similar small study using

diltiazem.

181 A small study found benefit associated with vitamin B complex

administration for nocturnal leg cramps, but no quantification of a decrease in the

number of cramps was provided.

182 Two small crossover studies suggested that

chronic magnesium administration is not effective for the treatment of nocturnal leg

cramps.

183,184

Although nocturnal leg cramps are relatively benign, they do cause considerable

discomfort. Nonpharmacologic measures should be maximized before drug therapy is

contemplated. If drug therapy is warranted, quinine can be tried, but the potential for

side effects, especially in the elderly population, is very real. Careful patient

selection, patient education, and vigilant monitoring for side effects should all be

used to minimize the occurrence and progression of adverse effects from quinine.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

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