Letters to the Editor
Off-Label Uses for Selective Serotonin Reuptake Inhibitors
to the editor: In the August 1, 2003, issue of American Family Physician, Stone and colleagues reported on off-label applications for selective serotonin reuptake inhibitors (SSRIs).1 Unfortunately, the article1 was somewhat misleading and incomplete. The U.S. Food and Drug Administration (FDA) has approved several SSRIs for the treatment of generalized anxiety disorder. The FDA also has approved venlafaxine (Effexor), which is an SSRI in low doses but a dual action SSRI/serotonergic noradrenergic reuptake inhibitor (SNRI) in high doses, for this use. In fact, all SSRIs are equally effective in the treatment of all anxiety disorders (including panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, and social anxiety), whether or not they have received specific approval from the FDA for this purpose.2 SSRIs also have been found useful in treating eating disorders (bulimia, binge eating)3 and menopausal hot flushes (natural or induced by antihormone cancer treatment); paroxetine (Paxil), which also inhibits norepinephrine at higher doses, and venlafaxine have been more effective than the "pure” SSRIs for treating hot flushes.4 In fact, dual action (SSRI/SNRI) agents (higher-dose Effexor and Paxil) and tricyclic antidepressants have been shown to be helpful for neuropathic pain,5 fibromyalgia, and migraine prophylaxis,5 where pure SSRIs have been relatively ineffective.
REFERENCES
1. Stone KJ, Viera AJ, Parman CL. Off-label applications for SSRIs. Am Fam Physician 2003;68:498-504.
2. Recommendations for the long-term treatment of anxiety disorders. CNS Spectr 2003;8(suppl 1).
3. Yager J, ed. Treatment of bulimia nervosa and binge eating disorder [Monograph]. University of South Florida College of Medicine. 2003.
4. Schober CE, Ansani NT. Venlafaxine hydrochloride for the treatment of hot flashes. Ann Pharmacother 2003;37:1703-7.
5. Stahl SM. Here today and not gone tomorrow: the curse of chronic pain and other central sensitization syndromes. J Clin Psychiatry 2003;64:863-4.
in reply: In our article,1 we selected six conditions for which the off-label use of selective serotonin reuptake inhibitors (SSRIs) had the most evidence. We certainly acknowledge that SSRIs are used off-label for other conditions, but we had to consider the space constraints of the journal. We did not include hot flushes in our article,1 but we find SSRIs (including venlafaxine, which also inhibits norepinephrine) to be very useful in relieving menopausal or perimenopausal hot flushes in women who are not taking (or cannot take) estrogen therapy.2-4 There is no doubt that in addition to the conditions mentioned in our article and the conditions mentioned by Dr. Hoffman, SSRIs will prove to be useful in other conditions. Likewise, SSRIs will be tried for other conditions and fail to show any benefit over placebo. Evidence, of course, takes time to accumulate.
Other SSRIs have come on the market since the writing of our article. At that time, of those available, only paroxetine had the FDA approval for generalized anxiety disorder. In a revision of our article, we had included venlafaxine, but that information was subsequently edited out. We appreciate Dr. Hoffman taking the time to write and for highlighting this additional useful information about SSRIs and venlafaxine.
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Navy medical department or the U.S. Navy at large.
REFERENCES
1. Stone KJ, Viera AJ, Parman CL. Off-label applications for SSRIs. Am Fam Physician 2003;68:498-504.
2. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA 2003;289:2827-34.
3. Loprinzi CL, Sloan JA, Perez EA, Quella SK, Stella PJ, Mailliard JA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002;20:1578-83.
4. Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI, Barton DL, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 2000;356:2059-63.
Vitamin D Insufficiency as a Cause of Hyperparathyroidism
to the editor: I read with interest the article on hyperparathyroidism in the January 15, 2004, issue of American Family Physician.1 However, I noticed that hypovitaminosis D (vitamin D insufficiency) was not mentioned in much detail. Although the concept is not new, I would like to point out that this is an under-recognized but increasingly important cause of secondary hyperparathyroidism, which is a condition that may be of significant relevance to family physicians and their patients.
Hypovitaminosis D increases the risk for fractures, bone pain, and the development of either osteomalacia or rickets. Risk factors include lack of sun exposure, inadequate dietary intake, and advanced age (caused by the skin's decreasing ability to synthesize vitamin D). Studies have shown a prevalence of 30 to 50 percent in elderly persons in community settings.2 Even in the nonelderly, 57 percent of hospitalized patients in Boston had evidence of vitamin D deficiency.3 In a recent study conducted in Minnesota,4 an alarming 93 percent of children and adults with chronic musculoskeletal pain were vitamin D deficient. Surprisingly, the most severely deficient persons were patients aged 10 to 29 years.
Diagnosis of vitamin D deficiency is based on a low 25-hydroxyvitamin D3 level. Traditionally, levels less than 12 ng per mL (31 nmol per L) have been considered the lower limits of normal. However, levels of 25-hydroxyvitamin D3 less than 20 ng per mL (52 nmol per L)) triggers a compensatory increase in parathyroid hormone (PTH) and, hence, accelerates bone resorption. This suggests that vitamin D deficiency occurs before the lower limits of traditional population-based values for PTH.5 Unlike primary hyperparathyroidism, PTH levels are usually less than 100 pg per mL (850 pmol per L) in secondary hyperparathyroidism caused by hypovitaminosis D. Overall, optimal bone health may occur with 25-hydroxyvitamin D3 levels greater than 30 to 50 ng per mL (78 to 130 nmol per L).
Treatment for hypovitaminosis D is supplementation with vitamin D and calcium. Two methods are suggested here. Replacement with 50,000 IU vitamin D once a week for eight weeks given with supplemental calcium will restore tissue stores quickly and may be more useful for patients with levels of 25-hydroxyvitamin D3 less than 20 ng per mL. Daily supplementation with 800 IU of vitamin D and calcium for those patients with levels between 20 and 30 ng per mL also is safe and effective.6 Repeating levels of 25-hydroxyvitamin D3 and PTH after two to three months ensures adequate treatment and compliance.
Family physicians should consider screening for hypovitaminosis D in all patients who may be at risk, regardless of age. Elderly persons, and even children with dietary lack and limited sun exposure, are vulnerable to vitamin D deficiency. The American Academy of Pediatrics recently recognized the continuing reports of rickets and recommends 200 to 400 IU of daily vitamin D supplementation to all children. Older adults also may warrant vitamin D and calcium supplementation without screening. Understanding the risk factors, and recognizing subnormal 25-hydroxyvitamin D3 levels and mild hyperparathyroidism will allow the family physician to detect hypovitaminosis D. Early diagnosis and treatment is critical to prevent the more serious complications of rickets in children and osteomalacia in adults.
The opinions and assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the U.S. Army medical department or the U.S. Army at large.
REFERENCES
1. Taniegra ED. Hyperparathyroidism. Am Fam Physician 2004;69:333-9.
2. Allain TJ, Dhesi J. Hypovitaminosis D in older adults. Gerontology 2003;49:273-8.
3. Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT, et al. Hypovitaminosis D in medical inpatients. N Engl J Med 1998;338:777-83.
4. Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clin Proc 2003;78:1463-70.
5. Malabanan A, Veronikis IE, Holick MF. Redefining vitamin D insufficiency. Lancet 1998;351:805-6.
6. Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev 2001;22:477-501.
Use of the Term Conjunctival Icterus Instead of Scleral Icterus
to the editor: I read with great interest the article1 on jaundice in the adult patient in the January 15, 2004, issue of American Family Physician. It was a very informative and useful article. However, I noticed the authors used the term "scleral icterus.” This is a term that is commonly used in textbooks; however, from a histopathologic perspective, it is a misnomer. Bilirubin has a high affinity for elastin which is an abundant protein in the conjunctivae as well as the superficial, fibrovascular episclerae, but not the sclerae proper.2 A more accurate description would therefore be conjunctival icterus.
REFERENCES
1. Roche SP, Kobos R. Jaundice in the adult patient. Am Fam Physician 2004;69:299-304.
2. Kuiper JJ. Conjunctival icterus. Ann Intern Med 2001;134:345-6.
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