A 21-year-old woman presents with a history of recurrent renal stones. Her serum calcium level is 11.5 mg/dL (normal, 8.6 to 10.5 mg/dL); serum phosphorus, 2.4 mg/dL (2.5 to 4.8 mg/dL); intact parathyroid hormone (PTH), 198 pg/mL (7 to 53 pg/mL); and serum 25-hydroxyvitamin D [25(OH)D], 12.6 ng/mL (30 to 60 ng/mL). After six weeks of therapy with vitamin D (50,000 IU three times/week), the serum calcium level is 11 mg/dL; PTH, 164 pg/mL; and 25(OH)D, 28 ng/mL. With all lab results improved but still abnormal, what other information would be helpful?

With this particular case, the striking history is recurrent renal stones. Analysis of one of the stones to determine if they are calcium oxalate would be beneficial; however, a 24-hour urine calcium measurement would provide useful information about the potential cause of the renal stones. Vitamin D deficiency can cause mild hypercalcemia but can also mask underlying primary hyperparathyroidism—as it did in this case. A Tc-99 sestamibi parathyroid scan will often localize a parathyroid adenoma.

This patient’s 24-hour urine calcium was high, and her parathyroid scan suggested an adenoma in the left lower lobe of the thyroid. An experienced parathyroid surgeon was consulted, and surgical excision of a 1.5-cm parathyroid adenoma followed. The intraoperative PTH went from 183 to 39 pg/mL, and the intraoperative calcium from 11.6 to 9.2 mg/dL. There was no postoperative hypocalcemia.

Q: What is the differential diagnosis for hypercalcemia?

• Parathyroid adenoma or carcinoma

• Hypercalcemia of malignancy (eg, breast, lung, pancreas)

• Multiple myeloma

• Multiple endocrine neoplasia types 1 and 2

• Familial hypocalciuric hypercalcemia

• Excess 1,25 dihydroxy vitamin D [1,25(OH)2D] production: sarcoid or other granulomatous disorders, lymphomas

• Miscellaneous: immobilization, milk-alkali syndrome, and parenteral nutrition

• Drug-related: vitamin D deficiency or intoxication; use of thiazide diuretics or lithium

• Nonparathyroid endocrine causes: hyperthyroidism, pheo­chromocytoma, Addison’s disease, islet cell tumors

Q: What are the clinical manifestations of hypercalcemia?

Mild hypercalcemia is usually asymp­tomatic, especially if serum calcium is 10.5 to 11.5 mg/dL. Polyuria and polydypsia, renal stones, constipation, nausea, and weight loss are nonspecific symptoms. Decreased mental alertness and depression can be seen, especially if calcium is higher than 12 mg/dL. Bone pain, arthralgias, and decreased bone density can occur with longstanding hypercalcemia. ECG changes, including bradycardia, atrioventricular block, and short QT interval, are sometimes noted.

Q: What is the significance of familial hypocalciuric hypercalcemia (FHH)?   

Patients with this genetic disorder, which involves mutated calcium-sensor receptors, often have a mildly elevated PTH but may have a normal PTH in the presence of hypercalcemia. A 24-hour urine calcium level below 100 mg is indicative of FHH.

A calcium/creatinine clearance ratio (calculated as urine calcium/serum calcium divided by urine creatinine/serum creatinine) of < 0.01 is suggestive of FHH, particularly if there is a family history of mild hypercalcemia.

An important point is that parathyroid surgery is ineffective in these patients, and they seldom develop clinical symptoms or stones.

Q: Often, hypercalcemia is identified through routine labs. What diagnostic studies should be obtained with the initial work-up?

Since it is not uncommon to discover mild hypercalcemia on routine labs, it may be prudent to simply recheck serum calcium before launching into an extensive work-up. A comprehensive metabolic panel will give you the calcium, albumin, and serum protein. 

When serum albumin is reduced, a corrected calcium level is calculated by adding 0.8 mg/dL to the total calcium for every decrement of 1 g/dL in serum albumin below the reference value of 4 g/dL. Serum phosphate is often low, except in secondary hyperparathyroidism due to renal failure, in which case phosphate is high. Urine calcium excretion may be high or normal. 

A 25(OH)D level should also be obtained, as vitamin D deficiency is a common cause of hypercalcemia. Adequate vitamin D replacement will often correct the hypercalcemia; however, vitamin D deficiency may be masking underlying primary hyperparathyroidism. 

The PTH level will be high in primary hyperparathyroidism, although it is possible to have a normal intact PTH in patients who have had long-standing mild primary hyperparathyroidism. Secondary hyperparathyroidism due to vitamin D deficiency will also result in an elevated PTH.

A suppressed PTH level in the presence of severe hypercalcemia suggests nonparathyroid-mediated hypercalcemia, often due to malignancy. Hypercalcemia of malignancy is usually symptomatic and severe (≥ 15 mg/dL). 

Q: What other nonroutine studies should be considered in the work-up?

A 24-hour urine for calcium, phosphorus, and creatinine clearance, as well as a DXA bone density test, are important for making treatment decisions. A Tc-99 sestamibi parathyroid scan is important to localize a parathyroid adenoma.

Ultrasound of the neck may help to localize an enlarged parathyroid gland, especially if the scan is negative or equivocal. 

Q: What are the complications of untreated hypercalcemia?

These include renal stones and urinary tract infections; peptic ulcer; altered mental status; pancreatitis; and during pregnancy, neonatal hypocalcemia.

Q: What is the medical treatment for hypercalcemia?

For acute hypercalcemia, use IV fluids at a high rate, such as normal saline 2,000 cc/hr, unless contraindicated.

Bisphosphonates, such as IV zoledronic acid, are potent inhibitors of bone resorption of calcium and can temporarily treat hypercalcemia, especially in cases of malignancy or severe hyperparathyroidism. It is important to know that oral bisphosphonates are not effective in treating hypercalcemia.

Avoid thiazide diuretics, as well as vitamin A, vitamin D, and calcium supplements. Another caveat: In the face of vitamin D deficiency, correct the vitamin D level to 40 to 60 ng/dL. Patients with 1,25(OH)2D-mediated hypercalcemia should be treated with glucocorticoids (prednisone or IV hydrocortisone), as they decrease 1,25(OH)2D.

Cinacalcet is approved for treatment of secondary hyperparathyroidism due to chronic renal failure, parathyroid carcinoma, and severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy. The mode of action of cinacalcet is by binding to the parathyroid glands’ extracellular calcium-sensing receptors (CaSRs) to increase their affinity for extracellular calcium and decrease PTH secretion production.

Q: What are the indications for surgical intervention?

Surgery is recommended for patients with kidney stones or bone disease or with notable symptoms; those who have osteoporosis (identified on DXA scan); patients younger than 50; and those with a glomerular filtration rate below 60 mL/min and calcium 1.0 mg/dL or more above the upper limit of normal. Surgical removal of a parathyroid adenoma usually results in a cure.

Q: What causes secondary hyperparathyroidism?

Chronic renal failure is usually the cause. Hyperphosphatemia and decreased 1,25(OH)2D produce a decrease in ionized calcium. The parathyroid glands are thus stimulated and enlarge.

Vitamin D deficiency is another common cause; it is corrected with adequate vitamin D replacement. Once the vitamin D level is corrected, additional calcium supplementation should be given.

Q: What is the prognosis of hypercalcemia?

Primary hyperparathyroidism is usually chronic and progressive unless surgically cured or medically corrected. The prognosis of hypercalcemia is directly related to the degree of renal impairment or the underlying cause, such as malignancy. The presence of pancreatitis increases the mortality rate.

Regular monitoring and follow-up are important, especially if there is a trend of worsening hypercalcemia and etiology has not been identified. Monitor calcium and albumin at least every three months and renal function at least every six months.

Furthermore, check the 24-hour urine calcium and order DXA bone density testing annually.           

SUGGESTED READING
American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons. AACE/AAES position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Prac. 2005;11(1): 49-54.

McPhee SJ, Papadakis MA, eds. 2011 Current Medical Diagnosis and Treatment. McGraw Hill; 2011:1090-1097; 1098-1105; 1575-1579.

Jameson J, ed. Harrison’s Endocrinology. 2nd ed. McGraw Hill; 2010:367-378; 406-410; 411-442.

Brown SA. Hyperparathyroidism. In: Runge MS, Greganti MA, eds. Netter’s Internal Medicine. 2nd ed. Saunders; 2009:316-320.

Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Third International Workshop. J Clin Endocrinol Metab. 2009;94(2):335-339.

A 21-year-old woman presents with a history of recurrent renal stones. Her serum calcium level is 11.5 mg/dL (normal, 8.6 to 10.5 mg/dL); serum phosphorus, 2.4 mg/dL (2.5 to 4.8 mg/dL); intact parathyroid hormone (PTH), 198 pg/mL (7 to 53 pg/mL); and serum 25-hydroxyvitamin D [25(OH)D], 12.6 ng/mL (30 to 60 ng/mL). After six weeks of therapy with vitamin D (50,000 IU three times/week), the serum calcium level is 11 mg/dL; PTH, 164 pg/mL; and 25(OH)D, 28 ng/mL. With all lab results improved but still abnormal, what other information would be helpful?

With this particular case, the striking history is recurrent renal stones. Analysis of one of the stones to determine if they are calcium oxalate would be beneficial; however, a 24-hour urine calcium measurement would provide useful information about the potential cause of the renal stones. Vitamin D deficiency can cause mild hypercalcemia but can also mask underlying primary hyperparathyroidism—as it did in this case. A Tc-99 sestamibi parathyroid scan will often localize a parathyroid adenoma.

This patient’s 24-hour urine calcium was high, and her parathyroid scan suggested an adenoma in the left lower lobe of the thyroid. An experienced parathyroid surgeon was consulted, and surgical excision of a 1.5-cm parathyroid adenoma followed. The intraoperative PTH went from 183 to 39 pg/mL, and the intraoperative calcium from 11.6 to 9.2 mg/dL. There was no postoperative hypocalcemia.

Q: What is the differential diagnosis for hypercalcemia?

• Parathyroid adenoma or carcinoma

• Hypercalcemia of malignancy (eg, breast, lung, pancreas)

• Multiple myeloma

• Multiple endocrine neoplasia types 1 and 2

• Familial hypocalciuric hypercalcemia

• Excess 1,25 dihydroxy vitamin D [1,25(OH)2D] production: sarcoid or other granulomatous disorders, lymphomas

• Miscellaneous: immobilization, milk-alkali syndrome, and parenteral nutrition

• Drug-related: vitamin D deficiency or intoxication; use of thiazide diuretics or lithium

• Nonparathyroid endocrine causes: hyperthyroidism, pheo­chromocytoma, Addison’s disease, islet cell tumors

Q: What are the clinical manifestations of hypercalcemia?

Mild hypercalcemia is usually asymp­tomatic, especially if serum calcium is 10.5 to 11.5 mg/dL. Polyuria and polydypsia, renal stones, constipation, nausea, and weight loss are nonspecific symptoms. Decreased mental alertness and depression can be seen, especially if calcium is higher than 12 mg/dL. Bone pain, arthralgias, and decreased bone density can occur with longstanding hypercalcemia. ECG changes, including bradycardia, atrioventricular block, and short QT interval, are sometimes noted.

Q: What is the significance of familial hypocalciuric hypercalcemia (FHH)?   

Patients with this genetic disorder, which involves mutated calcium-sensor receptors, often have a mildly elevated PTH but may have a normal PTH in the presence of hypercalcemia. A 24-hour urine calcium level below 100 mg is indicative of FHH.

A calcium/creatinine clearance ratio (calculated as urine calcium/serum calcium divided by urine creatinine/serum creatinine) of < 0.01 is suggestive of FHH, particularly if there is a family history of mild hypercalcemia.

An important point is that parathyroid surgery is ineffective in these patients, and they seldom develop clinical symptoms or stones.

Q: Often, hypercalcemia is identified through routine labs. What diagnostic studies should be obtained with the initial work-up?

Since it is not uncommon to discover mild hypercalcemia on routine labs, it may be prudent to simply recheck serum calcium before launching into an extensive work-up. A comprehensive metabolic panel will give you the calcium, albumin, and serum protein. 

When serum albumin is reduced, a corrected calcium level is calculated by adding 0.8 mg/dL to the total calcium for every decrement of 1 g/dL in serum albumin below the reference value of 4 g/dL. Serum phosphate is often low, except in secondary hyperparathyroidism due to renal failure, in which case phosphate is high. Urine calcium excretion may be high or normal. 

A 25(OH)D level should also be obtained, as vitamin D deficiency is a common cause of hypercalcemia. Adequate vitamin D replacement will often correct the hypercalcemia; however, vitamin D deficiency may be masking underlying primary hyperparathyroidism. 

The PTH level will be high in primary hyperparathyroidism, although it is possible to have a normal intact PTH in patients who have had long-standing mild primary hyperparathyroidism. Secondary hyperparathyroidism due to vitamin D deficiency will also result in an elevated PTH.

A suppressed PTH level in the presence of severe hypercalcemia suggests nonparathyroid-mediated hypercalcemia, often due to malignancy. Hypercalcemia of malignancy is usually symptomatic and severe (≥ 15 mg/dL). 

Q: What other nonroutine studies should be considered in the work-up?

A 24-hour urine for calcium, phosphorus, and creatinine clearance, as well as a DXA bone density test, are important for making treatment decisions. A Tc-99 sestamibi parathyroid scan is important to localize a parathyroid adenoma.

Ultrasound of the neck may help to localize an enlarged parathyroid gland, especially if the scan is negative or equivocal. 

Q: What are the complications of untreated hypercalcemia?

These include renal stones and urinary tract infections; peptic ulcer; altered mental status; pancreatitis; and during pregnancy, neonatal hypocalcemia.

Q: What is the medical treatment for hypercalcemia?

For acute hypercalcemia, use IV fluids at a high rate, such as normal saline 2,000 cc/hr, unless contraindicated.

Bisphosphonates, such as IV zoledronic acid, are potent inhibitors of bone resorption of calcium and can temporarily treat hypercalcemia, especially in cases of malignancy or severe hyperparathyroidism. It is important to know that oral bisphosphonates are not effective in treating hypercalcemia.

Avoid thiazide diuretics, as well as vitamin A, vitamin D, and calcium supplements. Another caveat: In the face of vitamin D deficiency, correct the vitamin D level to 40 to 60 ng/dL. Patients with 1,25(OH)2D-mediated hypercalcemia should be treated with glucocorticoids (prednisone or IV hydrocortisone), as they decrease 1,25(OH)2D.

Cinacalcet is approved for treatment of secondary hyperparathyroidism due to chronic renal failure, parathyroid carcinoma, and severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy. The mode of action of cinacalcet is by binding to the parathyroid glands’ extracellular calcium-sensing receptors (CaSRs) to increase their affinity for extracellular calcium and decrease PTH secretion production.

Q: What are the indications for surgical intervention?

Surgery is recommended for patients with kidney stones or bone disease or with notable symptoms; those who have osteoporosis (identified on DXA scan); patients younger than 50; and those with a glomerular filtration rate below 60 mL/min and calcium 1.0 mg/dL or more above the upper limit of normal. Surgical removal of a parathyroid adenoma usually results in a cure.

Q: What causes secondary hyperparathyroidism?

Chronic renal failure is usually the cause. Hyperphosphatemia and decreased 1,25(OH)2D produce a decrease in ionized calcium. The parathyroid glands are thus stimulated and enlarge.

Vitamin D deficiency is another common cause; it is corrected with adequate vitamin D replacement. Once the vitamin D level is corrected, additional calcium supplementation should be given.

Q: What is the prognosis of hypercalcemia?

Primary hyperparathyroidism is usually chronic and progressive unless surgically cured or medically corrected. The prognosis of hypercalcemia is directly related to the degree of renal impairment or the underlying cause, such as malignancy. The presence of pancreatitis increases the mortality rate.

Regular monitoring and follow-up are important, especially if there is a trend of worsening hypercalcemia and etiology has not been identified. Monitor calcium and albumin at least every three months and renal function at least every six months.

Furthermore, check the 24-hour urine calcium and order DXA bone density testing annually.           

SUGGESTED READING
American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons. AACE/AAES position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Prac. 2005;11(1): 49-54.

McPhee SJ, Papadakis MA, eds. 2011 Current Medical Diagnosis and Treatment. McGraw Hill; 2011:1090-1097; 1098-1105; 1575-1579.

Jameson J, ed. Harrison’s Endocrinology. 2nd ed. McGraw Hill; 2010:367-378; 406-410; 411-442.

Brown SA. Hyperparathyroidism. In: Runge MS, Greganti MA, eds. Netter’s Internal Medicine. 2nd ed. Saunders; 2009:316-320.

Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Third International Workshop. J Clin Endocrinol Metab. 2009;94(2):335-339.

A 21-year-old woman presents with a history of recurrent renal stones. Her serum calcium level is 11.5 mg/dL (normal, 8.6 to 10.5 mg/dL); serum phosphorus, 2.4 mg/dL (2.5 to 4.8 mg/dL); intact parathyroid hormone (PTH), 198 pg/mL (7 to 53 pg/mL); and serum 25-hydroxyvitamin D [25(OH)D], 12.6 ng/mL (30 to 60 ng/mL). After six weeks of therapy with vitamin D (50,000 IU three times/week), the serum calcium level is 11 mg/dL; PTH, 164 pg/mL; and 25(OH)D, 28 ng/mL. With all lab results improved but still abnormal, what other information would be helpful?

With this particular case, the striking history is recurrent renal stones. Analysis of one of the stones to determine if they are calcium oxalate would be beneficial; however, a 24-hour urine calcium measurement would provide useful information about the potential cause of the renal stones. Vitamin D deficiency can cause mild hypercalcemia but can also mask underlying primary hyperparathyroidism—as it did in this case. A Tc-99 sestamibi parathyroid scan will often localize a parathyroid adenoma.

This patient’s 24-hour urine calcium was high, and her parathyroid scan suggested an adenoma in the left lower lobe of the thyroid. An experienced parathyroid surgeon was consulted, and surgical excision of a 1.5-cm parathyroid adenoma followed. The intraoperative PTH went from 183 to 39 pg/mL, and the intraoperative calcium from 11.6 to 9.2 mg/dL. There was no postoperative hypocalcemia.

Q: What is the differential diagnosis for hypercalcemia?

• Parathyroid adenoma or carcinoma

• Hypercalcemia of malignancy (eg, breast, lung, pancreas)

• Multiple myeloma

• Multiple endocrine neoplasia types 1 and 2

• Familial hypocalciuric hypercalcemia

• Excess 1,25 dihydroxy vitamin D [1,25(OH)2D] production: sarcoid or other granulomatous disorders, lymphomas

• Miscellaneous: immobilization, milk-alkali syndrome, and parenteral nutrition

• Drug-related: vitamin D deficiency or intoxication; use of thiazide diuretics or lithium

• Nonparathyroid endocrine causes: hyperthyroidism, pheo­chromocytoma, Addison’s disease, islet cell tumors

Q: What are the clinical manifestations of hypercalcemia?

Mild hypercalcemia is usually asymp­tomatic, especially if serum calcium is 10.5 to 11.5 mg/dL. Polyuria and polydypsia, renal stones, constipation, nausea, and weight loss are nonspecific symptoms. Decreased mental alertness and depression can be seen, especially if calcium is higher than 12 mg/dL. Bone pain, arthralgias, and decreased bone density can occur with longstanding hypercalcemia. ECG changes, including bradycardia, atrioventricular block, and short QT interval, are sometimes noted.

Q: What is the significance of familial hypocalciuric hypercalcemia (FHH)?   

Patients with this genetic disorder, which involves mutated calcium-sensor receptors, often have a mildly elevated PTH but may have a normal PTH in the presence of hypercalcemia. A 24-hour urine calcium level below 100 mg is indicative of FHH.

A calcium/creatinine clearance ratio (calculated as urine calcium/serum calcium divided by urine creatinine/serum creatinine) of < 0.01 is suggestive of FHH, particularly if there is a family history of mild hypercalcemia.

An important point is that parathyroid surgery is ineffective in these patients, and they seldom develop clinical symptoms or stones.

Q: Often, hypercalcemia is identified through routine labs. What diagnostic studies should be obtained with the initial work-up?

Since it is not uncommon to discover mild hypercalcemia on routine labs, it may be prudent to simply recheck serum calcium before launching into an extensive work-up. A comprehensive metabolic panel will give you the calcium, albumin, and serum protein. 

When serum albumin is reduced, a corrected calcium level is calculated by adding 0.8 mg/dL to the total calcium for every decrement of 1 g/dL in serum albumin below the reference value of 4 g/dL. Serum phosphate is often low, except in secondary hyperparathyroidism due to renal failure, in which case phosphate is high. Urine calcium excretion may be high or normal. 

A 25(OH)D level should also be obtained, as vitamin D deficiency is a common cause of hypercalcemia. Adequate vitamin D replacement will often correct the hypercalcemia; however, vitamin D deficiency may be masking underlying primary hyperparathyroidism. 

The PTH level will be high in primary hyperparathyroidism, although it is possible to have a normal intact PTH in patients who have had long-standing mild primary hyperparathyroidism. Secondary hyperparathyroidism due to vitamin D deficiency will also result in an elevated PTH.

A suppressed PTH level in the presence of severe hypercalcemia suggests nonparathyroid-mediated hypercalcemia, often due to malignancy. Hypercalcemia of malignancy is usually symptomatic and severe (≥ 15 mg/dL). 

Q: What other nonroutine studies should be considered in the work-up?

A 24-hour urine for calcium, phosphorus, and creatinine clearance, as well as a DXA bone density test, are important for making treatment decisions. A Tc-99 sestamibi parathyroid scan is important to localize a parathyroid adenoma.

Ultrasound of the neck may help to localize an enlarged parathyroid gland, especially if the scan is negative or equivocal. 

Q: What are the complications of untreated hypercalcemia?

These include renal stones and urinary tract infections; peptic ulcer; altered mental status; pancreatitis; and during pregnancy, neonatal hypocalcemia.

Q: What is the medical treatment for hypercalcemia?

For acute hypercalcemia, use IV fluids at a high rate, such as normal saline 2,000 cc/hr, unless contraindicated.

Bisphosphonates, such as IV zoledronic acid, are potent inhibitors of bone resorption of calcium and can temporarily treat hypercalcemia, especially in cases of malignancy or severe hyperparathyroidism. It is important to know that oral bisphosphonates are not effective in treating hypercalcemia.

Avoid thiazide diuretics, as well as vitamin A, vitamin D, and calcium supplements. Another caveat: In the face of vitamin D deficiency, correct the vitamin D level to 40 to 60 ng/dL. Patients with 1,25(OH)2D-mediated hypercalcemia should be treated with glucocorticoids (prednisone or IV hydrocortisone), as they decrease 1,25(OH)2D.

Cinacalcet is approved for treatment of secondary hyperparathyroidism due to chronic renal failure, parathyroid carcinoma, and severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy. The mode of action of cinacalcet is by binding to the parathyroid glands’ extracellular calcium-sensing receptors (CaSRs) to increase their affinity for extracellular calcium and decrease PTH secretion production.

Q: What are the indications for surgical intervention?

Surgery is recommended for patients with kidney stones or bone disease or with notable symptoms; those who have osteoporosis (identified on DXA scan); patients younger than 50; and those with a glomerular filtration rate below 60 mL/min and calcium 1.0 mg/dL or more above the upper limit of normal. Surgical removal of a parathyroid adenoma usually results in a cure.

Q: What causes secondary hyperparathyroidism?

Chronic renal failure is usually the cause. Hyperphosphatemia and decreased 1,25(OH)2D produce a decrease in ionized calcium. The parathyroid glands are thus stimulated and enlarge.

Vitamin D deficiency is another common cause; it is corrected with adequate vitamin D replacement. Once the vitamin D level is corrected, additional calcium supplementation should be given.

Q: What is the prognosis of hypercalcemia?

Primary hyperparathyroidism is usually chronic and progressive unless surgically cured or medically corrected. The prognosis of hypercalcemia is directly related to the degree of renal impairment or the underlying cause, such as malignancy. The presence of pancreatitis increases the mortality rate.

Regular monitoring and follow-up are important, especially if there is a trend of worsening hypercalcemia and etiology has not been identified. Monitor calcium and albumin at least every three months and renal function at least every six months.

Furthermore, check the 24-hour urine calcium and order DXA bone density testing annually.           

SUGGESTED READING
American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons. AACE/AAES position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Prac. 2005;11(1): 49-54.

McPhee SJ, Papadakis MA, eds. 2011 Current Medical Diagnosis and Treatment. McGraw Hill; 2011:1090-1097; 1098-1105; 1575-1579.

Jameson J, ed. Harrison’s Endocrinology. 2nd ed. McGraw Hill; 2010:367-378; 406-410; 411-442.

Brown SA. Hyperparathyroidism. In: Runge MS, Greganti MA, eds. Netter’s Internal Medicine. 2nd ed. Saunders; 2009:316-320.

Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Third International Workshop. J Clin Endocrinol Metab. 2009;94(2):335-339.

Discuss this article at www.facebook.com/CurrentPsychiatry

Of the 56 million American adults who report living with chronic pain almost 60% also exhibit psychiatric disorders such as depression or anxiety.^1,2 Because patients with chronic pain suffer from a mixture of physical and psychological components, managing such conditions is complicated, and using opioids is tempting. However, treatment needs to address the underlying pathology along with social and psychological factors.

Because substance abuse treatment admissions increased by 400% from 1998 to 2008,³ many physicians look to non-opioids and other treatment modalities to control chronic non-cancer pain. Common pharmacologic therapies used to treat chronic pain include tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), antiepileptic drugs (AEDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and, to a lesser extent, atypical antipsychotics. TCAs, SNRIs, AEDs, NSAIDs, and atypical antipsychotics influence a variety of presumed underlying pathophysiological processes, including inflammatory mediators, activity of N-methyl-d-aspartate (NMDA) receptors, and voltage-gated calcium channels. In addition, they increase activity of descending inhibitory pain pathways. Animal studies suggest dysfunction of these inhibitory mechanisms contributes to the central sensitization and hyperexcitability of pain transmitting pathways.⁴

In this article, we discuss psychotropics and other non-opioid agents for treating pain. However, no single solution is best for all patients with chronic pain and this article is not a “how to” guide to avoid administering opioid medication. Also incorporate a multimodal, non-pharmacologic approach whenever possible.

Tricyclic antidepressants

Although this class acts primarily by increasing serotonin levels, norepinephrine and dopamine also are affected depending on the particular medication. Studies have shown that amitriptyline, nortriptyline, and desipramine function well as analgesics independent of their antidepressant effects.⁵ TCAs may improve pain symptoms at lower therapeutic dosages than those used for treating depression.⁵

Although researchers have not elucidated TCAs’ mechanism of action with regards to analgesia, they are thought to act within the concept of the gating theory of pain control,⁶ which functions by activation and inhibition of pain signal transmission. It is believed TCAs act on nociceptive pathways by blocking serotonin and norepinephrine reuptake. Although researchers previously thought that TCAs’ analgesic mechanism was correlated to serotonin reuptake inhibition, this theory has changed. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine have not demonstrated substantial effectiveness in neuropathic pain when compared with TCAs and SNRIs. Recent studies have shown that TCAs may work by blocking sodium channels, similar to local anesthetics and antiarrhythmic agents.⁷

Psychiatrists prescribe TCAs infrequently because of these drugs’ unfavorable side effect profile compared with SSRIs and SNRIs. However, TCAs often are prescribed for pain management as an adjunct to other medications for neuropathic conditions and at lower dosages than those used for treating depression (Table 1).⁸

Table 1

Tricyclic antidepressants used to treat pain

SNRIs

Evidence supports using duloxetine, a potent SNRI that mediates pain inhibition in the descending pathways, for 4 chronic pain conditions:

• diabetic peripheral neuropathic pain
• fibromyalgia
• mechanical low back pain
• pain associated with osteoarthritis.⁹

Titrate the dosage to 60 mg/d and maintain the patient at this dose for at least 4 weeks. Thereafter, according to patient response, the dosage may be titrated to 120 mg/d (off-label) with appropriate vital sign monitoring and routine lab analysis.

Venlafaxine also can mediate pain response in a similar manner to duloxetine, but is not FDA-approved for treating pain. Use caution when prescribing venlafaxine for patients with a history of hypertension. Milnacipran is a relatively new SNRI that has been shown to be effective in treating fibromyalgia in divided doses of 100 to 200 mg/d (Table 2).^9-11

Table 2

Treating pain with serotonin-norepinephrine reuptake inhibitors

Antiepileptic drugs

Several AEDs are used for pain management (Table 3).^12-16 Gabapentin and pregabalin work by binding to voltage-gated calcium channels and decreasing excitatory neurotransmitter release. Along with TCAs, they are considered a first-line treatment for managing neuropathic pain.¹⁷ Gabapentin is FDA-approved for seizures and postherpetic neuralgia, but evidence supports its use in most types of neuropathic pain. Pregabalin is FDA-approved for treating seizures, diabetic peripheral neuropathy, central neuropathic pain, postherpetic neuralgia, and fibromyalgia.

Topiramate inhibits excitatory neurotransmission by enhancing the effects of gamma-aminobutyric acid, and also by blocking NMDA receptors. Topiramate is FDA-approved for seizures and migraine prophylaxis, and is used off-label for treating neuropathic pain. A 12-week trial of topiramate for diabetic neuropathy found significant analgesia in 50% of patients taking the drug, compared with 34% receiving placebo.¹⁸

Lamotrigine is approved for several types of seizures and maintenance of bipolar I disorder, and is used off-label for neuropathic pain. A recent Cochrane database review concluded that lamotrigine is ineffective for neuropathic pain¹⁴; however, some guidelines recommend using lamotrigine to treat neuropathies that do not respond to treatment with carbamazepine.¹⁹

Carbamazepine is a complex AED that is structurally similar to TCAs. It blocks sodium channels and has various pharmacologic properties, including anticholinergic, muscle relaxant, antidepressant, and sedative effects. Carbamazepine has analgesic effects through blockade of synaptic transmission in the trigeminal nucleus and is FDA-approved for seizures, bipolar disorder, neuropathic pain, and trigeminal neuralgia. In a systematic review of 12 trials of carbamazepine that included 4 placebo-controlled trials for trigeminal neuralgia, 2 studies showed a number needed to treat (NNT) of 1.8.²⁰ For diabetic neuropathy, there was insufficient data to calculate NNT.

Oxcarbazepine, an analog of carbamazepine, also is FDA-approved for seizures and is used off-label for neuropathic pain. In the only double-blind trial with positive results, oxcarbazepine titrated to 1,800 mg/d reduced diabetic neuropathy pain scores on a visual analog scale by 24 points—roughly 25%.¹⁵

Table 3

Antiepileptic drugs for pain treatment

Non-opioid analgesics

NSAIDs have antipyretic, analgesic, and anti-inflammatory effects and are used for fever, headache, mild-to-moderate pain, musculoskeletal pain, menstrual pain, and dental pain. They are particularly useful in treating acute pain, often in combination with opioid analgesics. NSAIDs exert their analgesic action through blockade of prostaglandin production via reversible inhibition of cyclooxygenase-1 and cyclooxygenase-2.

The most common side effects of NSAIDs are the result of gastrointestinal (GI) toxicity and include dyspepsia, heartburn, nausea, anorexia, and epigastric pain.²¹ GI ulceration and bleeding are rare but serious complications. To decrease these risks, tell patients to take NSAIDs with food. Add a GI protective agent, such as an H2 blocker or proton pump inhibitor, for patients at higher risk for GI complications.²²

In addition, inhibition of renal prostaglandins by NSAIDs can cause renal toxicity, fluid retention, and edema, potentially exacerbating existing cardiovascular conditions such as hypertension and heart failure. NSAIDs may increase the risk of serious thrombotic events such as myocardial infarction and stroke. Use NSAIDs at the lowest effective dose for the shortest duration possible and generally avoid prescribing in patients at high risk for cardiovascular disease and pregnant women, especially those in their third trimester.^23,24

NSAIDs may cause pharmacodynamic and pharmacokinetic drug-drug interactions. The risk of GI toxicity and bleeding increases when NSAIDs are administered with drugs that also irritate the gastric mucosa or have antiplatelet/anticoagulant effects.²¹ Plasma concentrations of drugs with a narrow therapeutic index that are renally eliminated, such as methotrexate and lithium, can increase to potentially toxic levels with concurrent NSAID use because NSAIDs decrease renal perfusion.²¹ Also, the therapeutic effects of antihypertensives may be attenuated because NSAIDs cause fluid retention.²⁵

Acetaminophen (APAP) is available in several dosage forms as a single ingredient and in combination with opioids in prescription products. For more information about APAP, see the Box below.

Atypical antipsychotics

Although atypical antipsychotics are not often used to treat pain, studies indicate that fibromyalgia patients may benefit from ziprasidone²⁶ and olanzapine,²⁷ most often as an adjunctive treatment rather than monotherapy. Randomized controlled studies indicate poor tolerability with several atypical antipsychotics. Weight gain, akathisia, and somnolence are side effects of some atypical antipsychotics. Additionally, ziprasidone has been associated with QTc prolongation. For chronic pain patients, atypical antipsychotics are most useful for treating psychiatric comorbidities.

Box

Related Resources

• Leo RJ. Chronic nonmalignant pain: How to ‘turn down’ its physiologic triggers. Current Psychiatry. 2008;7(8):19-36.
• Nikolaus T, Zeyfang A. Pharmacological treatments for persistent non-malignant pain in older persons. Drugs Aging. 2004;21(1):19-41.
• World Health Organization. WHO’s pain ladder. www.who.int/cancer/palliative/painladder/en.

Drug Brand Names

• Acetaminophen • Tylenol
• Amitriptyline • Elavil, others
• Amoxapine • Asendin
• Carbamazepine • Tegretol, Carbatrol, others
• Clomipramine • Anafranil
• Desipramine • Norpramin
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Gabapentin • Neurontin, Gralise
• Imipramine • Tofranil
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Methotrexate • Rheumatrex, Trexall
• Milnacipran • Savella
• Nortriptyline • Aventyl, Pamelor
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Pregabalin • Lyrica
• Topiramate • Topamax, Topiragen
• Venlafaxine • Effexor
• iprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Of the 56 million American adults who report living with chronic pain almost 60% also exhibit psychiatric disorders such as depression or anxiety.^1,2 Because patients with chronic pain suffer from a mixture of physical and psychological components, managing such conditions is complicated, and using opioids is tempting. However, treatment needs to address the underlying pathology along with social and psychological factors.

Because substance abuse treatment admissions increased by 400% from 1998 to 2008,³ many physicians look to non-opioids and other treatment modalities to control chronic non-cancer pain. Common pharmacologic therapies used to treat chronic pain include tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), antiepileptic drugs (AEDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and, to a lesser extent, atypical antipsychotics. TCAs, SNRIs, AEDs, NSAIDs, and atypical antipsychotics influence a variety of presumed underlying pathophysiological processes, including inflammatory mediators, activity of N-methyl-d-aspartate (NMDA) receptors, and voltage-gated calcium channels. In addition, they increase activity of descending inhibitory pain pathways. Animal studies suggest dysfunction of these inhibitory mechanisms contributes to the central sensitization and hyperexcitability of pain transmitting pathways.⁴

In this article, we discuss psychotropics and other non-opioid agents for treating pain. However, no single solution is best for all patients with chronic pain and this article is not a “how to” guide to avoid administering opioid medication. Also incorporate a multimodal, non-pharmacologic approach whenever possible.

Tricyclic antidepressants

Although this class acts primarily by increasing serotonin levels, norepinephrine and dopamine also are affected depending on the particular medication. Studies have shown that amitriptyline, nortriptyline, and desipramine function well as analgesics independent of their antidepressant effects.⁵ TCAs may improve pain symptoms at lower therapeutic dosages than those used for treating depression.⁵

Although researchers have not elucidated TCAs’ mechanism of action with regards to analgesia, they are thought to act within the concept of the gating theory of pain control,⁶ which functions by activation and inhibition of pain signal transmission. It is believed TCAs act on nociceptive pathways by blocking serotonin and norepinephrine reuptake. Although researchers previously thought that TCAs’ analgesic mechanism was correlated to serotonin reuptake inhibition, this theory has changed. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine have not demonstrated substantial effectiveness in neuropathic pain when compared with TCAs and SNRIs. Recent studies have shown that TCAs may work by blocking sodium channels, similar to local anesthetics and antiarrhythmic agents.⁷

Psychiatrists prescribe TCAs infrequently because of these drugs’ unfavorable side effect profile compared with SSRIs and SNRIs. However, TCAs often are prescribed for pain management as an adjunct to other medications for neuropathic conditions and at lower dosages than those used for treating depression (Table 1).⁸

Table 1

Tricyclic antidepressants used to treat pain

SNRIs

Evidence supports using duloxetine, a potent SNRI that mediates pain inhibition in the descending pathways, for 4 chronic pain conditions:

• diabetic peripheral neuropathic pain
• fibromyalgia
• mechanical low back pain
• pain associated with osteoarthritis.⁹

Titrate the dosage to 60 mg/d and maintain the patient at this dose for at least 4 weeks. Thereafter, according to patient response, the dosage may be titrated to 120 mg/d (off-label) with appropriate vital sign monitoring and routine lab analysis.

Venlafaxine also can mediate pain response in a similar manner to duloxetine, but is not FDA-approved for treating pain. Use caution when prescribing venlafaxine for patients with a history of hypertension. Milnacipran is a relatively new SNRI that has been shown to be effective in treating fibromyalgia in divided doses of 100 to 200 mg/d (Table 2).^9-11

Table 2

Treating pain with serotonin-norepinephrine reuptake inhibitors

Antiepileptic drugs

Several AEDs are used for pain management (Table 3).^12-16 Gabapentin and pregabalin work by binding to voltage-gated calcium channels and decreasing excitatory neurotransmitter release. Along with TCAs, they are considered a first-line treatment for managing neuropathic pain.¹⁷ Gabapentin is FDA-approved for seizures and postherpetic neuralgia, but evidence supports its use in most types of neuropathic pain. Pregabalin is FDA-approved for treating seizures, diabetic peripheral neuropathy, central neuropathic pain, postherpetic neuralgia, and fibromyalgia.

Topiramate inhibits excitatory neurotransmission by enhancing the effects of gamma-aminobutyric acid, and also by blocking NMDA receptors. Topiramate is FDA-approved for seizures and migraine prophylaxis, and is used off-label for treating neuropathic pain. A 12-week trial of topiramate for diabetic neuropathy found significant analgesia in 50% of patients taking the drug, compared with 34% receiving placebo.¹⁸

Lamotrigine is approved for several types of seizures and maintenance of bipolar I disorder, and is used off-label for neuropathic pain. A recent Cochrane database review concluded that lamotrigine is ineffective for neuropathic pain¹⁴; however, some guidelines recommend using lamotrigine to treat neuropathies that do not respond to treatment with carbamazepine.¹⁹

Carbamazepine is a complex AED that is structurally similar to TCAs. It blocks sodium channels and has various pharmacologic properties, including anticholinergic, muscle relaxant, antidepressant, and sedative effects. Carbamazepine has analgesic effects through blockade of synaptic transmission in the trigeminal nucleus and is FDA-approved for seizures, bipolar disorder, neuropathic pain, and trigeminal neuralgia. In a systematic review of 12 trials of carbamazepine that included 4 placebo-controlled trials for trigeminal neuralgia, 2 studies showed a number needed to treat (NNT) of 1.8.²⁰ For diabetic neuropathy, there was insufficient data to calculate NNT.

Oxcarbazepine, an analog of carbamazepine, also is FDA-approved for seizures and is used off-label for neuropathic pain. In the only double-blind trial with positive results, oxcarbazepine titrated to 1,800 mg/d reduced diabetic neuropathy pain scores on a visual analog scale by 24 points—roughly 25%.¹⁵

Table 3

Antiepileptic drugs for pain treatment

Non-opioid analgesics

NSAIDs have antipyretic, analgesic, and anti-inflammatory effects and are used for fever, headache, mild-to-moderate pain, musculoskeletal pain, menstrual pain, and dental pain. They are particularly useful in treating acute pain, often in combination with opioid analgesics. NSAIDs exert their analgesic action through blockade of prostaglandin production via reversible inhibition of cyclooxygenase-1 and cyclooxygenase-2.

The most common side effects of NSAIDs are the result of gastrointestinal (GI) toxicity and include dyspepsia, heartburn, nausea, anorexia, and epigastric pain.²¹ GI ulceration and bleeding are rare but serious complications. To decrease these risks, tell patients to take NSAIDs with food. Add a GI protective agent, such as an H2 blocker or proton pump inhibitor, for patients at higher risk for GI complications.²²

In addition, inhibition of renal prostaglandins by NSAIDs can cause renal toxicity, fluid retention, and edema, potentially exacerbating existing cardiovascular conditions such as hypertension and heart failure. NSAIDs may increase the risk of serious thrombotic events such as myocardial infarction and stroke. Use NSAIDs at the lowest effective dose for the shortest duration possible and generally avoid prescribing in patients at high risk for cardiovascular disease and pregnant women, especially those in their third trimester.^23,24

NSAIDs may cause pharmacodynamic and pharmacokinetic drug-drug interactions. The risk of GI toxicity and bleeding increases when NSAIDs are administered with drugs that also irritate the gastric mucosa or have antiplatelet/anticoagulant effects.²¹ Plasma concentrations of drugs with a narrow therapeutic index that are renally eliminated, such as methotrexate and lithium, can increase to potentially toxic levels with concurrent NSAID use because NSAIDs decrease renal perfusion.²¹ Also, the therapeutic effects of antihypertensives may be attenuated because NSAIDs cause fluid retention.²⁵

Acetaminophen (APAP) is available in several dosage forms as a single ingredient and in combination with opioids in prescription products. For more information about APAP, see the Box below.

Atypical antipsychotics

Although atypical antipsychotics are not often used to treat pain, studies indicate that fibromyalgia patients may benefit from ziprasidone²⁶ and olanzapine,²⁷ most often as an adjunctive treatment rather than monotherapy. Randomized controlled studies indicate poor tolerability with several atypical antipsychotics. Weight gain, akathisia, and somnolence are side effects of some atypical antipsychotics. Additionally, ziprasidone has been associated with QTc prolongation. For chronic pain patients, atypical antipsychotics are most useful for treating psychiatric comorbidities.

Box

Related Resources

• Leo RJ. Chronic nonmalignant pain: How to ‘turn down’ its physiologic triggers. Current Psychiatry. 2008;7(8):19-36.
• Nikolaus T, Zeyfang A. Pharmacological treatments for persistent non-malignant pain in older persons. Drugs Aging. 2004;21(1):19-41.
• World Health Organization. WHO’s pain ladder. www.who.int/cancer/palliative/painladder/en.

Drug Brand Names

• Acetaminophen • Tylenol
• Amitriptyline • Elavil, others
• Amoxapine • Asendin
• Carbamazepine • Tegretol, Carbatrol, others
• Clomipramine • Anafranil
• Desipramine • Norpramin
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Gabapentin • Neurontin, Gralise
• Imipramine • Tofranil
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Methotrexate • Rheumatrex, Trexall
• Milnacipran • Savella
• Nortriptyline • Aventyl, Pamelor
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Pregabalin • Lyrica
• Topiramate • Topamax, Topiragen
• Venlafaxine • Effexor
• iprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Of the 56 million American adults who report living with chronic pain almost 60% also exhibit psychiatric disorders such as depression or anxiety.^1,2 Because patients with chronic pain suffer from a mixture of physical and psychological components, managing such conditions is complicated, and using opioids is tempting. However, treatment needs to address the underlying pathology along with social and psychological factors.

Because substance abuse treatment admissions increased by 400% from 1998 to 2008,³ many physicians look to non-opioids and other treatment modalities to control chronic non-cancer pain. Common pharmacologic therapies used to treat chronic pain include tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), antiepileptic drugs (AEDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and, to a lesser extent, atypical antipsychotics. TCAs, SNRIs, AEDs, NSAIDs, and atypical antipsychotics influence a variety of presumed underlying pathophysiological processes, including inflammatory mediators, activity of N-methyl-d-aspartate (NMDA) receptors, and voltage-gated calcium channels. In addition, they increase activity of descending inhibitory pain pathways. Animal studies suggest dysfunction of these inhibitory mechanisms contributes to the central sensitization and hyperexcitability of pain transmitting pathways.⁴

In this article, we discuss psychotropics and other non-opioid agents for treating pain. However, no single solution is best for all patients with chronic pain and this article is not a “how to” guide to avoid administering opioid medication. Also incorporate a multimodal, non-pharmacologic approach whenever possible.

Tricyclic antidepressants

Although this class acts primarily by increasing serotonin levels, norepinephrine and dopamine also are affected depending on the particular medication. Studies have shown that amitriptyline, nortriptyline, and desipramine function well as analgesics independent of their antidepressant effects.⁵ TCAs may improve pain symptoms at lower therapeutic dosages than those used for treating depression.⁵

Although researchers have not elucidated TCAs’ mechanism of action with regards to analgesia, they are thought to act within the concept of the gating theory of pain control,⁶ which functions by activation and inhibition of pain signal transmission. It is believed TCAs act on nociceptive pathways by blocking serotonin and norepinephrine reuptake. Although researchers previously thought that TCAs’ analgesic mechanism was correlated to serotonin reuptake inhibition, this theory has changed. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine have not demonstrated substantial effectiveness in neuropathic pain when compared with TCAs and SNRIs. Recent studies have shown that TCAs may work by blocking sodium channels, similar to local anesthetics and antiarrhythmic agents.⁷

Psychiatrists prescribe TCAs infrequently because of these drugs’ unfavorable side effect profile compared with SSRIs and SNRIs. However, TCAs often are prescribed for pain management as an adjunct to other medications for neuropathic conditions and at lower dosages than those used for treating depression (Table 1).⁸

Table 1

Tricyclic antidepressants used to treat pain

SNRIs

Evidence supports using duloxetine, a potent SNRI that mediates pain inhibition in the descending pathways, for 4 chronic pain conditions:

• diabetic peripheral neuropathic pain
• fibromyalgia
• mechanical low back pain
• pain associated with osteoarthritis.⁹

Titrate the dosage to 60 mg/d and maintain the patient at this dose for at least 4 weeks. Thereafter, according to patient response, the dosage may be titrated to 120 mg/d (off-label) with appropriate vital sign monitoring and routine lab analysis.

Venlafaxine also can mediate pain response in a similar manner to duloxetine, but is not FDA-approved for treating pain. Use caution when prescribing venlafaxine for patients with a history of hypertension. Milnacipran is a relatively new SNRI that has been shown to be effective in treating fibromyalgia in divided doses of 100 to 200 mg/d (Table 2).^9-11

Table 2

Treating pain with serotonin-norepinephrine reuptake inhibitors

Antiepileptic drugs

Several AEDs are used for pain management (Table 3).^12-16 Gabapentin and pregabalin work by binding to voltage-gated calcium channels and decreasing excitatory neurotransmitter release. Along with TCAs, they are considered a first-line treatment for managing neuropathic pain.¹⁷ Gabapentin is FDA-approved for seizures and postherpetic neuralgia, but evidence supports its use in most types of neuropathic pain. Pregabalin is FDA-approved for treating seizures, diabetic peripheral neuropathy, central neuropathic pain, postherpetic neuralgia, and fibromyalgia.

Topiramate inhibits excitatory neurotransmission by enhancing the effects of gamma-aminobutyric acid, and also by blocking NMDA receptors. Topiramate is FDA-approved for seizures and migraine prophylaxis, and is used off-label for treating neuropathic pain. A 12-week trial of topiramate for diabetic neuropathy found significant analgesia in 50% of patients taking the drug, compared with 34% receiving placebo.¹⁸

Lamotrigine is approved for several types of seizures and maintenance of bipolar I disorder, and is used off-label for neuropathic pain. A recent Cochrane database review concluded that lamotrigine is ineffective for neuropathic pain¹⁴; however, some guidelines recommend using lamotrigine to treat neuropathies that do not respond to treatment with carbamazepine.¹⁹

Carbamazepine is a complex AED that is structurally similar to TCAs. It blocks sodium channels and has various pharmacologic properties, including anticholinergic, muscle relaxant, antidepressant, and sedative effects. Carbamazepine has analgesic effects through blockade of synaptic transmission in the trigeminal nucleus and is FDA-approved for seizures, bipolar disorder, neuropathic pain, and trigeminal neuralgia. In a systematic review of 12 trials of carbamazepine that included 4 placebo-controlled trials for trigeminal neuralgia, 2 studies showed a number needed to treat (NNT) of 1.8.²⁰ For diabetic neuropathy, there was insufficient data to calculate NNT.

Oxcarbazepine, an analog of carbamazepine, also is FDA-approved for seizures and is used off-label for neuropathic pain. In the only double-blind trial with positive results, oxcarbazepine titrated to 1,800 mg/d reduced diabetic neuropathy pain scores on a visual analog scale by 24 points—roughly 25%.¹⁵

Table 3

Antiepileptic drugs for pain treatment

Non-opioid analgesics

NSAIDs have antipyretic, analgesic, and anti-inflammatory effects and are used for fever, headache, mild-to-moderate pain, musculoskeletal pain, menstrual pain, and dental pain. They are particularly useful in treating acute pain, often in combination with opioid analgesics. NSAIDs exert their analgesic action through blockade of prostaglandin production via reversible inhibition of cyclooxygenase-1 and cyclooxygenase-2.

The most common side effects of NSAIDs are the result of gastrointestinal (GI) toxicity and include dyspepsia, heartburn, nausea, anorexia, and epigastric pain.²¹ GI ulceration and bleeding are rare but serious complications. To decrease these risks, tell patients to take NSAIDs with food. Add a GI protective agent, such as an H2 blocker or proton pump inhibitor, for patients at higher risk for GI complications.²²

In addition, inhibition of renal prostaglandins by NSAIDs can cause renal toxicity, fluid retention, and edema, potentially exacerbating existing cardiovascular conditions such as hypertension and heart failure. NSAIDs may increase the risk of serious thrombotic events such as myocardial infarction and stroke. Use NSAIDs at the lowest effective dose for the shortest duration possible and generally avoid prescribing in patients at high risk for cardiovascular disease and pregnant women, especially those in their third trimester.^23,24

NSAIDs may cause pharmacodynamic and pharmacokinetic drug-drug interactions. The risk of GI toxicity and bleeding increases when NSAIDs are administered with drugs that also irritate the gastric mucosa or have antiplatelet/anticoagulant effects.²¹ Plasma concentrations of drugs with a narrow therapeutic index that are renally eliminated, such as methotrexate and lithium, can increase to potentially toxic levels with concurrent NSAID use because NSAIDs decrease renal perfusion.²¹ Also, the therapeutic effects of antihypertensives may be attenuated because NSAIDs cause fluid retention.²⁵

Acetaminophen (APAP) is available in several dosage forms as a single ingredient and in combination with opioids in prescription products. For more information about APAP, see the Box below.

Atypical antipsychotics

Although atypical antipsychotics are not often used to treat pain, studies indicate that fibromyalgia patients may benefit from ziprasidone²⁶ and olanzapine,²⁷ most often as an adjunctive treatment rather than monotherapy. Randomized controlled studies indicate poor tolerability with several atypical antipsychotics. Weight gain, akathisia, and somnolence are side effects of some atypical antipsychotics. Additionally, ziprasidone has been associated with QTc prolongation. For chronic pain patients, atypical antipsychotics are most useful for treating psychiatric comorbidities.

Box

Related Resources

• Leo RJ. Chronic nonmalignant pain: How to ‘turn down’ its physiologic triggers. Current Psychiatry. 2008;7(8):19-36.
• Nikolaus T, Zeyfang A. Pharmacological treatments for persistent non-malignant pain in older persons. Drugs Aging. 2004;21(1):19-41.
• World Health Organization. WHO’s pain ladder. www.who.int/cancer/palliative/painladder/en.

Drug Brand Names

• Acetaminophen • Tylenol
• Amitriptyline • Elavil, others
• Amoxapine • Asendin
• Carbamazepine • Tegretol, Carbatrol, others
• Clomipramine • Anafranil
• Desipramine • Norpramin
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Gabapentin • Neurontin, Gralise
• Imipramine • Tofranil
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Methotrexate • Rheumatrex, Trexall
• Milnacipran • Savella
• Nortriptyline • Aventyl, Pamelor
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Pregabalin • Lyrica
• Topiramate • Topamax, Topiragen
• Venlafaxine • Effexor
• iprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Dr. Goldberg makes an important point that not all mood lability indicates bipolar disorder (BD) in “Ultra-rapid cycling bipolar disorder: A critical look” (Current Psychiatry, December 2011, p. 42-52).

However, there was 1 significant diagnostic omission. Patients with adult attention-deficit/hyperactivity disorder (ADHD) can present with an unremarkable mental status exam, yet can give a history of abrupt episodes of dyscontrol, often in interpersonal situations. As opposed to children manifesting ADHD, where comorbidity with BD is substantial, adults may primarily display impulsivity rather than hyperactivity or inattention. By ignoring this diagnostic consideration, important pharmacotherapeutic options have been discarded, although cognitive-behavioral therapy and dialectical behavior therapy for “borderline” patients are always relevant. Regardless of diagnostic terms and the fate of DSM-5, our treatment approach serves to strengthen prefrontal cortex inhibitory activity and block limbic system reactivity.

Robert Barris, MD
Attending Psychiatrist
Nassau University Medical Center
East Meadow, NY

Dr. Goldberg responds

Drs. Bunt and Barris each raise the clinically and theoretically interesting observation that in patients whose childhood attention-deficit/hyperactivity disorder (ADHD) persists into adulthood, affective instability may be a prominent feature. Consequently, they advise that complaints of frequent mood swings within 1 day should alert clinicians to consider ADHD in their differential diagnosis.

Importantly, emotional dysregulation is not an established criterion for ADHD, although investigators have begun to study impaired emotional processing in adults with ADHD.¹ Because observational research examining emotional dysregulation in adult ADHD is preliminary, I cannot concur with Dr. Bunt’s assertion that “an omission of this sort does a disservice to the field.”

To the contrary, it would seem premature to counsel practitioners to look for mood instability as a red flag for adult ADHD. In fact, given the nontrivial rates of comorbid mood disorders with ADHD as cited by Dr. Bunt, it’s plausible that mood instability co-occurring with ADHD simply may be the epiphenomenon of a psychiatric comorbidity such as borderline personality disorder,² a disruptive behavior disorder,³ or substance abuse.³

Moreover, endophenotype studies suggest that emotional lability and ADHD do not cosegregate in families.³ Further research is needed to determine whether moment-to-moment mood fluctuations are an intrinsic feature of ADHD that is not better accounted for by another accompanying condition.

Dr. Bunt appears to have misconstrued my use of the term “validation” with respect to ultra-rapid cycling (URC) as if I had been referring to validation of URC as a diagnosis—which I never suggested—rather than as a putative course modifier or specifier in an otherwise-diagnosed bipolar disorder patient—as was the case when researchers empirically validated rapid cycling (RC) as a bipolar course specifier, leading to its inclusion in DSM-IV.⁴ To my knowledge there’s no movement to consider URC as a bipolar course specifier in DSM-5, which would be a difficult undertaking in the absence of field trials such as those conducted for bipolar RC.

Drs. Barris, Bunt, and I seem to agree that mood shifts occurring on a daily or more frequent basis constitute a non-pathognomonic phenomenon for which “careful evaluation” is necessary to discern the broader psychopathologic condition and context in which it arises.

Joseph F. Goldberg, MD
Associate Clinical Professor of Psychiatry
Mt. Sinai School of Medicine
New York, NY

References

1. Herrmann MJ, Biehl SC, Jacob C, et al. Neurobiological and psychophysiological correlates of emotional dysregulation in ADHD patients. Atten Defic Hyperact Disord. 2010;2(4):233-239.

2. Philipsen A, Feige B, Hesslinger B, et al. Borderline typical symptoms in adult patients with attention deficit/hyperactivity disorder. Atten Defic Hyperact Disord. 2009;1(1):11-18.

3. Sobanski E, Banaschewski T, Asherson P, et al. Emotional lability in children and adolescents with attention deficit/hyperactivity disorder (ADHD): clinical correlates and familial prevalence. J Child Psychol Psychiatry. 2010;51(8):915-923.

4. Bauer MS, Calabrese J, Dunner DL, et al. Multisite data reanalysis of the validity of rapid cycling as a course modifier for bipolar disorder in DSM-IV. Am J Psychiatry. 1994;151(4):506-515.

Discuss this article at www.facebook.com/CurrentPsychiatry

Dr. Goldberg makes an important point that not all mood lability indicates bipolar disorder (BD) in “Ultra-rapid cycling bipolar disorder: A critical look” (Current Psychiatry, December 2011, p. 42-52).

However, there was 1 significant diagnostic omission. Patients with adult attention-deficit/hyperactivity disorder (ADHD) can present with an unremarkable mental status exam, yet can give a history of abrupt episodes of dyscontrol, often in interpersonal situations. As opposed to children manifesting ADHD, where comorbidity with BD is substantial, adults may primarily display impulsivity rather than hyperactivity or inattention. By ignoring this diagnostic consideration, important pharmacotherapeutic options have been discarded, although cognitive-behavioral therapy and dialectical behavior therapy for “borderline” patients are always relevant. Regardless of diagnostic terms and the fate of DSM-5, our treatment approach serves to strengthen prefrontal cortex inhibitory activity and block limbic system reactivity.

Robert Barris, MD
Attending Psychiatrist
Nassau University Medical Center
East Meadow, NY

Dr. Goldberg responds

Drs. Bunt and Barris each raise the clinically and theoretically interesting observation that in patients whose childhood attention-deficit/hyperactivity disorder (ADHD) persists into adulthood, affective instability may be a prominent feature. Consequently, they advise that complaints of frequent mood swings within 1 day should alert clinicians to consider ADHD in their differential diagnosis.

Importantly, emotional dysregulation is not an established criterion for ADHD, although investigators have begun to study impaired emotional processing in adults with ADHD.¹ Because observational research examining emotional dysregulation in adult ADHD is preliminary, I cannot concur with Dr. Bunt’s assertion that “an omission of this sort does a disservice to the field.”

To the contrary, it would seem premature to counsel practitioners to look for mood instability as a red flag for adult ADHD. In fact, given the nontrivial rates of comorbid mood disorders with ADHD as cited by Dr. Bunt, it’s plausible that mood instability co-occurring with ADHD simply may be the epiphenomenon of a psychiatric comorbidity such as borderline personality disorder,² a disruptive behavior disorder,³ or substance abuse.³

Moreover, endophenotype studies suggest that emotional lability and ADHD do not cosegregate in families.³ Further research is needed to determine whether moment-to-moment mood fluctuations are an intrinsic feature of ADHD that is not better accounted for by another accompanying condition.

Dr. Bunt appears to have misconstrued my use of the term “validation” with respect to ultra-rapid cycling (URC) as if I had been referring to validation of URC as a diagnosis—which I never suggested—rather than as a putative course modifier or specifier in an otherwise-diagnosed bipolar disorder patient—as was the case when researchers empirically validated rapid cycling (RC) as a bipolar course specifier, leading to its inclusion in DSM-IV.⁴ To my knowledge there’s no movement to consider URC as a bipolar course specifier in DSM-5, which would be a difficult undertaking in the absence of field trials such as those conducted for bipolar RC.

Drs. Barris, Bunt, and I seem to agree that mood shifts occurring on a daily or more frequent basis constitute a non-pathognomonic phenomenon for which “careful evaluation” is necessary to discern the broader psychopathologic condition and context in which it arises.

Joseph F. Goldberg, MD
Associate Clinical Professor of Psychiatry
Mt. Sinai School of Medicine
New York, NY

References

1. Herrmann MJ, Biehl SC, Jacob C, et al. Neurobiological and psychophysiological correlates of emotional dysregulation in ADHD patients. Atten Defic Hyperact Disord. 2010;2(4):233-239.

2. Philipsen A, Feige B, Hesslinger B, et al. Borderline typical symptoms in adult patients with attention deficit/hyperactivity disorder. Atten Defic Hyperact Disord. 2009;1(1):11-18.

3. Sobanski E, Banaschewski T, Asherson P, et al. Emotional lability in children and adolescents with attention deficit/hyperactivity disorder (ADHD): clinical correlates and familial prevalence. J Child Psychol Psychiatry. 2010;51(8):915-923.

4. Bauer MS, Calabrese J, Dunner DL, et al. Multisite data reanalysis of the validity of rapid cycling as a course modifier for bipolar disorder in DSM-IV. Am J Psychiatry. 1994;151(4):506-515.

Discuss this article at www.facebook.com/CurrentPsychiatry

Dr. Goldberg makes an important point that not all mood lability indicates bipolar disorder (BD) in “Ultra-rapid cycling bipolar disorder: A critical look” (Current Psychiatry, December 2011, p. 42-52).

However, there was 1 significant diagnostic omission. Patients with adult attention-deficit/hyperactivity disorder (ADHD) can present with an unremarkable mental status exam, yet can give a history of abrupt episodes of dyscontrol, often in interpersonal situations. As opposed to children manifesting ADHD, where comorbidity with BD is substantial, adults may primarily display impulsivity rather than hyperactivity or inattention. By ignoring this diagnostic consideration, important pharmacotherapeutic options have been discarded, although cognitive-behavioral therapy and dialectical behavior therapy for “borderline” patients are always relevant. Regardless of diagnostic terms and the fate of DSM-5, our treatment approach serves to strengthen prefrontal cortex inhibitory activity and block limbic system reactivity.

Robert Barris, MD
Attending Psychiatrist
Nassau University Medical Center
East Meadow, NY

Dr. Goldberg responds

Drs. Bunt and Barris each raise the clinically and theoretically interesting observation that in patients whose childhood attention-deficit/hyperactivity disorder (ADHD) persists into adulthood, affective instability may be a prominent feature. Consequently, they advise that complaints of frequent mood swings within 1 day should alert clinicians to consider ADHD in their differential diagnosis.

Importantly, emotional dysregulation is not an established criterion for ADHD, although investigators have begun to study impaired emotional processing in adults with ADHD.¹ Because observational research examining emotional dysregulation in adult ADHD is preliminary, I cannot concur with Dr. Bunt’s assertion that “an omission of this sort does a disservice to the field.”

To the contrary, it would seem premature to counsel practitioners to look for mood instability as a red flag for adult ADHD. In fact, given the nontrivial rates of comorbid mood disorders with ADHD as cited by Dr. Bunt, it’s plausible that mood instability co-occurring with ADHD simply may be the epiphenomenon of a psychiatric comorbidity such as borderline personality disorder,² a disruptive behavior disorder,³ or substance abuse.³

Moreover, endophenotype studies suggest that emotional lability and ADHD do not cosegregate in families.³ Further research is needed to determine whether moment-to-moment mood fluctuations are an intrinsic feature of ADHD that is not better accounted for by another accompanying condition.

Dr. Bunt appears to have misconstrued my use of the term “validation” with respect to ultra-rapid cycling (URC) as if I had been referring to validation of URC as a diagnosis—which I never suggested—rather than as a putative course modifier or specifier in an otherwise-diagnosed bipolar disorder patient—as was the case when researchers empirically validated rapid cycling (RC) as a bipolar course specifier, leading to its inclusion in DSM-IV.⁴ To my knowledge there’s no movement to consider URC as a bipolar course specifier in DSM-5, which would be a difficult undertaking in the absence of field trials such as those conducted for bipolar RC.

Drs. Barris, Bunt, and I seem to agree that mood shifts occurring on a daily or more frequent basis constitute a non-pathognomonic phenomenon for which “careful evaluation” is necessary to discern the broader psychopathologic condition and context in which it arises.

Joseph F. Goldberg, MD
Associate Clinical Professor of Psychiatry
Mt. Sinai School of Medicine
New York, NY

References

1. Herrmann MJ, Biehl SC, Jacob C, et al. Neurobiological and psychophysiological correlates of emotional dysregulation in ADHD patients. Atten Defic Hyperact Disord. 2010;2(4):233-239.

2. Philipsen A, Feige B, Hesslinger B, et al. Borderline typical symptoms in adult patients with attention deficit/hyperactivity disorder. Atten Defic Hyperact Disord. 2009;1(1):11-18.

3. Sobanski E, Banaschewski T, Asherson P, et al. Emotional lability in children and adolescents with attention deficit/hyperactivity disorder (ADHD): clinical correlates and familial prevalence. J Child Psychol Psychiatry. 2010;51(8):915-923.

4. Bauer MS, Calabrese J, Dunner DL, et al. Multisite data reanalysis of the validity of rapid cycling as a course modifier for bipolar disorder in DSM-IV. Am J Psychiatry. 1994;151(4):506-515.

Discuss this article at www.facebook.com/CurrentPsychiatry

CASE: Sleepless and paranoid

Ms. V, age 16, is referred to our psychiatric hospital from a juvenile detention center after she is charged with killing her sister with a hammer. She reports paranoid delusions, including believing that her sister was poisoning her food. Ms. V’s troubling behavior increased in the 6 months before the murder. She began to ask her mother to smell her food for possible poison. Her school grades dropped and she experienced decreased sleep and appetite. According to her mother, Ms. V’s insomnia worsened recently because of her paranoid thinking, which was evident when she noticed that her daughter slept with a hammer. Ms. V stopped socializing with her peers and no longer went to the gym.

Ms. V’s mother describes her daughter’s negative symptoms as consisting of social isolation and a flat affect. There was no evidence of auditory or visual hallucinations. After noticing the change in her daughter’s behavior, Ms. V’s mother attempted to schedule an appointment with a mental health professional, but there was a 2-month waiting list.

Ms. V cleaned her room before the murder, which was uncharacteristic of her routine behavior. On the day of the murder, Ms. V approached her sister while she was sleeping on the sofa and struck her on the head several times with a hammer. After the sister died, neighbors spotted Ms. V washing blood off her hands in their backyard with a sprinkler. Soaked in blood, she approached one of the neighbors and said that someone had been killed in the house. The neighbors called the police and Ms. V was arrested. She did not express remorse. She did not exhibit physical aggression toward others before the murder. Ms. V’s sense of entitlement and grandiosity persisted after the murder.

The authors’ observations

Paranoid delusions are fixed false beliefs with severe fears of others that may impair functioning at school or work, in personal relationships, and in other social dimensions. Paranoid thinking can have diverse presentations, ranging from social concerns such as fear of rejection to severe threat perceptions of people trying to cause substantial physical harm.¹ Paranoid thoughts can be a result of misinterpretation of language, a personality disorder, anxiety, or psychosis.

Feelings of low self-esteem² and anger¹ may develop in a patient experiencing paranoid ideations. When anger begins to escalate, it may erupt into violent behavior. In Ms. V’s case, her paranoid ideations increased until she killed her younger sister. Ms. V’s case is similar to a mass shooting near Tucson, AZ on January 8, 2011 in that it possibly could have been prevented with earlier psychiatric intervention (Box).^3-6

Box

EVALUATION: Remorseless

At admission, Ms. V’s affect is restricted and, at times, inappropriate. She is guarded about discussing the homicide but describes paranoid thoughts about her sister poisoning her. She is eager to learn if the police had found poison in her food. Her speech is soft with good articulation. Based on her presentation, her intelligence is average. She shows no evidence of remorse and is preoccupied with her sister poisoning her.

The Rorschach Inkblot Technique reveals positive evidence for a severe thought disorder. Ms. V’s thinking seems regressed. Ms. V’s medical workup, including MRI, electroencephalogram, and laboratory tests, are all within normal limits.

In the 5th grade, Ms. V’s primary care provider prescribed amphetamine and dextroamphetamine for attention-deficit/hyperactivity disorder, but she discontinued the drug after 1 year. Ms. V has never been hospitalized for psychiatric illness. She had no chronic medical conditions and no developmental delays.

Ms. V also has a history of periodic temper problems characterized by verbal aggression such as threatening the assistant principal at her school, and throwing her cellphone at her mother a few weeks before the murder, but no other aggressive episodes. Ms. V’s history does not suggest conduct disorder. She has no history of suicidal ideation or suicide attempts. Ms. V has used alcohol since age 15, but her mother reports that she was not a heavy or frequent user. Her last reported alcohol use was 10 days before the murder. A maternal uncle had been diagnosed with schizophrenia.

Before the murder, Ms. V lived with her sister and mother. Her parents were divorced. At age 9, Ms. V was sexually abused by a soccer coach; however, she denied symptoms of posttraumatic stress disorder related to the sexual abuse. She had no criminal history before the murder.

The authors’ observations

Based on Ms. V’s presentation and history, schizophrenia, paranoid type seems to be the most likely diagnosis because of her negative symptoms, including affective flattening, positive family history for schizophrenia, and paranoid delusions leading to dysfunction (Table).⁷ Delusional disorder seems less likely because Ms. V is young and has negative symptoms. Because she is generally healthy and her medical workup is negative, psychotic disorder due to a general medical condition is ruled out. She does not appear to be over-reporting, malingering, or exaggerating symptoms. In the context of psychosis, adolescent psychopathy does not seem likely even though there is evidence of grandiosity and a lack of remorse.

Table

DSM-IV-TR criteria for schizophrenia

The authors’ observations

Various treatments can be used for paranoia with aggression, but the severity of the paranoia should be assessed before initiating treatment. Although categorizing paranoid ideations as mild, moderate, and severe is mainly a clinical judgment, Freeman et al¹ have attempted to design a paranoia hierarchy from social concerns to severe threats. CBT⁸ and antipsychotic medication may help reduce mild to moderate paranoid delusions, particularly those associated with schizophrenia or mood disorders. For severe paranoia, hospitalization should carefully be considered.

When a patient exhibits moderate paranoia, the probability of progressing to severe symptoms or improving to mild symptoms depends on several variables. Pharmacologic treatment, family insight, and social support may be important variables in such circumstances. Psychoeducation for the family is vital.

In patients experiencing paranoia, violence may be prevented by proper assessment and treatment. The patient’s family should be educated about paranoid ideation and the need for treatment to improve symptoms and ensure safety. The long-term effects of untreated paranoia and types of treatment modalities available should be discussed with the family and the patient. During these teaching sessions, focus on improving the overall insight of the family and the patient about the psychotic illness to improve treatment adherence.⁹ This step may be challenging if the family is resistant to the patient receiving mental health treatment.

Gaining a detailed clinical history of a patient’s paranoia is important. A clinician should look for changes in behavior, such as the patient becoming quieter or more hostile, and impaired academic or social functioning. After gathering sufficient evidence contrary to the delusion, clinicians can help patients improve their reality testing.

Rule out medical and neurologic conditions that may be contributing to paranoia and aggression.

TREATMENT: Some improvement

Ms. V is started on risperidone, 1 mg/d, which leads to a partial response. She starts interacting more with staff and her peers on the unit, but her delusions of her sister poisioning her persist. Given the severity of the crime, Ms. V is sent to adult court, where she is found not guilty by reason of insanity and committed to a state hospital.

The authors’ observations

New-onset paranoia is a serious symptom that requires immediate evaluation and treatment. We recommend an approach presened in a flowchart (Figure) that highlights the importance of early intervention and aggressive treatment.

The MacArthur Violence Risk Assessment Study¹⁰ indicated that a “suspicious” attitude toward others can be a precipitating cause for increased violence in some cases. In light of ongoing controversy regarding the link between violence and mental illnesses such as schizophrenia,^10-12 addressing an individual’s psychiatric illness early is preferable to prevent possible complications such as violent crimes. Because patients with paranoid ideations may have severely impaired ego control, they may be at risk for acting out aggressive and/or destructive urges. Therefore, new-onset paranoia should be thought of as a medical emergency similar to chest pain. Although accurately predicting and preventing violence may be impossible, in Ms. V’s case, earlier mental health treatment and intervention may have been able to prevent a murder.

Figure: Paranoia: A suggested approach to treatment

Related Resource

• Marneros A, Pillmann F, Wustmann T. Delusional disorders—are they simply paranoid schizophrenia? [published online ahead of print November 15, 2010]. Schizophr Bull. doi: 10.1093/schbul/sbq125.

Drug Brand Names

Amphetamine and dextroamphetamine • Adderall

Risperidone • Risperdal

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Personal and clinical details of this case were altered to maintain patient confidentiality.

Discuss this article at www.facebook.com/CurrentPsychiatry

CASE: Sleepless and paranoid

Ms. V, age 16, is referred to our psychiatric hospital from a juvenile detention center after she is charged with killing her sister with a hammer. She reports paranoid delusions, including believing that her sister was poisoning her food. Ms. V’s troubling behavior increased in the 6 months before the murder. She began to ask her mother to smell her food for possible poison. Her school grades dropped and she experienced decreased sleep and appetite. According to her mother, Ms. V’s insomnia worsened recently because of her paranoid thinking, which was evident when she noticed that her daughter slept with a hammer. Ms. V stopped socializing with her peers and no longer went to the gym.

Ms. V’s mother describes her daughter’s negative symptoms as consisting of social isolation and a flat affect. There was no evidence of auditory or visual hallucinations. After noticing the change in her daughter’s behavior, Ms. V’s mother attempted to schedule an appointment with a mental health professional, but there was a 2-month waiting list.

Ms. V cleaned her room before the murder, which was uncharacteristic of her routine behavior. On the day of the murder, Ms. V approached her sister while she was sleeping on the sofa and struck her on the head several times with a hammer. After the sister died, neighbors spotted Ms. V washing blood off her hands in their backyard with a sprinkler. Soaked in blood, she approached one of the neighbors and said that someone had been killed in the house. The neighbors called the police and Ms. V was arrested. She did not express remorse. She did not exhibit physical aggression toward others before the murder. Ms. V’s sense of entitlement and grandiosity persisted after the murder.

The authors’ observations

Paranoid delusions are fixed false beliefs with severe fears of others that may impair functioning at school or work, in personal relationships, and in other social dimensions. Paranoid thinking can have diverse presentations, ranging from social concerns such as fear of rejection to severe threat perceptions of people trying to cause substantial physical harm.¹ Paranoid thoughts can be a result of misinterpretation of language, a personality disorder, anxiety, or psychosis.

Feelings of low self-esteem² and anger¹ may develop in a patient experiencing paranoid ideations. When anger begins to escalate, it may erupt into violent behavior. In Ms. V’s case, her paranoid ideations increased until she killed her younger sister. Ms. V’s case is similar to a mass shooting near Tucson, AZ on January 8, 2011 in that it possibly could have been prevented with earlier psychiatric intervention (Box).^3-6

Box

EVALUATION: Remorseless

At admission, Ms. V’s affect is restricted and, at times, inappropriate. She is guarded about discussing the homicide but describes paranoid thoughts about her sister poisoning her. She is eager to learn if the police had found poison in her food. Her speech is soft with good articulation. Based on her presentation, her intelligence is average. She shows no evidence of remorse and is preoccupied with her sister poisoning her.

The Rorschach Inkblot Technique reveals positive evidence for a severe thought disorder. Ms. V’s thinking seems regressed. Ms. V’s medical workup, including MRI, electroencephalogram, and laboratory tests, are all within normal limits.

In the 5th grade, Ms. V’s primary care provider prescribed amphetamine and dextroamphetamine for attention-deficit/hyperactivity disorder, but she discontinued the drug after 1 year. Ms. V has never been hospitalized for psychiatric illness. She had no chronic medical conditions and no developmental delays.

Ms. V also has a history of periodic temper problems characterized by verbal aggression such as threatening the assistant principal at her school, and throwing her cellphone at her mother a few weeks before the murder, but no other aggressive episodes. Ms. V’s history does not suggest conduct disorder. She has no history of suicidal ideation or suicide attempts. Ms. V has used alcohol since age 15, but her mother reports that she was not a heavy or frequent user. Her last reported alcohol use was 10 days before the murder. A maternal uncle had been diagnosed with schizophrenia.

Before the murder, Ms. V lived with her sister and mother. Her parents were divorced. At age 9, Ms. V was sexually abused by a soccer coach; however, she denied symptoms of posttraumatic stress disorder related to the sexual abuse. She had no criminal history before the murder.

The authors’ observations

Based on Ms. V’s presentation and history, schizophrenia, paranoid type seems to be the most likely diagnosis because of her negative symptoms, including affective flattening, positive family history for schizophrenia, and paranoid delusions leading to dysfunction (Table).⁷ Delusional disorder seems less likely because Ms. V is young and has negative symptoms. Because she is generally healthy and her medical workup is negative, psychotic disorder due to a general medical condition is ruled out. She does not appear to be over-reporting, malingering, or exaggerating symptoms. In the context of psychosis, adolescent psychopathy does not seem likely even though there is evidence of grandiosity and a lack of remorse.

Table

DSM-IV-TR criteria for schizophrenia

The authors’ observations

Various treatments can be used for paranoia with aggression, but the severity of the paranoia should be assessed before initiating treatment. Although categorizing paranoid ideations as mild, moderate, and severe is mainly a clinical judgment, Freeman et al¹ have attempted to design a paranoia hierarchy from social concerns to severe threats. CBT⁸ and antipsychotic medication may help reduce mild to moderate paranoid delusions, particularly those associated with schizophrenia or mood disorders. For severe paranoia, hospitalization should carefully be considered.

When a patient exhibits moderate paranoia, the probability of progressing to severe symptoms or improving to mild symptoms depends on several variables. Pharmacologic treatment, family insight, and social support may be important variables in such circumstances. Psychoeducation for the family is vital.

In patients experiencing paranoia, violence may be prevented by proper assessment and treatment. The patient’s family should be educated about paranoid ideation and the need for treatment to improve symptoms and ensure safety. The long-term effects of untreated paranoia and types of treatment modalities available should be discussed with the family and the patient. During these teaching sessions, focus on improving the overall insight of the family and the patient about the psychotic illness to improve treatment adherence.⁹ This step may be challenging if the family is resistant to the patient receiving mental health treatment.

Gaining a detailed clinical history of a patient’s paranoia is important. A clinician should look for changes in behavior, such as the patient becoming quieter or more hostile, and impaired academic or social functioning. After gathering sufficient evidence contrary to the delusion, clinicians can help patients improve their reality testing.

Rule out medical and neurologic conditions that may be contributing to paranoia and aggression.

TREATMENT: Some improvement

Ms. V is started on risperidone, 1 mg/d, which leads to a partial response. She starts interacting more with staff and her peers on the unit, but her delusions of her sister poisioning her persist. Given the severity of the crime, Ms. V is sent to adult court, where she is found not guilty by reason of insanity and committed to a state hospital.

The authors’ observations

New-onset paranoia is a serious symptom that requires immediate evaluation and treatment. We recommend an approach presened in a flowchart (Figure) that highlights the importance of early intervention and aggressive treatment.

The MacArthur Violence Risk Assessment Study¹⁰ indicated that a “suspicious” attitude toward others can be a precipitating cause for increased violence in some cases. In light of ongoing controversy regarding the link between violence and mental illnesses such as schizophrenia,^10-12 addressing an individual’s psychiatric illness early is preferable to prevent possible complications such as violent crimes. Because patients with paranoid ideations may have severely impaired ego control, they may be at risk for acting out aggressive and/or destructive urges. Therefore, new-onset paranoia should be thought of as a medical emergency similar to chest pain. Although accurately predicting and preventing violence may be impossible, in Ms. V’s case, earlier mental health treatment and intervention may have been able to prevent a murder.

Figure: Paranoia: A suggested approach to treatment

Related Resource

• Marneros A, Pillmann F, Wustmann T. Delusional disorders—are they simply paranoid schizophrenia? [published online ahead of print November 15, 2010]. Schizophr Bull. doi: 10.1093/schbul/sbq125.

Drug Brand Names

Amphetamine and dextroamphetamine • Adderall

Risperidone • Risperdal

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Personal and clinical details of this case were altered to maintain patient confidentiality.

Discuss this article at www.facebook.com/CurrentPsychiatry

CASE: Sleepless and paranoid

Ms. V, age 16, is referred to our psychiatric hospital from a juvenile detention center after she is charged with killing her sister with a hammer. She reports paranoid delusions, including believing that her sister was poisoning her food. Ms. V’s troubling behavior increased in the 6 months before the murder. She began to ask her mother to smell her food for possible poison. Her school grades dropped and she experienced decreased sleep and appetite. According to her mother, Ms. V’s insomnia worsened recently because of her paranoid thinking, which was evident when she noticed that her daughter slept with a hammer. Ms. V stopped socializing with her peers and no longer went to the gym.

Ms. V’s mother describes her daughter’s negative symptoms as consisting of social isolation and a flat affect. There was no evidence of auditory or visual hallucinations. After noticing the change in her daughter’s behavior, Ms. V’s mother attempted to schedule an appointment with a mental health professional, but there was a 2-month waiting list.

Ms. V cleaned her room before the murder, which was uncharacteristic of her routine behavior. On the day of the murder, Ms. V approached her sister while she was sleeping on the sofa and struck her on the head several times with a hammer. After the sister died, neighbors spotted Ms. V washing blood off her hands in their backyard with a sprinkler. Soaked in blood, she approached one of the neighbors and said that someone had been killed in the house. The neighbors called the police and Ms. V was arrested. She did not express remorse. She did not exhibit physical aggression toward others before the murder. Ms. V’s sense of entitlement and grandiosity persisted after the murder.

The authors’ observations

Paranoid delusions are fixed false beliefs with severe fears of others that may impair functioning at school or work, in personal relationships, and in other social dimensions. Paranoid thinking can have diverse presentations, ranging from social concerns such as fear of rejection to severe threat perceptions of people trying to cause substantial physical harm.¹ Paranoid thoughts can be a result of misinterpretation of language, a personality disorder, anxiety, or psychosis.

Feelings of low self-esteem² and anger¹ may develop in a patient experiencing paranoid ideations. When anger begins to escalate, it may erupt into violent behavior. In Ms. V’s case, her paranoid ideations increased until she killed her younger sister. Ms. V’s case is similar to a mass shooting near Tucson, AZ on January 8, 2011 in that it possibly could have been prevented with earlier psychiatric intervention (Box).^3-6

Box

EVALUATION: Remorseless

At admission, Ms. V’s affect is restricted and, at times, inappropriate. She is guarded about discussing the homicide but describes paranoid thoughts about her sister poisoning her. She is eager to learn if the police had found poison in her food. Her speech is soft with good articulation. Based on her presentation, her intelligence is average. She shows no evidence of remorse and is preoccupied with her sister poisoning her.

The Rorschach Inkblot Technique reveals positive evidence for a severe thought disorder. Ms. V’s thinking seems regressed. Ms. V’s medical workup, including MRI, electroencephalogram, and laboratory tests, are all within normal limits.

In the 5th grade, Ms. V’s primary care provider prescribed amphetamine and dextroamphetamine for attention-deficit/hyperactivity disorder, but she discontinued the drug after 1 year. Ms. V has never been hospitalized for psychiatric illness. She had no chronic medical conditions and no developmental delays.

Ms. V also has a history of periodic temper problems characterized by verbal aggression such as threatening the assistant principal at her school, and throwing her cellphone at her mother a few weeks before the murder, but no other aggressive episodes. Ms. V’s history does not suggest conduct disorder. She has no history of suicidal ideation or suicide attempts. Ms. V has used alcohol since age 15, but her mother reports that she was not a heavy or frequent user. Her last reported alcohol use was 10 days before the murder. A maternal uncle had been diagnosed with schizophrenia.

Before the murder, Ms. V lived with her sister and mother. Her parents were divorced. At age 9, Ms. V was sexually abused by a soccer coach; however, she denied symptoms of posttraumatic stress disorder related to the sexual abuse. She had no criminal history before the murder.

The authors’ observations

Based on Ms. V’s presentation and history, schizophrenia, paranoid type seems to be the most likely diagnosis because of her negative symptoms, including affective flattening, positive family history for schizophrenia, and paranoid delusions leading to dysfunction (Table).⁷ Delusional disorder seems less likely because Ms. V is young and has negative symptoms. Because she is generally healthy and her medical workup is negative, psychotic disorder due to a general medical condition is ruled out. She does not appear to be over-reporting, malingering, or exaggerating symptoms. In the context of psychosis, adolescent psychopathy does not seem likely even though there is evidence of grandiosity and a lack of remorse.

Table

DSM-IV-TR criteria for schizophrenia

The authors’ observations

Various treatments can be used for paranoia with aggression, but the severity of the paranoia should be assessed before initiating treatment. Although categorizing paranoid ideations as mild, moderate, and severe is mainly a clinical judgment, Freeman et al¹ have attempted to design a paranoia hierarchy from social concerns to severe threats. CBT⁸ and antipsychotic medication may help reduce mild to moderate paranoid delusions, particularly those associated with schizophrenia or mood disorders. For severe paranoia, hospitalization should carefully be considered.

When a patient exhibits moderate paranoia, the probability of progressing to severe symptoms or improving to mild symptoms depends on several variables. Pharmacologic treatment, family insight, and social support may be important variables in such circumstances. Psychoeducation for the family is vital.

In patients experiencing paranoia, violence may be prevented by proper assessment and treatment. The patient’s family should be educated about paranoid ideation and the need for treatment to improve symptoms and ensure safety. The long-term effects of untreated paranoia and types of treatment modalities available should be discussed with the family and the patient. During these teaching sessions, focus on improving the overall insight of the family and the patient about the psychotic illness to improve treatment adherence.⁹ This step may be challenging if the family is resistant to the patient receiving mental health treatment.

Gaining a detailed clinical history of a patient’s paranoia is important. A clinician should look for changes in behavior, such as the patient becoming quieter or more hostile, and impaired academic or social functioning. After gathering sufficient evidence contrary to the delusion, clinicians can help patients improve their reality testing.

Rule out medical and neurologic conditions that may be contributing to paranoia and aggression.

TREATMENT: Some improvement

Ms. V is started on risperidone, 1 mg/d, which leads to a partial response. She starts interacting more with staff and her peers on the unit, but her delusions of her sister poisioning her persist. Given the severity of the crime, Ms. V is sent to adult court, where she is found not guilty by reason of insanity and committed to a state hospital.

The authors’ observations

New-onset paranoia is a serious symptom that requires immediate evaluation and treatment. We recommend an approach presened in a flowchart (Figure) that highlights the importance of early intervention and aggressive treatment.

The MacArthur Violence Risk Assessment Study¹⁰ indicated that a “suspicious” attitude toward others can be a precipitating cause for increased violence in some cases. In light of ongoing controversy regarding the link between violence and mental illnesses such as schizophrenia,^10-12 addressing an individual’s psychiatric illness early is preferable to prevent possible complications such as violent crimes. Because patients with paranoid ideations may have severely impaired ego control, they may be at risk for acting out aggressive and/or destructive urges. Therefore, new-onset paranoia should be thought of as a medical emergency similar to chest pain. Although accurately predicting and preventing violence may be impossible, in Ms. V’s case, earlier mental health treatment and intervention may have been able to prevent a murder.

Figure: Paranoia: A suggested approach to treatment

Related Resource

• Marneros A, Pillmann F, Wustmann T. Delusional disorders—are they simply paranoid schizophrenia? [published online ahead of print November 15, 2010]. Schizophr Bull. doi: 10.1093/schbul/sbq125.

Drug Brand Names

Amphetamine and dextroamphetamine • Adderall

Risperidone • Risperdal

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Personal and clinical details of this case were altered to maintain patient confidentiality.

Not your garden variety neck pain

PERSISTENT BILATERAL NECK PAIN so severe that he couldn’t sit down brought a man to the emergency department (ED), where he was given ketorolac and diazepam. About an hour later, he said that the pain was better and was discharged with a diagnosis of neck strain and spasm and instructions to see his primary care physician if the pain persisted or worsened.

Four days later, the patient went to his primary care physician complaining of neck pain radiating down both arms, numbness in the right thumb, fever, chills, dysuria, and myalgia in his legs. The doctor observed decreased range of motion of the neck in all directions and diagnosed likely prostatitis. He ordered co-trimoxazole (trimethoprim and sulfamethoxazole), a nonemergent magnetic resonance imaging (MRI) scan, and physical therapy.

Fourteen hours after the doctor visit, the patient went back to the ED in a wheelchair. An emergency MRI showed epidural disease up and down the cervical spine and extending into the thoracic spine. An epidural abscess with spinal cord compression was diagnosed and decompression and evacuation surgery with spinal fusion was performed.

After several weeks in the hospital, the patient was referred to rehabilitation for partial quadriplegia. He has no use of his legs and very limited use of his hands and fingers. He’s confined to a wheelchair and needs help with most activities of daily living.

PLAINTIFF’S CLAIM When the patient visited his primary care physician, he had a classic presentation of a spinal abscess and should have undergone an emergent MRI, which would have revealed the abscess and allowed treatment with antibiotics and surgery before permanent damage occurred.

THE DEFENSE The patient’s symptoms weren’t a typical presentation of spinal abscess. There was no way the physician could have known what would happen the next day.

VERDICT $3 million Massachusetts settlement.

COMMENT Yes, there are zebras among the horses. We have to be vigilant to diagnose the rare serious cause of common problems such as neck pain. The combination of neck pain, patchy neurologic findings, signs of infection, and bladder symptoms should have raised red flags.

Untimely death blamed on undiagnosed PE

A 28-YEAR-OLD MAN went to the emergency department (ED) complaining of low-grade fever, nonproductive cough, and dizziness for 2 days. He also had tachycardia and significant hypoxia. An ED physician who saw the patient an hour after his arrival noted that he complained of weakness, shortness of breath, and light-headedness. The differential diagnosis included pneumonia, congestive heart failure, and pulmonary embolism.

After reviewing an electrocardiogram, chest radiograph, and laboratory studies, the ED doctor diagnosed pneumonia and renal insufficiency. The patient was admitted to the hospital, then transferred to another hospital about 8 hours later. He wasn’t evaluated by a physician when he was admitted to the second hospital.

About 5 hours after admission, the patient got out of bed and collapsed in the presence of his wife. A code was called, but the patient never regained consciousness and died about an hour and a half later. An autopsy established a pulmonary embolism as the cause of death.

PLAINTIFF’S CLAIM The doctors were negligent in failing to diagnose and treat the pulmonary embolism. Proper treatment would have allowed the patient to survive.

THE DEFENSE There was no negligence; heparin therapy wouldn’t have prevented the patient’s death.

VERDICT $6.1 million Maryland verdict.

COMMENT It isn’t enough to think of pulmonary embolism; a prompt definitive diagnostic work-up and timely treatment are key to preventing such a catastrophic outcome.

Delayed herpes diagnosis leads to lifelong consequences

A 10-DAY-OLD INFANT was examined by a pediatrician, who noted vesicles dotting the baby’s tongue, a possible manifestation of herpes, and observed herpes labialis on the mother’s lips. The pediatrician concluded that the vesicles didn’t indicate herpes and discharged the baby, instructing the parents to have him reexamined if he developed a fever, irritability, or lethargy. The next day the pediatrician consulted a neonatologist, who advised immediate reexamination. The baby was taken to a hospital, but then was immediately transported to another hospital.

At the second hospital, a physician examined the baby and consulted an oral surgeon. The surgeon believed that the vesicles were caused by burns from a hot baby bottle. The baby was discharged.

Six days later, the mother brought the baby to his regular pediatrician. She reported that the infant had been feverish and lethargic. The pediatrician didn’t find vesicles or other abnormalities. She ordered a complete blood count and blood culture, gave antibiotics, and told the parents to bring the baby back to see her the next day.

Very early the next day, the parents brought the baby to a hospital with a temperature of 101.2°F. The examining physician contacted the child’s pediatrician, who said she wanted to see the baby at 8:00 AM. When the pediatrician examined him, the infant’s temperature was 100.5°F. She gave antibiotics and instructed the parents to bring the baby back the next day, when his test results would be available.

The next day, the parents told the pediatrician’s assistant who examined the baby that his arms and legs had been twitching the previous evening. The infant received antibiotics but began to exhibit jerky movements. The parents were told to take him to a hospital, where he was diagnosed with herpes simplex and residual brain damage.

The child has quadriparesis and can’t talk, walk, or feed himself. He can eat only pureed food.

PLAINTIFF’S CLAIM The herpes simplex infection should have been diagnosed earlier. The pediatrician who examined the infant initially should have cultured the vesicles (and made sure that acyclovir was given) or consulted with, or referred the child to, a specialist. The physician who saw the child at the second hospital should have consulted a specialist, which would have led to the administration of acyclovir.

THE DEFENSE Hospitalization wasn’t necessary and a culture wasn’t appropriate. The appearance of the vesicles when the baby was examined at the second hospital didn’t suggest herpes.

VERDICT Multiple New York settlements totaling $10.2 million.

COMMENT As with many malpractice cases, there were many opportunities to prevent an egregious outcome. I wonder whether anyone involved stopped to entertain a differential diagnosis and note the urgent conditions the presentation clearly suggested.

Not your garden variety neck pain

PERSISTENT BILATERAL NECK PAIN so severe that he couldn’t sit down brought a man to the emergency department (ED), where he was given ketorolac and diazepam. About an hour later, he said that the pain was better and was discharged with a diagnosis of neck strain and spasm and instructions to see his primary care physician if the pain persisted or worsened.

Four days later, the patient went to his primary care physician complaining of neck pain radiating down both arms, numbness in the right thumb, fever, chills, dysuria, and myalgia in his legs. The doctor observed decreased range of motion of the neck in all directions and diagnosed likely prostatitis. He ordered co-trimoxazole (trimethoprim and sulfamethoxazole), a nonemergent magnetic resonance imaging (MRI) scan, and physical therapy.

Fourteen hours after the doctor visit, the patient went back to the ED in a wheelchair. An emergency MRI showed epidural disease up and down the cervical spine and extending into the thoracic spine. An epidural abscess with spinal cord compression was diagnosed and decompression and evacuation surgery with spinal fusion was performed.

After several weeks in the hospital, the patient was referred to rehabilitation for partial quadriplegia. He has no use of his legs and very limited use of his hands and fingers. He’s confined to a wheelchair and needs help with most activities of daily living.

PLAINTIFF’S CLAIM When the patient visited his primary care physician, he had a classic presentation of a spinal abscess and should have undergone an emergent MRI, which would have revealed the abscess and allowed treatment with antibiotics and surgery before permanent damage occurred.

THE DEFENSE The patient’s symptoms weren’t a typical presentation of spinal abscess. There was no way the physician could have known what would happen the next day.

VERDICT $3 million Massachusetts settlement.

COMMENT Yes, there are zebras among the horses. We have to be vigilant to diagnose the rare serious cause of common problems such as neck pain. The combination of neck pain, patchy neurologic findings, signs of infection, and bladder symptoms should have raised red flags.

Untimely death blamed on undiagnosed PE

A 28-YEAR-OLD MAN went to the emergency department (ED) complaining of low-grade fever, nonproductive cough, and dizziness for 2 days. He also had tachycardia and significant hypoxia. An ED physician who saw the patient an hour after his arrival noted that he complained of weakness, shortness of breath, and light-headedness. The differential diagnosis included pneumonia, congestive heart failure, and pulmonary embolism.

After reviewing an electrocardiogram, chest radiograph, and laboratory studies, the ED doctor diagnosed pneumonia and renal insufficiency. The patient was admitted to the hospital, then transferred to another hospital about 8 hours later. He wasn’t evaluated by a physician when he was admitted to the second hospital.

About 5 hours after admission, the patient got out of bed and collapsed in the presence of his wife. A code was called, but the patient never regained consciousness and died about an hour and a half later. An autopsy established a pulmonary embolism as the cause of death.

PLAINTIFF’S CLAIM The doctors were negligent in failing to diagnose and treat the pulmonary embolism. Proper treatment would have allowed the patient to survive.

THE DEFENSE There was no negligence; heparin therapy wouldn’t have prevented the patient’s death.

VERDICT $6.1 million Maryland verdict.

COMMENT It isn’t enough to think of pulmonary embolism; a prompt definitive diagnostic work-up and timely treatment are key to preventing such a catastrophic outcome.

Delayed herpes diagnosis leads to lifelong consequences

A 10-DAY-OLD INFANT was examined by a pediatrician, who noted vesicles dotting the baby’s tongue, a possible manifestation of herpes, and observed herpes labialis on the mother’s lips. The pediatrician concluded that the vesicles didn’t indicate herpes and discharged the baby, instructing the parents to have him reexamined if he developed a fever, irritability, or lethargy. The next day the pediatrician consulted a neonatologist, who advised immediate reexamination. The baby was taken to a hospital, but then was immediately transported to another hospital.

At the second hospital, a physician examined the baby and consulted an oral surgeon. The surgeon believed that the vesicles were caused by burns from a hot baby bottle. The baby was discharged.

Six days later, the mother brought the baby to his regular pediatrician. She reported that the infant had been feverish and lethargic. The pediatrician didn’t find vesicles or other abnormalities. She ordered a complete blood count and blood culture, gave antibiotics, and told the parents to bring the baby back to see her the next day.

Very early the next day, the parents brought the baby to a hospital with a temperature of 101.2°F. The examining physician contacted the child’s pediatrician, who said she wanted to see the baby at 8:00 AM. When the pediatrician examined him, the infant’s temperature was 100.5°F. She gave antibiotics and instructed the parents to bring the baby back the next day, when his test results would be available.

The next day, the parents told the pediatrician’s assistant who examined the baby that his arms and legs had been twitching the previous evening. The infant received antibiotics but began to exhibit jerky movements. The parents were told to take him to a hospital, where he was diagnosed with herpes simplex and residual brain damage.

The child has quadriparesis and can’t talk, walk, or feed himself. He can eat only pureed food.

PLAINTIFF’S CLAIM The herpes simplex infection should have been diagnosed earlier. The pediatrician who examined the infant initially should have cultured the vesicles (and made sure that acyclovir was given) or consulted with, or referred the child to, a specialist. The physician who saw the child at the second hospital should have consulted a specialist, which would have led to the administration of acyclovir.

THE DEFENSE Hospitalization wasn’t necessary and a culture wasn’t appropriate. The appearance of the vesicles when the baby was examined at the second hospital didn’t suggest herpes.

VERDICT Multiple New York settlements totaling $10.2 million.

COMMENT As with many malpractice cases, there were many opportunities to prevent an egregious outcome. I wonder whether anyone involved stopped to entertain a differential diagnosis and note the urgent conditions the presentation clearly suggested.

Not your garden variety neck pain

PERSISTENT BILATERAL NECK PAIN so severe that he couldn’t sit down brought a man to the emergency department (ED), where he was given ketorolac and diazepam. About an hour later, he said that the pain was better and was discharged with a diagnosis of neck strain and spasm and instructions to see his primary care physician if the pain persisted or worsened.

Four days later, the patient went to his primary care physician complaining of neck pain radiating down both arms, numbness in the right thumb, fever, chills, dysuria, and myalgia in his legs. The doctor observed decreased range of motion of the neck in all directions and diagnosed likely prostatitis. He ordered co-trimoxazole (trimethoprim and sulfamethoxazole), a nonemergent magnetic resonance imaging (MRI) scan, and physical therapy.

Fourteen hours after the doctor visit, the patient went back to the ED in a wheelchair. An emergency MRI showed epidural disease up and down the cervical spine and extending into the thoracic spine. An epidural abscess with spinal cord compression was diagnosed and decompression and evacuation surgery with spinal fusion was performed.

After several weeks in the hospital, the patient was referred to rehabilitation for partial quadriplegia. He has no use of his legs and very limited use of his hands and fingers. He’s confined to a wheelchair and needs help with most activities of daily living.

PLAINTIFF’S CLAIM When the patient visited his primary care physician, he had a classic presentation of a spinal abscess and should have undergone an emergent MRI, which would have revealed the abscess and allowed treatment with antibiotics and surgery before permanent damage occurred.

THE DEFENSE The patient’s symptoms weren’t a typical presentation of spinal abscess. There was no way the physician could have known what would happen the next day.

VERDICT $3 million Massachusetts settlement.

COMMENT Yes, there are zebras among the horses. We have to be vigilant to diagnose the rare serious cause of common problems such as neck pain. The combination of neck pain, patchy neurologic findings, signs of infection, and bladder symptoms should have raised red flags.

Untimely death blamed on undiagnosed PE

A 28-YEAR-OLD MAN went to the emergency department (ED) complaining of low-grade fever, nonproductive cough, and dizziness for 2 days. He also had tachycardia and significant hypoxia. An ED physician who saw the patient an hour after his arrival noted that he complained of weakness, shortness of breath, and light-headedness. The differential diagnosis included pneumonia, congestive heart failure, and pulmonary embolism.

After reviewing an electrocardiogram, chest radiograph, and laboratory studies, the ED doctor diagnosed pneumonia and renal insufficiency. The patient was admitted to the hospital, then transferred to another hospital about 8 hours later. He wasn’t evaluated by a physician when he was admitted to the second hospital.

About 5 hours after admission, the patient got out of bed and collapsed in the presence of his wife. A code was called, but the patient never regained consciousness and died about an hour and a half later. An autopsy established a pulmonary embolism as the cause of death.

PLAINTIFF’S CLAIM The doctors were negligent in failing to diagnose and treat the pulmonary embolism. Proper treatment would have allowed the patient to survive.

THE DEFENSE There was no negligence; heparin therapy wouldn’t have prevented the patient’s death.

VERDICT $6.1 million Maryland verdict.

COMMENT It isn’t enough to think of pulmonary embolism; a prompt definitive diagnostic work-up and timely treatment are key to preventing such a catastrophic outcome.

Delayed herpes diagnosis leads to lifelong consequences

A 10-DAY-OLD INFANT was examined by a pediatrician, who noted vesicles dotting the baby’s tongue, a possible manifestation of herpes, and observed herpes labialis on the mother’s lips. The pediatrician concluded that the vesicles didn’t indicate herpes and discharged the baby, instructing the parents to have him reexamined if he developed a fever, irritability, or lethargy. The next day the pediatrician consulted a neonatologist, who advised immediate reexamination. The baby was taken to a hospital, but then was immediately transported to another hospital.

At the second hospital, a physician examined the baby and consulted an oral surgeon. The surgeon believed that the vesicles were caused by burns from a hot baby bottle. The baby was discharged.

Six days later, the mother brought the baby to his regular pediatrician. She reported that the infant had been feverish and lethargic. The pediatrician didn’t find vesicles or other abnormalities. She ordered a complete blood count and blood culture, gave antibiotics, and told the parents to bring the baby back to see her the next day.

Very early the next day, the parents brought the baby to a hospital with a temperature of 101.2°F. The examining physician contacted the child’s pediatrician, who said she wanted to see the baby at 8:00 AM. When the pediatrician examined him, the infant’s temperature was 100.5°F. She gave antibiotics and instructed the parents to bring the baby back the next day, when his test results would be available.

The next day, the parents told the pediatrician’s assistant who examined the baby that his arms and legs had been twitching the previous evening. The infant received antibiotics but began to exhibit jerky movements. The parents were told to take him to a hospital, where he was diagnosed with herpes simplex and residual brain damage.

The child has quadriparesis and can’t talk, walk, or feed himself. He can eat only pureed food.

PLAINTIFF’S CLAIM The herpes simplex infection should have been diagnosed earlier. The pediatrician who examined the infant initially should have cultured the vesicles (and made sure that acyclovir was given) or consulted with, or referred the child to, a specialist. The physician who saw the child at the second hospital should have consulted a specialist, which would have led to the administration of acyclovir.

THE DEFENSE Hospitalization wasn’t necessary and a culture wasn’t appropriate. The appearance of the vesicles when the baby was examined at the second hospital didn’t suggest herpes.

VERDICT Multiple New York settlements totaling $10.2 million.

COMMENT As with many malpractice cases, there were many opportunities to prevent an egregious outcome. I wonder whether anyone involved stopped to entertain a differential diagnosis and note the urgent conditions the presentation clearly suggested.

Evidence summary

Levodopa/carbidopa is the most commonly prescribed medication for Parkinson’s disease. Although its efficacy is established, it can cause dyskinesia and dystonia.¹ Recent studies (TABLE) have evaluated the use of other medications early in the course of Parkinson’s disease in hopes of delaying the waning effectiveness of levodopa over time.

TABLE
Medications commonly used to treat Parkinson’s disease

Dopamine agonists: Dyskinesia reduction, but at a price
A Cochrane review of 29 trials with 5247 patients compared dopamine agonists with levodopa.² Levodopa controlled symptoms better than dopamine agonists, but inconsistent data reporting prevented quantifying this result.

Compared with the group taking levodopa, patients taking dopamine agonists demonstrated a significant reduction in dyskinesia (odds ratio [OR]=0.45; 95% CI, 0.37-0.54), dystonia (OR=0.64; 95% CI, 0.51-0.81), and motor fluctuations (OR= 0.71; 95% CI, 0.58-0.87).

However, patients taking dopamine agonists with or without levodopa experienced significantly more adverse effects than patients taking levodopa alone. Side effects included increased edema (OR=3.68; 95% CI, 2.62-5.18), somnolence (OR=1.49; 95% CI, 1.12-2.00), constipation (OR=1.59; 95% CI, 1.11-2.28), dizziness (OR=1.45; 95% CI, 1.09-1.92), hallucinations (OR=1.69; 95% CI, 1.13-2.52), and nausea (OR=1.32; 95% CI, 1.05-1.66). Patients treated with dopamine agonists were also significantly more likely to discontinue treatment because of adverse events (OR=2.49; 95% CI, 2.08-2.98; P<.00001).

Bromocriptine studies hampered by poor quality
Two Cochrane reviews specifically evaluated the dopamine agonist bromocriptine.^3,4 The first focused on 6 head-to-head trials with levodopa that enrolled 850 patients.³ The studies were of poor quality, marred by methodological flaws and clinical heterogeneity. Problems included inadequate power, high variability in study duration (23 weeks to 5 years), differences in reporting, and lack of description of the randomization method in 3 of the 6 trials. Although bromocriptine showed a trend toward lower incidence of motor complications, many patients dropped out of the studies because of increased non-motor adverse effects and inadequate response to treatment.

The second review, of 7 trials with a total of 1100 patients, compared bromocriptine plus levodopa with levodopa alone.⁴ The studies were of poor quality for reasons similar to the studies in the first review. Researchers found no statistically significant or consistent evidence to determine whether bromocriptine plus levodopa prevents or delays motor complications.

MAO-B inhibitors: Minimally effective with troubling side effects
A Cochrane review of monoamine oxidase type B (MAO-B) inhibitors included 10 trials with 2422 participants.⁵ The review found statistically, but not clinically, significant improvements in scores on 2 sections of the United Parkinson Disease Rating Scale (UPDRS), a standardized assessment tool that facilitates accurate documentation of disease progression and treatment response.

Compared with the control groups (either placebo or levodopa at study onset), the MAO-B group (either alone or with levodopa) showed significant improvement on the motor section (weighted mean difference [WMD]=–3.81 on a 108-point scale; 95% CI, –5.36 to –2.27) and activities of daily living section (WMD=–1.50 on a 52-point scale; 95% CI, –2.53 to –0.48). Fewer motor complications occurred in the MAO-B group (OR=0.75; 95% CI, 0.59-0.94) than the control group. Lower doses and shorter treatment with levodopa were necessary to control symptoms in the MAO-B group.

The clinical impact of MAO-B inhibitors on Parkinson’s symptoms was small, and almost all patients required the addition of levodopa to the treatment regimen after 3 or 4 years. Withdrawals because of medication side effects were significantly higher in the MAO-B inhibitor group than controls (OR=2.36; 95% CI, 1.32-4.20). Side effects included nausea, confusion, hallucinations, and postural hypotension. Concerns about cardiovascular adverse effects raised in previous studies, especially with selegiline, weren’t found to be significant (OR=1.15; 95% CI, 0.92-1.44). Because of their minimal effectiveness and worrisome adverse effects, MAO-B inhibitors aren’t recommended for routine use in early Parkinson’s disease.

COMT inhibitors may boost levodopa/carbidopa’s effects
A randomized double-blinded trial followed 423 patients for 39 weeks to compare the combination of the catechol-O-methyltransferase (COMT) inhibitor entacapone and levodopa/carbidopa (LCE) with levodopa/carbidopa alone (LC).⁶ The researchers found statistically significant improvements with LCE in UPDRS scores for activities of daily living (mean change from baseline=3.0 for LCE vs 2.3 for LC on a 52-point scale; P=.025) but not mentation or motor symptoms.

Dyskinesia and wearing-off symptoms (motor fluctuations) didn’t differ significantly between the 2 groups. LCE was associated with a higher incidence of adverse effects than LC, and involved mostly nausea (26.6% vs 13.5%) and diarrhea (8.7% vs 2.8%).

Anticholinergics may help, but cause adverse mental effects
Another Cochrane review compared anticholinergic agents with placebo or no treatment in 9 studies that included 221 patients.⁷ Meta-analysis wasn’t possible because of heterogeneity in patient populations, outcomes, and measurements and incomplete reporting. Compared with placebo, anticholinergic agents may improve Parkinson’s-related motor symptoms but have significant mental adverse effects, including confusion, memory problems, restlessness, and hallucinations.

Recommendations

The most recent guidelines (2002) from the American Academy of Neurology recommend levodopa and dopamine agonists as first-line therapies.⁸ Levodopa is more effective at improving the motor symptoms of Parkinson’s disease but is associated with a higher risk of dyskinesia than dopamine agonists. No compelling evidence suggests a difference in efficacy between long- and short-acting levodopa.

Evidence summary

Levodopa/carbidopa is the most commonly prescribed medication for Parkinson’s disease. Although its efficacy is established, it can cause dyskinesia and dystonia.¹ Recent studies (TABLE) have evaluated the use of other medications early in the course of Parkinson’s disease in hopes of delaying the waning effectiveness of levodopa over time.

TABLE
Medications commonly used to treat Parkinson’s disease

Dopamine agonists: Dyskinesia reduction, but at a price
A Cochrane review of 29 trials with 5247 patients compared dopamine agonists with levodopa.² Levodopa controlled symptoms better than dopamine agonists, but inconsistent data reporting prevented quantifying this result.

Compared with the group taking levodopa, patients taking dopamine agonists demonstrated a significant reduction in dyskinesia (odds ratio [OR]=0.45; 95% CI, 0.37-0.54), dystonia (OR=0.64; 95% CI, 0.51-0.81), and motor fluctuations (OR= 0.71; 95% CI, 0.58-0.87).

However, patients taking dopamine agonists with or without levodopa experienced significantly more adverse effects than patients taking levodopa alone. Side effects included increased edema (OR=3.68; 95% CI, 2.62-5.18), somnolence (OR=1.49; 95% CI, 1.12-2.00), constipation (OR=1.59; 95% CI, 1.11-2.28), dizziness (OR=1.45; 95% CI, 1.09-1.92), hallucinations (OR=1.69; 95% CI, 1.13-2.52), and nausea (OR=1.32; 95% CI, 1.05-1.66). Patients treated with dopamine agonists were also significantly more likely to discontinue treatment because of adverse events (OR=2.49; 95% CI, 2.08-2.98; P<.00001).

Bromocriptine studies hampered by poor quality
Two Cochrane reviews specifically evaluated the dopamine agonist bromocriptine.^3,4 The first focused on 6 head-to-head trials with levodopa that enrolled 850 patients.³ The studies were of poor quality, marred by methodological flaws and clinical heterogeneity. Problems included inadequate power, high variability in study duration (23 weeks to 5 years), differences in reporting, and lack of description of the randomization method in 3 of the 6 trials. Although bromocriptine showed a trend toward lower incidence of motor complications, many patients dropped out of the studies because of increased non-motor adverse effects and inadequate response to treatment.

The second review, of 7 trials with a total of 1100 patients, compared bromocriptine plus levodopa with levodopa alone.⁴ The studies were of poor quality for reasons similar to the studies in the first review. Researchers found no statistically significant or consistent evidence to determine whether bromocriptine plus levodopa prevents or delays motor complications.

MAO-B inhibitors: Minimally effective with troubling side effects
A Cochrane review of monoamine oxidase type B (MAO-B) inhibitors included 10 trials with 2422 participants.⁵ The review found statistically, but not clinically, significant improvements in scores on 2 sections of the United Parkinson Disease Rating Scale (UPDRS), a standardized assessment tool that facilitates accurate documentation of disease progression and treatment response.

Compared with the control groups (either placebo or levodopa at study onset), the MAO-B group (either alone or with levodopa) showed significant improvement on the motor section (weighted mean difference [WMD]=–3.81 on a 108-point scale; 95% CI, –5.36 to –2.27) and activities of daily living section (WMD=–1.50 on a 52-point scale; 95% CI, –2.53 to –0.48). Fewer motor complications occurred in the MAO-B group (OR=0.75; 95% CI, 0.59-0.94) than the control group. Lower doses and shorter treatment with levodopa were necessary to control symptoms in the MAO-B group.

The clinical impact of MAO-B inhibitors on Parkinson’s symptoms was small, and almost all patients required the addition of levodopa to the treatment regimen after 3 or 4 years. Withdrawals because of medication side effects were significantly higher in the MAO-B inhibitor group than controls (OR=2.36; 95% CI, 1.32-4.20). Side effects included nausea, confusion, hallucinations, and postural hypotension. Concerns about cardiovascular adverse effects raised in previous studies, especially with selegiline, weren’t found to be significant (OR=1.15; 95% CI, 0.92-1.44). Because of their minimal effectiveness and worrisome adverse effects, MAO-B inhibitors aren’t recommended for routine use in early Parkinson’s disease.

COMT inhibitors may boost levodopa/carbidopa’s effects
A randomized double-blinded trial followed 423 patients for 39 weeks to compare the combination of the catechol-O-methyltransferase (COMT) inhibitor entacapone and levodopa/carbidopa (LCE) with levodopa/carbidopa alone (LC).⁶ The researchers found statistically significant improvements with LCE in UPDRS scores for activities of daily living (mean change from baseline=3.0 for LCE vs 2.3 for LC on a 52-point scale; P=.025) but not mentation or motor symptoms.

Dyskinesia and wearing-off symptoms (motor fluctuations) didn’t differ significantly between the 2 groups. LCE was associated with a higher incidence of adverse effects than LC, and involved mostly nausea (26.6% vs 13.5%) and diarrhea (8.7% vs 2.8%).

Anticholinergics may help, but cause adverse mental effects
Another Cochrane review compared anticholinergic agents with placebo or no treatment in 9 studies that included 221 patients.⁷ Meta-analysis wasn’t possible because of heterogeneity in patient populations, outcomes, and measurements and incomplete reporting. Compared with placebo, anticholinergic agents may improve Parkinson’s-related motor symptoms but have significant mental adverse effects, including confusion, memory problems, restlessness, and hallucinations.

Recommendations

The most recent guidelines (2002) from the American Academy of Neurology recommend levodopa and dopamine agonists as first-line therapies.⁸ Levodopa is more effective at improving the motor symptoms of Parkinson’s disease but is associated with a higher risk of dyskinesia than dopamine agonists. No compelling evidence suggests a difference in efficacy between long- and short-acting levodopa.

Evidence summary

Levodopa/carbidopa is the most commonly prescribed medication for Parkinson’s disease. Although its efficacy is established, it can cause dyskinesia and dystonia.¹ Recent studies (TABLE) have evaluated the use of other medications early in the course of Parkinson’s disease in hopes of delaying the waning effectiveness of levodopa over time.

TABLE
Medications commonly used to treat Parkinson’s disease

Dopamine agonists: Dyskinesia reduction, but at a price
A Cochrane review of 29 trials with 5247 patients compared dopamine agonists with levodopa.² Levodopa controlled symptoms better than dopamine agonists, but inconsistent data reporting prevented quantifying this result.

Compared with the group taking levodopa, patients taking dopamine agonists demonstrated a significant reduction in dyskinesia (odds ratio [OR]=0.45; 95% CI, 0.37-0.54), dystonia (OR=0.64; 95% CI, 0.51-0.81), and motor fluctuations (OR= 0.71; 95% CI, 0.58-0.87).

However, patients taking dopamine agonists with or without levodopa experienced significantly more adverse effects than patients taking levodopa alone. Side effects included increased edema (OR=3.68; 95% CI, 2.62-5.18), somnolence (OR=1.49; 95% CI, 1.12-2.00), constipation (OR=1.59; 95% CI, 1.11-2.28), dizziness (OR=1.45; 95% CI, 1.09-1.92), hallucinations (OR=1.69; 95% CI, 1.13-2.52), and nausea (OR=1.32; 95% CI, 1.05-1.66). Patients treated with dopamine agonists were also significantly more likely to discontinue treatment because of adverse events (OR=2.49; 95% CI, 2.08-2.98; P<.00001).

Bromocriptine studies hampered by poor quality
Two Cochrane reviews specifically evaluated the dopamine agonist bromocriptine.^3,4 The first focused on 6 head-to-head trials with levodopa that enrolled 850 patients.³ The studies were of poor quality, marred by methodological flaws and clinical heterogeneity. Problems included inadequate power, high variability in study duration (23 weeks to 5 years), differences in reporting, and lack of description of the randomization method in 3 of the 6 trials. Although bromocriptine showed a trend toward lower incidence of motor complications, many patients dropped out of the studies because of increased non-motor adverse effects and inadequate response to treatment.

The second review, of 7 trials with a total of 1100 patients, compared bromocriptine plus levodopa with levodopa alone.⁴ The studies were of poor quality for reasons similar to the studies in the first review. Researchers found no statistically significant or consistent evidence to determine whether bromocriptine plus levodopa prevents or delays motor complications.

MAO-B inhibitors: Minimally effective with troubling side effects
A Cochrane review of monoamine oxidase type B (MAO-B) inhibitors included 10 trials with 2422 participants.⁵ The review found statistically, but not clinically, significant improvements in scores on 2 sections of the United Parkinson Disease Rating Scale (UPDRS), a standardized assessment tool that facilitates accurate documentation of disease progression and treatment response.

Compared with the control groups (either placebo or levodopa at study onset), the MAO-B group (either alone or with levodopa) showed significant improvement on the motor section (weighted mean difference [WMD]=–3.81 on a 108-point scale; 95% CI, –5.36 to –2.27) and activities of daily living section (WMD=–1.50 on a 52-point scale; 95% CI, –2.53 to –0.48). Fewer motor complications occurred in the MAO-B group (OR=0.75; 95% CI, 0.59-0.94) than the control group. Lower doses and shorter treatment with levodopa were necessary to control symptoms in the MAO-B group.

The clinical impact of MAO-B inhibitors on Parkinson’s symptoms was small, and almost all patients required the addition of levodopa to the treatment regimen after 3 or 4 years. Withdrawals because of medication side effects were significantly higher in the MAO-B inhibitor group than controls (OR=2.36; 95% CI, 1.32-4.20). Side effects included nausea, confusion, hallucinations, and postural hypotension. Concerns about cardiovascular adverse effects raised in previous studies, especially with selegiline, weren’t found to be significant (OR=1.15; 95% CI, 0.92-1.44). Because of their minimal effectiveness and worrisome adverse effects, MAO-B inhibitors aren’t recommended for routine use in early Parkinson’s disease.

COMT inhibitors may boost levodopa/carbidopa’s effects
A randomized double-blinded trial followed 423 patients for 39 weeks to compare the combination of the catechol-O-methyltransferase (COMT) inhibitor entacapone and levodopa/carbidopa (LCE) with levodopa/carbidopa alone (LC).⁶ The researchers found statistically significant improvements with LCE in UPDRS scores for activities of daily living (mean change from baseline=3.0 for LCE vs 2.3 for LC on a 52-point scale; P=.025) but not mentation or motor symptoms.

Dyskinesia and wearing-off symptoms (motor fluctuations) didn’t differ significantly between the 2 groups. LCE was associated with a higher incidence of adverse effects than LC, and involved mostly nausea (26.6% vs 13.5%) and diarrhea (8.7% vs 2.8%).

Anticholinergics may help, but cause adverse mental effects
Another Cochrane review compared anticholinergic agents with placebo or no treatment in 9 studies that included 221 patients.⁷ Meta-analysis wasn’t possible because of heterogeneity in patient populations, outcomes, and measurements and incomplete reporting. Compared with placebo, anticholinergic agents may improve Parkinson’s-related motor symptoms but have significant mental adverse effects, including confusion, memory problems, restlessness, and hallucinations.

Recommendations

The most recent guidelines (2002) from the American Academy of Neurology recommend levodopa and dopamine agonists as first-line therapies.⁸ Levodopa is more effective at improving the motor symptoms of Parkinson’s disease but is associated with a higher risk of dyskinesia than dopamine agonists. No compelling evidence suggests a difference in efficacy between long- and short-acting levodopa.