Reviews

A 29-year-old white man with no chronic medical problems presents to the emergency department with shortness of breath, left-sided pleuritic chest pain, cough, and hemoptysis. These symptoms began abruptly 1 day ago and have persisted. He also has mild pain and swelling in both calves. He denies having any fever, night sweats, or chills. On further questioning, he reports having taken a long, nonstop driving trip that lasted 8 hours 1 week ago.

His medical history is negative, and he specifically reports no history of deep venous thrombosis or pulmonary embolism. He underwent appendectomy 10 years ago but has had no other operations. He does not take any medications. His family history is noncontributory and is negative for venous thromboembolism. He smokes and uses alcohol occasionally but not illicit drugs.

Examination. He appears to be in considerable distress because of his chest pain. His temperature is 100.4°F (38.0°C), blood pressure 125/70 mm Hg, heart rate 125 beats per minute, respiratory rate 26 breaths per minute, oxygen saturation 92% on room air, and body mass index 19 kg/m².

Chest examination reveals diminished vesicular breathing in the left base, which is normal to percussion without added sounds. Both calves are swollen and tender to palpation without skin discoloration. The rest of his examination is normal.

Laboratory values:

• White blood cell count 9.3 × 10⁹/L (reference range 4.5–11.0)
• Hemoglobin 15.9 g/dL (14.0–17.5)
• Platelets 205 × 10⁹/L (150–350)
• Sodium 140 mEq/L (136–142)
• Potassium 3.9 mEq/L (3.5–5.0)
• Chloride 108 mEq/L (96–106)
• Bicarbonate 23 mEq/L (21–28)
• Blood urea nitrogen 14 mg/dL (8–23)
• Creatinine 0.9 mg/dL (0.6–1.2)
• Glucose 95 mg/dL (70–110)
• International normalized ratio (INR) 0.90 (0.00–1.2)
• Partial thromboplastin time 27.5 seconds (24.6–31.8)
• Creatine phosphokinase 205 U/L (39–308)
• Troponin T < 0.015 ng/mL (0.01–0.045).

Pulmonary embolism is diagnosed

Electrocardiography shows sinus tachycardia. Chest radiography shows small atelectatic changes at the left lung base (Figure 1). Pulmonary embolism is suspected, and a serum Ddimer level is obtained; it is 4,054 ng/mL (reference range < 500). Computed tomography of the chest confirms bilateral acute pulmonary emboli (Figure 2). Doppler ultrasonography of both legs reveals bilateral deep venous thrombosis. Echocardiography shows mildly elevated right ventricular systolic pressure at 47 mm Hg.

Factor V Leiden is diagnosed, and the patient recovers with treatment

Anticoagulation is started in the emergency department.

Given this patient’s young age and clot burden, a hypercoagulable state is suspected. Thrombophilia screening is performed, with tests for the factor V Leiden mutation, the prothrombin G20210A mutation, and antiphospholipid and lupus anticoagulant antibodies. The rest of the thrombophilia panel, including antithrombin III, factor VIII, protein C, and protein S, is deferred because the levels of these substances would be expected to change during the acute thrombosis.

The direct test for factor V Leiden mutation is positive for the heterozygous type. The test for the prothrombin G20210A mutation is negative, and his antiphospholipid antibody levels, including the lupus anticoagulant titer, are within normal limits.

The patient is kept on a standard regimen of unfractionated heparin, overlapped with warfarin (Coumadin) until his INR is 2.0 to 3.0 on 2 consecutive days. His hospital course is uneventful and his condition gradually improves.

He is discharged home to continue on oral anticoagulation for 6 months with a target INR of 2.0 to 3.0. Two weeks after completing his anticoagulation therapy, his levels of antithrombin III, factor VIII, protein C, and protein S are all within normal limits.

FACTOR V LEIDEN IS COMMON

Factor V Leiden is the most common inherited thrombophilia, with a prevalence of 3% to 7% in the general US population,¹ approximately 5% in whites, 2.2% in Hispanics, and 1.2% in blacks.² Its prevalence in patients with venous thromboembolism, however, is 50%.^1,3 The annual incidence of venous thromboembolism in patients with factor V Leiden is 0.5%.^4,5

 

MORE COAGULATION, LESS ANTICOAGULATION

Factor V has a critical position in both the coagulant and anticoagulant pathways. Factor V Leiden results in a hypercoagulable state by both increasing coagulation and decreasing anticoagulation.

This mutation causes factor V to be resistant to being cleaved and inactivated by activated protein C, a condition known as APC resistance. As a result, more factor Va is available within the prothrombinase complex, increasing coagulation by increased generation of thrombin.^6–8

Furthermore, a cofactor formed by cleavage of factor V at position 506 is thought to support activated protein C in degrading factor VIIIa (in the tenase complex), along with protein S. People with factor V Leiden lack this cleavage product and thus have less anticoagulant activity from activated protein C. The increased coagulation and decreased anticoagulation appear to contribute equally to the hypercoagulable state in factor V Leiden-associated APC resistance.^9–11

Heterozygosity for the factor V Leiden mutation accounts for 90% to 95% of cases of APC resistance. A much smaller number of people are homozygous for it.¹

People who are homozygous for factor V Leiden are at higher risk of venous thromboembolism than those who are heterozygous for it, since the latter group’s blood contains both factor V Leiden and normal factor V. The normal factor V allows anticoagulation via the second pathway of inactivation of factor VIIIa by activated protein C, giving some protection against thrombosis. In people who are homozygous for factor V Leiden, the lack of normal factor V acting as an anticoagulant protein results in a higher thrombotic risk.^9–11

Other factor V mutations may also cause APC resistance

Although factor V Leiden is the only genetic defect for which a causal relationship with APC resistance has been clearly determined, other, rarer hereditary factor V mutations or polymorphisms have been described, such as factor V Cambridge (Arg306Thr)¹² and factor V Hong Kong (Arg306Gly).¹³ These mutations may result in APC resistance, but their clinical association with thrombosis is less clear.¹⁴ Factor V Liverpool (Ile359Thr) is associated with a higher risk of thrombosis, apparently because of reduced APC-mediated inactivation of factor Va and because it is a poor cofactor with activated protein C for the inactivation of factor VIIIa.¹⁵

An R2 haplotype has also been described in association with APC resistance.^16,17 The phenomenon may be due to a reduction in activated protein C cofactor activity.⁹ However, not all studies have been convincing regarding the role of this haplotype in clinical disease.¹⁸ Coinheritance of this haplotype with factor V Leiden may increase the risk of venous thromboembolism above that associated with factor V Leiden alone.¹⁹

Although factor V Leiden is the most common cause of inherited APC resistance, other changes in hemostasis cause acquired APC resistance and may contribute to the thrombotic tendency in these patients.^20–22 The most common causes of acquired APC resistance include elevated factor VIII levels,^23–25 pregnancy,^26–28 use of oral contraceptives,^29,30 and antiphospholipid antibodies.³¹

USUALLY MANIFESTS AS DEEP VEIN THROMBOSIS

Factor V Leiden usually manifests as deep vein thrombosis with or without pulmonary embolism, but thrombosis in unusual locations also occurs.³²

The risk of a first episode of venous thromboembolism is two to five times higher with heterozygous factor V Leiden. However, even though the relative risk is high, the absolute risk is low. Furthermore, despite the higher risk of venous thrombosis, there is no evidence that heterozygosity for factor V Leiden increases the overall mortality rate.^4,33–36

In people with homozygous factor V Leiden or with combined inherited thrombophilias, the risk of venous thromboembolism is increased to a greater degree: it is 20 to 50 times higher.^7,8,37–39 However, whether the risk of death is higher is not clear.

VENOUS THROMBOEMBOLISM IS MULTIFACTORIAL

The pathogenesis of venous thromboembolism is multifactorial and involves an interaction between inherited and acquired factors. Very often, people with factor V Leiden have additional risk factors that contribute to the development of venous clots, and it is very unusual for them to have thrombosis in the absence of these additional factors.

These factors include older age, surgery, obesity, prolonged travel, immobility, hospitalization, oral contraceptive use, hormonal replacement therapy, pregnancy, and malignancy. They increase the risk of venous thrombosis in normal individuals as well, but more so in people with factor V Leiden.^40–43

Testing for other known causes of thrombophilia may also be pursued. These include elevated homocysteine levels, the factor II (prothrombin) G20210A mutation, anticardiolipin antibody, lupus anticoagulant, and deficiencies of antithrombin III, protein C, and protein S.

Factor V Leiden by itself does not appear to increase the risk of arterial thrombosis, ie, heart attack and stroke.^{33,38,44–46}

Family history: A risk indicator for venous thrombosis

Family history is an important indicator of risk for a first venous thromboembolic event, regardless of other risk factors identified. The risk of a first event is two to three times higher in people with a family history of thrombosis in a first-degree relative. The risk is four times higher when multiple family members are affected, at least one of them before age 50.⁴⁷

In people with genetic thrombophilia, the risk of thrombosis (especially unprovoked thrombosis at a young age) is also higher in those with a strong family history than in those without a family history. In those with factor V Leiden, the risk of venous thromboembolism is three to four times higher if there is a positive family history. The risk is five times higher in carriers of factor V Leiden with a family history of venous thromboembolism before age 50, and 13 times higher in those with more than one affected family member.⁴⁷

Possible shared environmental factors or coinheritance of other unidentified genetic factors may also contribute to the higher susceptibility in thrombosis-prone families.

TESTING FOR APC RESISTANCE AND FACTOR V LEIDEN

The factor V Leiden mutation can be detected directly by genetic testing of peripheral blood mononuclear cells. This method is relatively time-consuming and expensive, however.

At present, the most cost-effective approach is to test first for APC resistance using a second-generation coagulation assay—the modified APC sensitivity test. In this clot-based method, the patient’s sample is prediluted with factor V-deficient plasma to eliminate the effect of lupus anticoagulants and factor deficiencies that could prolong the baseline clotting time, and heparin is inactivated by polybrene. Then either an augmented partial-thromboplastin-time-based assay or a tissue-factor-dependent factor V assay is performed.

This test is nearly 100% sensitive and specific for factor V Leiden, in contrast to the first-generation, or classic, APC sensitivity test, which lacked specificity and sensitivity for it.^{9–11,48–60} This modification also permits testing of patients receiving anticoagulants or who have abnormal augmented partial thromboplastin times due to coagulation factor deficiencies.

A positive result on the modified APC sensitivity test should be confirmed by a direct genetic test for the factor V Leiden mutation. An APC resistance assay is unnecessary if a direct genetic test is used initially.

 

HOW LONG TO GIVE ANTICOAGULATION AFTER VENOUS THROMBOEMBOLISM?

Patients who have had an episode of venous thromboembolism have to be treated with anticoagulants.

In general, the initial management of venous thromboembolism in patients with heritable thrombophilias is no different from that in any other patient with a clot. Anticoagulants such as warfarin are given at a target INR of 2.5 (range 2.0–3.0).³² The duration of treatment is based on the risk factors that resulted in the thrombotic event.

After a first event, some authorities recommend anticoagulant therapy for 6 months.³² A shorter period (3 months) is recommended if there is a transient risk factor (eg, surgery, oral contraceptive use, travel, pregnancy, the puerperium) and the thrombosis is confined to distal veins (eg, the calf veins).³²

Factor V Leiden does not necessarily increase the risk of recurrent events in patients who have a transient risk factor. Therefore, people who are heterozygous for this mutation do not usually need to be treated lifelong with anticoagulants if they have had only one episode of deep vein thrombosis or pulmonary embolism, given the risk of bleeding associated with anticoagulation, unless they have additional risk factors.

Conditions in which indefinite anticoagulation may be required after careful consideration of the risks and benefits are:

• Life-threatening events such as near-fatal pulmonary embolism
• Cerebral or visceral vein thrombosis
• Recurrent thrombotic events
• Additional persistent risk factors (eg, active malignant neoplasm, extremity paresis, and antiphospholipid antibodies)
• Combined thrombophilias (eg, combined heterozygosity for factor V Leiden and the prothrombin G20210A mutation)
• Homozygosity for factor V Leiden.^32,46,48

Factor V Leiden by itself or combined with other thrombophilic abnormalities is not associated with a higher risk of recurrent venous thromboembolism during warfarin therapy (a possible exception is the combination of factor V Leiden plus antiphospholipid antibodies).^32,34 Furthermore, current evidence suggests that no thrombophilic defect is a clinically important risk factor for recurrent venous thromboembolism after anticoagulant therapy is stopped. All these facts indicate that clinical factors are probably more important than laboratory abnormalities in determining the duration of anticoagulation therapy.^{32,35,36,61–63}

PRIMARY PROPHYLAXIS IN PATIENTS WITH FACTOR V LEIDEN

Factor V Leiden is only one of many risk factors for deep vein thrombosis or pulmonary embolism. If carriers of factor V Leiden have never had a blood clot, then they are not routinely treated with an anticoagulant. Rather, they should be counseled about reducing or eliminating other factors that may add to their risk of developing a clot in the future.

Usually, the effect of risk factors is additive: the more risk factors present, the higher the risk.^46,50 Sometimes, however, the effect of multiple risk factors is more than additive.

Some risk factors, such as genetics or age, are not alterable, but many can be controlled by medications or lifestyle modifications. Therefore, general measures and precautions are recommended to minimize the risk of thrombosis. For example:

Losing weight (if the patient is overweight) is an important intervention for risk reduction, since obesity is probably the most common modifiable risk factor for developing blood clots.

Avoiding long periods of immobility is recommended. For example, if the patient is taking a long car ride (more than 2 hours), then stopping every few hours and walking around for a few minutes is a good way to keep the blood circulating. If the patient has a desk job, getting up and walking around the office periodically is advised. On long airplane trips, a walk in the aisle every so often and preventing dehydration by drinking plenty of fluids and avoiding alcohol are recommended.

Wearing elastic stockings with a graduated elastic pressure may prevent deep venous thrombosis from developing on long flights.^63–65

Staying active and getting regular exercise through such activities as walking, bicycling, or swimming are helpful.

Avoiding smoking is critical.^50,63

Thromboprophylaxis is recommended for most acutely ill hospitalized patients, especially those confined to bed with additional risk factors. Guidelines for prophylaxis are based on an individualized risk assessment and not on thrombophilia status. Prophylactic anticoagulation is routinely recommended for patients undergoing major high-risk surgery, such as an orthopedic, urologic, gynecologic, or bariatric procedure. Any excess thrombotic risk conferred by thrombophilia is likely small compared with the risk of surgery, and recommendations on the duration and intensity of thromboprophylaxis are not based on thrombophilic status.^46,48

Education. Pain, swelling, redness of a limb, unexplained shortness of breath, and chest pain are the most common symptoms of deep vein thrombosis and pulmonary embolism.^46,50 It is crucial to teach patients with factor V Leiden to recognize these symptoms and to seek early medical attention in case they experience any of them.

SCREENING FAMILY MEMBERS FOR THE FACTOR V LEIDEN MUTATION

Factor V Leiden by itself is a relatively mild thrombophilic defect that does not cause thrombosis in all carriers, and there is no evidence that early diagnosis reduces rates of morbidity or mortality. Therefore, routine screening of all asymptomatic relatives of affected patients with venous thrombosis is not recommended. Rather, the decision to screen should be made on an individual basis.^50,66

Screening may be beneficial in selected cases, especially when patients have a strong family history of recurrent venous thrombosis at a young age (younger than 50 years) and the family member has additional risk factors for venous thromboembolism such as oral contraception or is planning for pregnancy.^32,48,49,66

A 29-year-old white man with no chronic medical problems presents to the emergency department with shortness of breath, left-sided pleuritic chest pain, cough, and hemoptysis. These symptoms began abruptly 1 day ago and have persisted. He also has mild pain and swelling in both calves. He denies having any fever, night sweats, or chills. On further questioning, he reports having taken a long, nonstop driving trip that lasted 8 hours 1 week ago.

His medical history is negative, and he specifically reports no history of deep venous thrombosis or pulmonary embolism. He underwent appendectomy 10 years ago but has had no other operations. He does not take any medications. His family history is noncontributory and is negative for venous thromboembolism. He smokes and uses alcohol occasionally but not illicit drugs.

Examination. He appears to be in considerable distress because of his chest pain. His temperature is 100.4°F (38.0°C), blood pressure 125/70 mm Hg, heart rate 125 beats per minute, respiratory rate 26 breaths per minute, oxygen saturation 92% on room air, and body mass index 19 kg/m².

Chest examination reveals diminished vesicular breathing in the left base, which is normal to percussion without added sounds. Both calves are swollen and tender to palpation without skin discoloration. The rest of his examination is normal.

Laboratory values:

• White blood cell count 9.3 × 10⁹/L (reference range 4.5–11.0)
• Hemoglobin 15.9 g/dL (14.0–17.5)
• Platelets 205 × 10⁹/L (150–350)
• Sodium 140 mEq/L (136–142)
• Potassium 3.9 mEq/L (3.5–5.0)
• Chloride 108 mEq/L (96–106)
• Bicarbonate 23 mEq/L (21–28)
• Blood urea nitrogen 14 mg/dL (8–23)
• Creatinine 0.9 mg/dL (0.6–1.2)
• Glucose 95 mg/dL (70–110)
• International normalized ratio (INR) 0.90 (0.00–1.2)
• Partial thromboplastin time 27.5 seconds (24.6–31.8)
• Creatine phosphokinase 205 U/L (39–308)
• Troponin T < 0.015 ng/mL (0.01–0.045).

Pulmonary embolism is diagnosed

Electrocardiography shows sinus tachycardia. Chest radiography shows small atelectatic changes at the left lung base (Figure 1). Pulmonary embolism is suspected, and a serum Ddimer level is obtained; it is 4,054 ng/mL (reference range < 500). Computed tomography of the chest confirms bilateral acute pulmonary emboli (Figure 2). Doppler ultrasonography of both legs reveals bilateral deep venous thrombosis. Echocardiography shows mildly elevated right ventricular systolic pressure at 47 mm Hg.

Factor V Leiden is diagnosed, and the patient recovers with treatment

Anticoagulation is started in the emergency department.

Given this patient’s young age and clot burden, a hypercoagulable state is suspected. Thrombophilia screening is performed, with tests for the factor V Leiden mutation, the prothrombin G20210A mutation, and antiphospholipid and lupus anticoagulant antibodies. The rest of the thrombophilia panel, including antithrombin III, factor VIII, protein C, and protein S, is deferred because the levels of these substances would be expected to change during the acute thrombosis.

The direct test for factor V Leiden mutation is positive for the heterozygous type. The test for the prothrombin G20210A mutation is negative, and his antiphospholipid antibody levels, including the lupus anticoagulant titer, are within normal limits.

The patient is kept on a standard regimen of unfractionated heparin, overlapped with warfarin (Coumadin) until his INR is 2.0 to 3.0 on 2 consecutive days. His hospital course is uneventful and his condition gradually improves.

He is discharged home to continue on oral anticoagulation for 6 months with a target INR of 2.0 to 3.0. Two weeks after completing his anticoagulation therapy, his levels of antithrombin III, factor VIII, protein C, and protein S are all within normal limits.

FACTOR V LEIDEN IS COMMON

Factor V Leiden is the most common inherited thrombophilia, with a prevalence of 3% to 7% in the general US population,¹ approximately 5% in whites, 2.2% in Hispanics, and 1.2% in blacks.² Its prevalence in patients with venous thromboembolism, however, is 50%.^1,3 The annual incidence of venous thromboembolism in patients with factor V Leiden is 0.5%.^4,5

 

MORE COAGULATION, LESS ANTICOAGULATION

Factor V has a critical position in both the coagulant and anticoagulant pathways. Factor V Leiden results in a hypercoagulable state by both increasing coagulation and decreasing anticoagulation.

This mutation causes factor V to be resistant to being cleaved and inactivated by activated protein C, a condition known as APC resistance. As a result, more factor Va is available within the prothrombinase complex, increasing coagulation by increased generation of thrombin.^6–8

Furthermore, a cofactor formed by cleavage of factor V at position 506 is thought to support activated protein C in degrading factor VIIIa (in the tenase complex), along with protein S. People with factor V Leiden lack this cleavage product and thus have less anticoagulant activity from activated protein C. The increased coagulation and decreased anticoagulation appear to contribute equally to the hypercoagulable state in factor V Leiden-associated APC resistance.^9–11

Heterozygosity for the factor V Leiden mutation accounts for 90% to 95% of cases of APC resistance. A much smaller number of people are homozygous for it.¹

People who are homozygous for factor V Leiden are at higher risk of venous thromboembolism than those who are heterozygous for it, since the latter group’s blood contains both factor V Leiden and normal factor V. The normal factor V allows anticoagulation via the second pathway of inactivation of factor VIIIa by activated protein C, giving some protection against thrombosis. In people who are homozygous for factor V Leiden, the lack of normal factor V acting as an anticoagulant protein results in a higher thrombotic risk.^9–11

Other factor V mutations may also cause APC resistance

Although factor V Leiden is the only genetic defect for which a causal relationship with APC resistance has been clearly determined, other, rarer hereditary factor V mutations or polymorphisms have been described, such as factor V Cambridge (Arg306Thr)¹² and factor V Hong Kong (Arg306Gly).¹³ These mutations may result in APC resistance, but their clinical association with thrombosis is less clear.¹⁴ Factor V Liverpool (Ile359Thr) is associated with a higher risk of thrombosis, apparently because of reduced APC-mediated inactivation of factor Va and because it is a poor cofactor with activated protein C for the inactivation of factor VIIIa.¹⁵

An R2 haplotype has also been described in association with APC resistance.^16,17 The phenomenon may be due to a reduction in activated protein C cofactor activity.⁹ However, not all studies have been convincing regarding the role of this haplotype in clinical disease.¹⁸ Coinheritance of this haplotype with factor V Leiden may increase the risk of venous thromboembolism above that associated with factor V Leiden alone.¹⁹

Although factor V Leiden is the most common cause of inherited APC resistance, other changes in hemostasis cause acquired APC resistance and may contribute to the thrombotic tendency in these patients.^20–22 The most common causes of acquired APC resistance include elevated factor VIII levels,^23–25 pregnancy,^26–28 use of oral contraceptives,^29,30 and antiphospholipid antibodies.³¹

USUALLY MANIFESTS AS DEEP VEIN THROMBOSIS

Factor V Leiden usually manifests as deep vein thrombosis with or without pulmonary embolism, but thrombosis in unusual locations also occurs.³²

The risk of a first episode of venous thromboembolism is two to five times higher with heterozygous factor V Leiden. However, even though the relative risk is high, the absolute risk is low. Furthermore, despite the higher risk of venous thrombosis, there is no evidence that heterozygosity for factor V Leiden increases the overall mortality rate.^4,33–36

In people with homozygous factor V Leiden or with combined inherited thrombophilias, the risk of venous thromboembolism is increased to a greater degree: it is 20 to 50 times higher.^7,8,37–39 However, whether the risk of death is higher is not clear.

VENOUS THROMBOEMBOLISM IS MULTIFACTORIAL

The pathogenesis of venous thromboembolism is multifactorial and involves an interaction between inherited and acquired factors. Very often, people with factor V Leiden have additional risk factors that contribute to the development of venous clots, and it is very unusual for them to have thrombosis in the absence of these additional factors.

These factors include older age, surgery, obesity, prolonged travel, immobility, hospitalization, oral contraceptive use, hormonal replacement therapy, pregnancy, and malignancy. They increase the risk of venous thrombosis in normal individuals as well, but more so in people with factor V Leiden.^40–43

Testing for other known causes of thrombophilia may also be pursued. These include elevated homocysteine levels, the factor II (prothrombin) G20210A mutation, anticardiolipin antibody, lupus anticoagulant, and deficiencies of antithrombin III, protein C, and protein S.

Factor V Leiden by itself does not appear to increase the risk of arterial thrombosis, ie, heart attack and stroke.^{33,38,44–46}

Family history: A risk indicator for venous thrombosis

Family history is an important indicator of risk for a first venous thromboembolic event, regardless of other risk factors identified. The risk of a first event is two to three times higher in people with a family history of thrombosis in a first-degree relative. The risk is four times higher when multiple family members are affected, at least one of them before age 50.⁴⁷

In people with genetic thrombophilia, the risk of thrombosis (especially unprovoked thrombosis at a young age) is also higher in those with a strong family history than in those without a family history. In those with factor V Leiden, the risk of venous thromboembolism is three to four times higher if there is a positive family history. The risk is five times higher in carriers of factor V Leiden with a family history of venous thromboembolism before age 50, and 13 times higher in those with more than one affected family member.⁴⁷

Possible shared environmental factors or coinheritance of other unidentified genetic factors may also contribute to the higher susceptibility in thrombosis-prone families.

TESTING FOR APC RESISTANCE AND FACTOR V LEIDEN

The factor V Leiden mutation can be detected directly by genetic testing of peripheral blood mononuclear cells. This method is relatively time-consuming and expensive, however.

At present, the most cost-effective approach is to test first for APC resistance using a second-generation coagulation assay—the modified APC sensitivity test. In this clot-based method, the patient’s sample is prediluted with factor V-deficient plasma to eliminate the effect of lupus anticoagulants and factor deficiencies that could prolong the baseline clotting time, and heparin is inactivated by polybrene. Then either an augmented partial-thromboplastin-time-based assay or a tissue-factor-dependent factor V assay is performed.

This test is nearly 100% sensitive and specific for factor V Leiden, in contrast to the first-generation, or classic, APC sensitivity test, which lacked specificity and sensitivity for it.^{9–11,48–60} This modification also permits testing of patients receiving anticoagulants or who have abnormal augmented partial thromboplastin times due to coagulation factor deficiencies.

A positive result on the modified APC sensitivity test should be confirmed by a direct genetic test for the factor V Leiden mutation. An APC resistance assay is unnecessary if a direct genetic test is used initially.

 

HOW LONG TO GIVE ANTICOAGULATION AFTER VENOUS THROMBOEMBOLISM?

Patients who have had an episode of venous thromboembolism have to be treated with anticoagulants.

In general, the initial management of venous thromboembolism in patients with heritable thrombophilias is no different from that in any other patient with a clot. Anticoagulants such as warfarin are given at a target INR of 2.5 (range 2.0–3.0).³² The duration of treatment is based on the risk factors that resulted in the thrombotic event.

After a first event, some authorities recommend anticoagulant therapy for 6 months.³² A shorter period (3 months) is recommended if there is a transient risk factor (eg, surgery, oral contraceptive use, travel, pregnancy, the puerperium) and the thrombosis is confined to distal veins (eg, the calf veins).³²

Factor V Leiden does not necessarily increase the risk of recurrent events in patients who have a transient risk factor. Therefore, people who are heterozygous for this mutation do not usually need to be treated lifelong with anticoagulants if they have had only one episode of deep vein thrombosis or pulmonary embolism, given the risk of bleeding associated with anticoagulation, unless they have additional risk factors.

Conditions in which indefinite anticoagulation may be required after careful consideration of the risks and benefits are:

• Life-threatening events such as near-fatal pulmonary embolism
• Cerebral or visceral vein thrombosis
• Recurrent thrombotic events
• Additional persistent risk factors (eg, active malignant neoplasm, extremity paresis, and antiphospholipid antibodies)
• Combined thrombophilias (eg, combined heterozygosity for factor V Leiden and the prothrombin G20210A mutation)
• Homozygosity for factor V Leiden.^32,46,48

Factor V Leiden by itself or combined with other thrombophilic abnormalities is not associated with a higher risk of recurrent venous thromboembolism during warfarin therapy (a possible exception is the combination of factor V Leiden plus antiphospholipid antibodies).^32,34 Furthermore, current evidence suggests that no thrombophilic defect is a clinically important risk factor for recurrent venous thromboembolism after anticoagulant therapy is stopped. All these facts indicate that clinical factors are probably more important than laboratory abnormalities in determining the duration of anticoagulation therapy.^{32,35,36,61–63}

PRIMARY PROPHYLAXIS IN PATIENTS WITH FACTOR V LEIDEN

Factor V Leiden is only one of many risk factors for deep vein thrombosis or pulmonary embolism. If carriers of factor V Leiden have never had a blood clot, then they are not routinely treated with an anticoagulant. Rather, they should be counseled about reducing or eliminating other factors that may add to their risk of developing a clot in the future.

Usually, the effect of risk factors is additive: the more risk factors present, the higher the risk.^46,50 Sometimes, however, the effect of multiple risk factors is more than additive.

Some risk factors, such as genetics or age, are not alterable, but many can be controlled by medications or lifestyle modifications. Therefore, general measures and precautions are recommended to minimize the risk of thrombosis. For example:

Losing weight (if the patient is overweight) is an important intervention for risk reduction, since obesity is probably the most common modifiable risk factor for developing blood clots.

Avoiding long periods of immobility is recommended. For example, if the patient is taking a long car ride (more than 2 hours), then stopping every few hours and walking around for a few minutes is a good way to keep the blood circulating. If the patient has a desk job, getting up and walking around the office periodically is advised. On long airplane trips, a walk in the aisle every so often and preventing dehydration by drinking plenty of fluids and avoiding alcohol are recommended.

Wearing elastic stockings with a graduated elastic pressure may prevent deep venous thrombosis from developing on long flights.^63–65

Staying active and getting regular exercise through such activities as walking, bicycling, or swimming are helpful.

Avoiding smoking is critical.^50,63

Thromboprophylaxis is recommended for most acutely ill hospitalized patients, especially those confined to bed with additional risk factors. Guidelines for prophylaxis are based on an individualized risk assessment and not on thrombophilia status. Prophylactic anticoagulation is routinely recommended for patients undergoing major high-risk surgery, such as an orthopedic, urologic, gynecologic, or bariatric procedure. Any excess thrombotic risk conferred by thrombophilia is likely small compared with the risk of surgery, and recommendations on the duration and intensity of thromboprophylaxis are not based on thrombophilic status.^46,48

Education. Pain, swelling, redness of a limb, unexplained shortness of breath, and chest pain are the most common symptoms of deep vein thrombosis and pulmonary embolism.^46,50 It is crucial to teach patients with factor V Leiden to recognize these symptoms and to seek early medical attention in case they experience any of them.

SCREENING FAMILY MEMBERS FOR THE FACTOR V LEIDEN MUTATION

Factor V Leiden by itself is a relatively mild thrombophilic defect that does not cause thrombosis in all carriers, and there is no evidence that early diagnosis reduces rates of morbidity or mortality. Therefore, routine screening of all asymptomatic relatives of affected patients with venous thrombosis is not recommended. Rather, the decision to screen should be made on an individual basis.^50,66

Screening may be beneficial in selected cases, especially when patients have a strong family history of recurrent venous thrombosis at a young age (younger than 50 years) and the family member has additional risk factors for venous thromboembolism such as oral contraception or is planning for pregnancy.^32,48,49,66

A 29-year-old white man with no chronic medical problems presents to the emergency department with shortness of breath, left-sided pleuritic chest pain, cough, and hemoptysis. These symptoms began abruptly 1 day ago and have persisted. He also has mild pain and swelling in both calves. He denies having any fever, night sweats, or chills. On further questioning, he reports having taken a long, nonstop driving trip that lasted 8 hours 1 week ago.

His medical history is negative, and he specifically reports no history of deep venous thrombosis or pulmonary embolism. He underwent appendectomy 10 years ago but has had no other operations. He does not take any medications. His family history is noncontributory and is negative for venous thromboembolism. He smokes and uses alcohol occasionally but not illicit drugs.

Examination. He appears to be in considerable distress because of his chest pain. His temperature is 100.4°F (38.0°C), blood pressure 125/70 mm Hg, heart rate 125 beats per minute, respiratory rate 26 breaths per minute, oxygen saturation 92% on room air, and body mass index 19 kg/m².

Chest examination reveals diminished vesicular breathing in the left base, which is normal to percussion without added sounds. Both calves are swollen and tender to palpation without skin discoloration. The rest of his examination is normal.

Laboratory values:

• White blood cell count 9.3 × 10⁹/L (reference range 4.5–11.0)
• Hemoglobin 15.9 g/dL (14.0–17.5)
• Platelets 205 × 10⁹/L (150–350)
• Sodium 140 mEq/L (136–142)
• Potassium 3.9 mEq/L (3.5–5.0)
• Chloride 108 mEq/L (96–106)
• Bicarbonate 23 mEq/L (21–28)
• Blood urea nitrogen 14 mg/dL (8–23)
• Creatinine 0.9 mg/dL (0.6–1.2)
• Glucose 95 mg/dL (70–110)
• International normalized ratio (INR) 0.90 (0.00–1.2)
• Partial thromboplastin time 27.5 seconds (24.6–31.8)
• Creatine phosphokinase 205 U/L (39–308)
• Troponin T < 0.015 ng/mL (0.01–0.045).

Pulmonary embolism is diagnosed

Electrocardiography shows sinus tachycardia. Chest radiography shows small atelectatic changes at the left lung base (Figure 1). Pulmonary embolism is suspected, and a serum Ddimer level is obtained; it is 4,054 ng/mL (reference range < 500). Computed tomography of the chest confirms bilateral acute pulmonary emboli (Figure 2). Doppler ultrasonography of both legs reveals bilateral deep venous thrombosis. Echocardiography shows mildly elevated right ventricular systolic pressure at 47 mm Hg.

Factor V Leiden is diagnosed, and the patient recovers with treatment

Anticoagulation is started in the emergency department.

Given this patient’s young age and clot burden, a hypercoagulable state is suspected. Thrombophilia screening is performed, with tests for the factor V Leiden mutation, the prothrombin G20210A mutation, and antiphospholipid and lupus anticoagulant antibodies. The rest of the thrombophilia panel, including antithrombin III, factor VIII, protein C, and protein S, is deferred because the levels of these substances would be expected to change during the acute thrombosis.

The direct test for factor V Leiden mutation is positive for the heterozygous type. The test for the prothrombin G20210A mutation is negative, and his antiphospholipid antibody levels, including the lupus anticoagulant titer, are within normal limits.

The patient is kept on a standard regimen of unfractionated heparin, overlapped with warfarin (Coumadin) until his INR is 2.0 to 3.0 on 2 consecutive days. His hospital course is uneventful and his condition gradually improves.

He is discharged home to continue on oral anticoagulation for 6 months with a target INR of 2.0 to 3.0. Two weeks after completing his anticoagulation therapy, his levels of antithrombin III, factor VIII, protein C, and protein S are all within normal limits.

FACTOR V LEIDEN IS COMMON

Factor V Leiden is the most common inherited thrombophilia, with a prevalence of 3% to 7% in the general US population,¹ approximately 5% in whites, 2.2% in Hispanics, and 1.2% in blacks.² Its prevalence in patients with venous thromboembolism, however, is 50%.^1,3 The annual incidence of venous thromboembolism in patients with factor V Leiden is 0.5%.^4,5

 

MORE COAGULATION, LESS ANTICOAGULATION

Factor V has a critical position in both the coagulant and anticoagulant pathways. Factor V Leiden results in a hypercoagulable state by both increasing coagulation and decreasing anticoagulation.

This mutation causes factor V to be resistant to being cleaved and inactivated by activated protein C, a condition known as APC resistance. As a result, more factor Va is available within the prothrombinase complex, increasing coagulation by increased generation of thrombin.^6–8

Furthermore, a cofactor formed by cleavage of factor V at position 506 is thought to support activated protein C in degrading factor VIIIa (in the tenase complex), along with protein S. People with factor V Leiden lack this cleavage product and thus have less anticoagulant activity from activated protein C. The increased coagulation and decreased anticoagulation appear to contribute equally to the hypercoagulable state in factor V Leiden-associated APC resistance.^9–11

Heterozygosity for the factor V Leiden mutation accounts for 90% to 95% of cases of APC resistance. A much smaller number of people are homozygous for it.¹

People who are homozygous for factor V Leiden are at higher risk of venous thromboembolism than those who are heterozygous for it, since the latter group’s blood contains both factor V Leiden and normal factor V. The normal factor V allows anticoagulation via the second pathway of inactivation of factor VIIIa by activated protein C, giving some protection against thrombosis. In people who are homozygous for factor V Leiden, the lack of normal factor V acting as an anticoagulant protein results in a higher thrombotic risk.^9–11

Other factor V mutations may also cause APC resistance

Although factor V Leiden is the only genetic defect for which a causal relationship with APC resistance has been clearly determined, other, rarer hereditary factor V mutations or polymorphisms have been described, such as factor V Cambridge (Arg306Thr)¹² and factor V Hong Kong (Arg306Gly).¹³ These mutations may result in APC resistance, but their clinical association with thrombosis is less clear.¹⁴ Factor V Liverpool (Ile359Thr) is associated with a higher risk of thrombosis, apparently because of reduced APC-mediated inactivation of factor Va and because it is a poor cofactor with activated protein C for the inactivation of factor VIIIa.¹⁵

An R2 haplotype has also been described in association with APC resistance.^16,17 The phenomenon may be due to a reduction in activated protein C cofactor activity.⁹ However, not all studies have been convincing regarding the role of this haplotype in clinical disease.¹⁸ Coinheritance of this haplotype with factor V Leiden may increase the risk of venous thromboembolism above that associated with factor V Leiden alone.¹⁹

Although factor V Leiden is the most common cause of inherited APC resistance, other changes in hemostasis cause acquired APC resistance and may contribute to the thrombotic tendency in these patients.^20–22 The most common causes of acquired APC resistance include elevated factor VIII levels,^23–25 pregnancy,^26–28 use of oral contraceptives,^29,30 and antiphospholipid antibodies.³¹

USUALLY MANIFESTS AS DEEP VEIN THROMBOSIS

Factor V Leiden usually manifests as deep vein thrombosis with or without pulmonary embolism, but thrombosis in unusual locations also occurs.³²

The risk of a first episode of venous thromboembolism is two to five times higher with heterozygous factor V Leiden. However, even though the relative risk is high, the absolute risk is low. Furthermore, despite the higher risk of venous thrombosis, there is no evidence that heterozygosity for factor V Leiden increases the overall mortality rate.^4,33–36

In people with homozygous factor V Leiden or with combined inherited thrombophilias, the risk of venous thromboembolism is increased to a greater degree: it is 20 to 50 times higher.^7,8,37–39 However, whether the risk of death is higher is not clear.

VENOUS THROMBOEMBOLISM IS MULTIFACTORIAL

The pathogenesis of venous thromboembolism is multifactorial and involves an interaction between inherited and acquired factors. Very often, people with factor V Leiden have additional risk factors that contribute to the development of venous clots, and it is very unusual for them to have thrombosis in the absence of these additional factors.

These factors include older age, surgery, obesity, prolonged travel, immobility, hospitalization, oral contraceptive use, hormonal replacement therapy, pregnancy, and malignancy. They increase the risk of venous thrombosis in normal individuals as well, but more so in people with factor V Leiden.^40–43

Testing for other known causes of thrombophilia may also be pursued. These include elevated homocysteine levels, the factor II (prothrombin) G20210A mutation, anticardiolipin antibody, lupus anticoagulant, and deficiencies of antithrombin III, protein C, and protein S.

Factor V Leiden by itself does not appear to increase the risk of arterial thrombosis, ie, heart attack and stroke.^{33,38,44–46}

Family history: A risk indicator for venous thrombosis

Family history is an important indicator of risk for a first venous thromboembolic event, regardless of other risk factors identified. The risk of a first event is two to three times higher in people with a family history of thrombosis in a first-degree relative. The risk is four times higher when multiple family members are affected, at least one of them before age 50.⁴⁷

In people with genetic thrombophilia, the risk of thrombosis (especially unprovoked thrombosis at a young age) is also higher in those with a strong family history than in those without a family history. In those with factor V Leiden, the risk of venous thromboembolism is three to four times higher if there is a positive family history. The risk is five times higher in carriers of factor V Leiden with a family history of venous thromboembolism before age 50, and 13 times higher in those with more than one affected family member.⁴⁷

Possible shared environmental factors or coinheritance of other unidentified genetic factors may also contribute to the higher susceptibility in thrombosis-prone families.

TESTING FOR APC RESISTANCE AND FACTOR V LEIDEN

The factor V Leiden mutation can be detected directly by genetic testing of peripheral blood mononuclear cells. This method is relatively time-consuming and expensive, however.

At present, the most cost-effective approach is to test first for APC resistance using a second-generation coagulation assay—the modified APC sensitivity test. In this clot-based method, the patient’s sample is prediluted with factor V-deficient plasma to eliminate the effect of lupus anticoagulants and factor deficiencies that could prolong the baseline clotting time, and heparin is inactivated by polybrene. Then either an augmented partial-thromboplastin-time-based assay or a tissue-factor-dependent factor V assay is performed.

This test is nearly 100% sensitive and specific for factor V Leiden, in contrast to the first-generation, or classic, APC sensitivity test, which lacked specificity and sensitivity for it.^{9–11,48–60} This modification also permits testing of patients receiving anticoagulants or who have abnormal augmented partial thromboplastin times due to coagulation factor deficiencies.

A positive result on the modified APC sensitivity test should be confirmed by a direct genetic test for the factor V Leiden mutation. An APC resistance assay is unnecessary if a direct genetic test is used initially.

 

HOW LONG TO GIVE ANTICOAGULATION AFTER VENOUS THROMBOEMBOLISM?

Patients who have had an episode of venous thromboembolism have to be treated with anticoagulants.

In general, the initial management of venous thromboembolism in patients with heritable thrombophilias is no different from that in any other patient with a clot. Anticoagulants such as warfarin are given at a target INR of 2.5 (range 2.0–3.0).³² The duration of treatment is based on the risk factors that resulted in the thrombotic event.

After a first event, some authorities recommend anticoagulant therapy for 6 months.³² A shorter period (3 months) is recommended if there is a transient risk factor (eg, surgery, oral contraceptive use, travel, pregnancy, the puerperium) and the thrombosis is confined to distal veins (eg, the calf veins).³²

Factor V Leiden does not necessarily increase the risk of recurrent events in patients who have a transient risk factor. Therefore, people who are heterozygous for this mutation do not usually need to be treated lifelong with anticoagulants if they have had only one episode of deep vein thrombosis or pulmonary embolism, given the risk of bleeding associated with anticoagulation, unless they have additional risk factors.

Conditions in which indefinite anticoagulation may be required after careful consideration of the risks and benefits are:

• Life-threatening events such as near-fatal pulmonary embolism
• Cerebral or visceral vein thrombosis
• Recurrent thrombotic events
• Additional persistent risk factors (eg, active malignant neoplasm, extremity paresis, and antiphospholipid antibodies)
• Combined thrombophilias (eg, combined heterozygosity for factor V Leiden and the prothrombin G20210A mutation)
• Homozygosity for factor V Leiden.^32,46,48

Factor V Leiden by itself or combined with other thrombophilic abnormalities is not associated with a higher risk of recurrent venous thromboembolism during warfarin therapy (a possible exception is the combination of factor V Leiden plus antiphospholipid antibodies).^32,34 Furthermore, current evidence suggests that no thrombophilic defect is a clinically important risk factor for recurrent venous thromboembolism after anticoagulant therapy is stopped. All these facts indicate that clinical factors are probably more important than laboratory abnormalities in determining the duration of anticoagulation therapy.^{32,35,36,61–63}

PRIMARY PROPHYLAXIS IN PATIENTS WITH FACTOR V LEIDEN

Factor V Leiden is only one of many risk factors for deep vein thrombosis or pulmonary embolism. If carriers of factor V Leiden have never had a blood clot, then they are not routinely treated with an anticoagulant. Rather, they should be counseled about reducing or eliminating other factors that may add to their risk of developing a clot in the future.

Usually, the effect of risk factors is additive: the more risk factors present, the higher the risk.^46,50 Sometimes, however, the effect of multiple risk factors is more than additive.

Some risk factors, such as genetics or age, are not alterable, but many can be controlled by medications or lifestyle modifications. Therefore, general measures and precautions are recommended to minimize the risk of thrombosis. For example:

Losing weight (if the patient is overweight) is an important intervention for risk reduction, since obesity is probably the most common modifiable risk factor for developing blood clots.

Avoiding long periods of immobility is recommended. For example, if the patient is taking a long car ride (more than 2 hours), then stopping every few hours and walking around for a few minutes is a good way to keep the blood circulating. If the patient has a desk job, getting up and walking around the office periodically is advised. On long airplane trips, a walk in the aisle every so often and preventing dehydration by drinking plenty of fluids and avoiding alcohol are recommended.

Wearing elastic stockings with a graduated elastic pressure may prevent deep venous thrombosis from developing on long flights.^63–65

Staying active and getting regular exercise through such activities as walking, bicycling, or swimming are helpful.

Avoiding smoking is critical.^50,63

Thromboprophylaxis is recommended for most acutely ill hospitalized patients, especially those confined to bed with additional risk factors. Guidelines for prophylaxis are based on an individualized risk assessment and not on thrombophilia status. Prophylactic anticoagulation is routinely recommended for patients undergoing major high-risk surgery, such as an orthopedic, urologic, gynecologic, or bariatric procedure. Any excess thrombotic risk conferred by thrombophilia is likely small compared with the risk of surgery, and recommendations on the duration and intensity of thromboprophylaxis are not based on thrombophilic status.^46,48

Education. Pain, swelling, redness of a limb, unexplained shortness of breath, and chest pain are the most common symptoms of deep vein thrombosis and pulmonary embolism.^46,50 It is crucial to teach patients with factor V Leiden to recognize these symptoms and to seek early medical attention in case they experience any of them.

SCREENING FAMILY MEMBERS FOR THE FACTOR V LEIDEN MUTATION

Factor V Leiden by itself is a relatively mild thrombophilic defect that does not cause thrombosis in all carriers, and there is no evidence that early diagnosis reduces rates of morbidity or mortality. Therefore, routine screening of all asymptomatic relatives of affected patients with venous thrombosis is not recommended. Rather, the decision to screen should be made on an individual basis.^50,66

Screening may be beneficial in selected cases, especially when patients have a strong family history of recurrent venous thrombosis at a young age (younger than 50 years) and the family member has additional risk factors for venous thromboembolism such as oral contraception or is planning for pregnancy.^32,48,49,66

Over the past year, it has been hard to avoid news reports involving people getting high on “bath salts” and “incense” (also known as “Spice” or “K2”). Addiction treatment professionals have been overwhelmed by questions regarding why one would want to “snort bath salts” or “smoke incense.”

These substances are not what they appear to be. They are sold as bath salts and incense and are labeled “not for human consumption” simply to avoid regulation by the US Food and Drug Administration (FDA). In reality, they are powerful psychoactive drugs, with effects that mimic those of more commonly abused drugs such as amphetamines and marijuana. Until recently, they were legally available over the counter at quick-marts, head shops, and on the Internet. Because they are relatively new, they may not be detectable on routine urine drug screens, and users may be unaware of the specific chemicals contained in them.

These drugs, which we have collectively termed synthetic legal intoxicating drugs (SLIDs), are increasing dramatically in use.^1–3 A survey of youths at a rave party indicated that 21% had used one of them on at least one occasion.⁴ The general impression held by the drug-using public is that SLIDs are relatively cheap, are not detected on standard urine drug screens, can produce a powerful high, and, until recently, were readily available through legitimate sources.

Physicians need to be aware of SLIDs in order to recognize and manage the intoxication syndromes associated with these substances when encountered in clinical practice, and in order to educate patients about their potential dangers.

SYNTHETIC CANNABINOIDS MARKETED AS INCENSE

Herbal incense products that could be smoked as an alternative to marijuana started appearing on the Internet in Europe in 2004. By 2008, when such products first appeared in the United States, their use in Europe was already widespread.

Initially, consumers were led to believe that such herbal smoking blends were safe, legal alternatives to marijuana, and that it was the proprietary blend of herbs that was responsible for the “natural” high. Spice, a specific brand name, was originally trademarked in England as incense and also as an herbal smoking product.⁵

Legal authorities, however, suspected that these herbal blends were adulterated with synthetic substances. In December 2008, the first such substance was found when Austrian authorities isolated a synthetic cannabinoid, JWH-018, from an herbal incense product.⁶ By the end of 2009, five other synthetic cannabinoids—CP-47,497, HU-210, JWH-073, JWH-250, and JWH-398—had been isolated from various herbal incense samples around the world.⁷

The synthetic cannabinoids in herbal incense products are not derived from the hemp plant (Cannabis sativa), but are synthesized in laboratories and are formulated to interact with the endogenous cannabinoid receptors in the brain to produce psychoactive effects.

Synthetic cannabinoids are full agonists; natural THC is only a partial agonist

Two types of cannabinoid receptors have been discovered in humans: CB1 and CB2. Both types are found in the central nervous system, and CB2 is also found extensively in the periphery. CB1 is the receptor responsible for the psychoactive effects of cannabinoids, including altered consciousness, euphoria, relaxation, perceptual disturbances, intensified sensory experiences, cognitive impairment, and increased reaction time.⁶ The physiologic role of CB2 remains uncertain.

The major psychoactive cannabinoid in naturally occurring marijuana is delta-9-tetrahydrocannabinol (THC). The so-called classic cannabinoids, such as HU-210, are analogues of THC and are based on its chemical structure. The rest of the synthetic cannabinoids commonly found in incense products differ in chemical structure from naturally occurring cannabinoids such as THC, but have activity at the CB1 receptor and are thus psychoactive.

Of clinical relevance is that THC is only a partial agonist at the CB1 receptor, while all synthetic cannabinoids commonly found in incense products are full agonists at CB1.⁷ This difference is important because partial agonists bind to receptors but stimulate them only partially and therefore exhibit a plateau effect in terms of dose vs clinical response. In contrast, full agonists have no ceiling on the dose-response relationship and therefore have a greater potential for overdose and severe toxic effects.

Despite uncertainties, use is widespread

Most of the synthetic cannabinoids in herbal incense products were developed for research purposes, and there are almost no reliable scientific data on their effects in humans. Of additional concern is that no research has been conducted on their pyrolytic effects, ie, how these chemicals are transformed when they are burned, such as when consumers smoke them. Furthermore, herbal incense products often vary in their active substances and concentrations, so consumers really do not know what they are getting.

Despite the many uncertainties, the use of these products is widespread. Data submitted to the US Drug Enforcement Administration (DEA) from a major toxicology laboratory indicated that from July through November of 2010, 3,700 samples tested positive for either JWH-018 or JWH-073. This report also indicated that 30% to 35% of specimens submitted by juvenile probation departments were positive for synthetic cannabinoids.⁸

 

MEDICAL CONCERNS OVER SYNTHETIC CANNABINOIDS

Amid the mysteries surrounding synthetic cannabinoids, one thing is clear: users are increasingly seeking medical attention. In 2010, there were 2,906 calls to poison control centers across the United States pertaining to “synthetic marijuana”; in 2011 there were 6,959 calls, and in January 2012, 639 such calls had been placed.⁹

Some of the more common complaints related to the use of synthetic cannabinoids are listed in Table 1 and may be potentially serious.^1,10,11 The greater potency of synthetic cannabinoids and their full-agonist mechanism of action may be to blame for the relatively high number of complaints not typically associated with the use of marijuana.

The duration of the intoxicating effects of synthetic cannabinoids is generally longer than that of THC, but this seems to be variable. JWH-018, for instance, seems to have a shorter duration of action, at around 1 to 2 hours, while a longer, 5- to 6-hour intoxicating effect has been observed with CP-47,497.^7,12

Serious adverse effects

Although the prevalence of serious adverse effects associated with the use of synthetic cannabinoids is not known, a number of serious complications have been recognized.

Seizures. One case of seizure has been reported in association with the use of synthetic cannabinoids, specifically JWH-018.¹² This case involved a previously healthy 48-year-old man who had ingested a powder that was subsequently confirmed to be JWH-018, which he mixed with alcohol. Of further concern in this case is that this individual developed a refractory supraventricular tachycardia that required cardioversion on the first hospital day.

The authors speculated that the seizure may have been due to a dose-response mechanism that resulted in either the release of presynaptic excitatory neurotransmitters or the decreased release of inhibitory neurotransmitters. They further postulated that the supraventricular tachycardia could have been caused by one of two mechanisms previously reported in association with CB1 agonists: an increase in circulating catecholamines or heightened oxidative demands on the myocardium.¹²

Psychosis. The occurrence of psychotic symptoms such as hallucinations and paranoid delusions in association with synthetic cannabinoids is not surprising, given the well-documented link between marijuana use and psychosis.^13,14

A case report of a 25-year-old patient with a 7-year history of recurrent psychosis that was initially triggered by cannabis use indicated that the use of 3 g of herbal incense on three occasions was associated with worsening of previous psychotic symptoms and the emergence of command and paranoid types of auditory hallucination.¹⁰

Semistructured interviews of 15 patients in a forensic rehabilitative service, all of whom had a history of psychotic illness, showed that 69% experienced symptoms consistent with psychotic relapse after smoking an herbal incense product containing JWH-018.¹⁵

It is possible that psychotic symptoms may be more prominent with synthetic cannabinoids than with natural marijuana because not only are synthetic cannabinoids more potent and work as full agonists, but, unlike marijuana, they do not contain cannabidiol, which is thought to have antipsychotic efficacy.^10,16 However, the risk of psychotic symptoms in association with synthetic cannabinoid usage in otherwise healthy people is unknown.

Regulation lags behind

Growing concern over the perceived dangers posed by synthetic cannabinoids has led to a ban on some of the more common ones contained in herbal incense preparations. On March 1, 2011, the US DEA temporarily placed five synthetic cannabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol) under schedule I (banned substances).

Such a ban, however, may be futile because there are an estimated 100 synthetic cannabinoids that have yet to enter the market, and when one is banned, a new one is likely to be introduced immediately as a replacement.⁸

SYNTHETIC STIMULANTS MARKETED AS BATH SALTS

Like the herbal incense products, “bath salts” may likewise not be what they appear to be. They too may be labeled “not for human consumption” in an effort to bypass laws governing mind-altering substances.

Several pharmacologically active substances have been marketed as bath salts. Two of the more common ingredients are 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylcathinone (mephedrone).

MDPV is a dopamine and norepineph-rine reuptake inhibitor that acts as a powerful stimulant. It has no FDA-approved medical use, but it is an analogue of the stimulant pyrovalerone, which was once used to treat chronic fatigue.¹⁷

MDPV seems to be the most common substance found in bath salt products in the United States. A sample of this substance was first seized on the streets by German authorities in 2007. A study in Finland conducted from August 2009 to September 2010 estimated that 5.7% of all arrests for driving under the influence (DUI) unrelated to alcohol consumption involved MDPV intoxication.¹⁷ In 2009, the National Forensic Laboratory Information System of the US DEA had seized only two samples of MDPV, but by 2010 that had increased to 161.¹⁸

Mephedrone is derived from phenethylamine and is closely related to cathinone, the active ingredient in the African khat plant (Catha edulis).¹⁹ Khat has a history of abuse, and the chemical structure of cathinone and its derivatives is similar to that of amphetamine.

Mephedrone, a powerful stimulant, is suspected of working as a monoamine reuptake inhibitor, and it may also directly induce the presynaptic release of monoamines.²⁰ The net effect is an increase in serotonin, norepineph-rine, and dopamine levels at neuronal synapses.

Mephedrone was first described in 1929 by chemist Saem de Burnaga Sanchez, and it remained an obscure research chemical for many years.²¹ It was formally recognized as a drug of abuse in Europe in 2007, and by 2009 it was the sixth most frequently used such drug in Europe.^8,22

Although MDPV and mephedrone are the most common psychoactive ingredients in bath salts, many other synthetic drugs have been found on the market.

A temporary ban

On September 7, 2011, the US government made it illegal to possess or sell any substance containing MDPV, mephedrone, or methy-lone. This temporary restriction was to remain in effect for 1 year to give the DEA time to collect data to support a move to permanently control these substances.³

Like synthetic cannabinoids, however, synthetic stimulants are very difficult to regulate because they are a large group of substances. As soon as one substance is outlawed, another synthetic stimulant will likely take its place.

 

MEDICAL CONCERNS REGARDING SYNTHETIC STIMULANTS

The medical and psychiatric sequelae that are associated with the use of bath salts have sent an increasing number of people to emergency rooms. The number of bath-salt-related calls to US poison control centers increased dramatically from 303 in 2010 to 4,720 by August 31, 2011. Most of these calls were related to tachycardia, agitation, hallucinations, extreme paranoia, delusions, and elevations in blood pressure.³

A report of 35 cases of people who had used bath salts and who had reported to Michigan emergency rooms between November 13, 2010, and March 31, 2011, indicated that agitation was present in 66%, tachycardia in 63%, delusions and hallucinations in 40%, seizure or tremor in 29%, hypertension in 23%, drowsiness in 23%, paranoia in 20%, and mydriasis in 20%; one patient was dead on arrival. Of the 34 patients who were alive on arrival, 17 (50%) were hospitalized, 15 were released, and 2 left against medical advice. In the patients in this study, 63% had injected the drug, 26% snorted it, and 11% ingested it orally.² Toxicology results obtained during an autopsy on the one person who died revealed a high level of MDPV, and the coroner ruled that MDPV toxicity was the primary cause of death.²

In some instances, more data are available on the presenting signs and symptoms of some of the specific substances contained in bath salts. For example, several studies reported the effects on those who specifically used mephedrone either alone or in combination with alcohol (Table 2).^23–27

Though the pharmacokinetic properties of mephedrone are unknown, James et al²⁴ noted that an interesting feature is that its clinical effects seem to persist for more than 24 hours after the last exposure to the drug, which would not be expected based on the rapid elimination of other similar cathinones.

Sympathomimetic toxicity. Many of the symptoms listed in Table 2 are consistent with a sympathomimetic syndrome. In a case series reported by Regan et al,²⁶ most of the 57 patients exhibited cardiovascular findings consistent with sympathomimetic toxicity.

In the study by James et al,²⁴ one of the patients with chest pain had electrocardiographic changes consistent with acute myocardial infarction. Though it is not possible to conclude from a single case that mephedrone poses a risk of myocardial infarction, such a risk has been reported with khat.²⁸ More research is needed to determine whether mephedrone poses a risk of cardiac events when used by people with or without an underlying cardiac condition.

Seizure also seems to be a relatively common feature associated with mephedrone use in case series of emergency room presentations. The US Centers for Disease Control and Prevention l² reported that of 35 patients who had used bath salts, 40% experienced seizures or “tremors.” A recent case series²⁷ of 15 patients presenting to an emergency department after mephedrone use reported that 20% had experienced seizures. In the study by James et al,²⁴ four patients (3% of the total group) experienced seizures after using mephedrone. It should be noted that, aside from people presenting to emergency rooms, seizures are rarely reported in the wider population of mephedrone users.

Psychotic symptoms are also quite common in users of synthetic stimulants who present to emergency rooms, occurring, as previously stated, in 14% to 40% of cases.^2,24

In a small case series, Penders and Gestring²⁹ pointed out some common features in three patients who had used MDPV and had presented with psychosis: sleep problems, inattention, vivid hallucinations of intruders, fearfulness, and inability to remember many of the events surrounding their drug use. The authors concluded that the psychotic syndrome present in their three patients was indicative of a short-term delirium rather than a substance-induced psychosis based on the presence of attention deficits and memory problems. The patients in this series responded well to brief hospitalization and antipsychotic medications.

As with seizure, extreme presentations such as psychosis are infrequently mentioned except in people requiring treatment at a hospital. There are simply no data regarding the prevalence of psychotic symptoms in the larger group of all synthetic stimulant users.

SUSPECT SLID INTOXICATION IN ‘PSYCHIATRIC’ PATIENTS

Despite the temporary ban on the more common substances found in Spice and bath salts, it is premature for the medical community to breath a sigh of relief. Producers of these products are already likely bringing to market new ones containing similar but as yet nonbanned substances. Furthermore, such bans will do little to affect Internet commerce; rather than go to a head shop, consumers will order the products online.

Doctors in urgent care centers, emergency rooms, and on general medical floors should pay close attention to any patient without a known psychiatric history who is acting in a bizarre fashion. Most SLID-intoxicated patients will present with anxiety, agitation, and psychosis. Rather than assume that they are psychiatric patients, one should consider the possibility of SLID intoxication and pay close attention to the possible medical sequelae associated with SLID use, such as elevated blood pressure, tachycardia, and seizure.

Benzodiazepines, especially lorazepam (Ativan), have been the agents most commonly used to treat both agitation and seizures associated with SLID intoxication.

Antipsychotics should be used judiciously because of their propensity to lower the seizure threshold, and patients with synthetic stimulant toxicity are already at increased risk of seizure.

A psychiatric consult should be considered in the event of any suspected toxicity or for any patient whose behavior is difficult to manage.

Restraints may be needed in some circumstances when agitation cannot be controlled with benzodiazepines alone, to ensure safety for the patient as well as that of others in the emergency department.

Routine laboratory tests should be part of the workup of patients suspected of being under the influence of SLIDs. These include a complete blood cell count, complete metabolic panel, and urine toxicology (Table 3).^23,25 A routine urine toxicology study will likely be negative, but either the patient or collateral information may give you a general idea of what the patient used, in which case the sample could be sent out for special tests for the more common substances found in herbal incense or bath salt products.

Electroencephalography may be indicated if there is any question as to whether the patient may have suffered a seizure. There should be a low threshold to order electrocardiography, especially in the case of synthetic stimulant intoxication.

Serial cardiac enzymes may be warranted if a patient with synthetic-stimulant intoxicated has chest pain.

Education, addiction treatment. Much is unknown about the risk of SLIDs, but given the adverse events reported in the literature, it seems likely that those with underlying cardiac or psychiatric issues may be at higher risk for the most serious drug-related consequences. With regard to synthetic stimulants, Winstock et al²⁰ recommend a harm-reduction approach involving educating patients about avoiding the development of tolerance, not engaging in polydrug use, not injecting, and paying special attention to remaining cool and well hydrated.

Experience shows that once SLID patients get through their acute crisis and are no longer psychotic, they tend to be forthright in divulging what they used to get high. At that point, consideration should be given to consulting an addiction treatment specialist for further evaluation of the patient’s drug use history and for formulation of a treatment plan to help ensure that the patient doesn’t return to using these drugs.

 

SLIDs POSE A REAL CHALLENGE

SLIDs present a real challenge to law enforcement, governments, the public, and the addiction treatment community. There is currently no way to routinely test for these substances. Furthermore, any tests that are developed or laws that are enacted will be easily evaded, as there are many more synthetic substances waiting in the wings to be released.

Don’t be lulled into thinking that SLIDs are gone with the recent bans against some of the more common substances. More SLIDs are coming, and more morbidity should be expected in medical settings.

Doctors in emergency departments and other settings need to be prepared for the agitated and often psychotic presentation of SLID-intoxicated patients and should be ready with benzodiazepines, restraints, and a calm and reassuring manner. And for patients who present with psychotic symptoms, medical staff should also be ready to consider involuntary short-term commitment to an inpatient psychiatric unit.

Once they recover, patients need to be educated about the dangers of substances such as SLIDs that, because of their novelty, may be perceived as less dangerous alternatives to traditional illicit drugs.

Over the past year, it has been hard to avoid news reports involving people getting high on “bath salts” and “incense” (also known as “Spice” or “K2”). Addiction treatment professionals have been overwhelmed by questions regarding why one would want to “snort bath salts” or “smoke incense.”

These substances are not what they appear to be. They are sold as bath salts and incense and are labeled “not for human consumption” simply to avoid regulation by the US Food and Drug Administration (FDA). In reality, they are powerful psychoactive drugs, with effects that mimic those of more commonly abused drugs such as amphetamines and marijuana. Until recently, they were legally available over the counter at quick-marts, head shops, and on the Internet. Because they are relatively new, they may not be detectable on routine urine drug screens, and users may be unaware of the specific chemicals contained in them.

These drugs, which we have collectively termed synthetic legal intoxicating drugs (SLIDs), are increasing dramatically in use.^1–3 A survey of youths at a rave party indicated that 21% had used one of them on at least one occasion.⁴ The general impression held by the drug-using public is that SLIDs are relatively cheap, are not detected on standard urine drug screens, can produce a powerful high, and, until recently, were readily available through legitimate sources.

Physicians need to be aware of SLIDs in order to recognize and manage the intoxication syndromes associated with these substances when encountered in clinical practice, and in order to educate patients about their potential dangers.

SYNTHETIC CANNABINOIDS MARKETED AS INCENSE

Herbal incense products that could be smoked as an alternative to marijuana started appearing on the Internet in Europe in 2004. By 2008, when such products first appeared in the United States, their use in Europe was already widespread.

Initially, consumers were led to believe that such herbal smoking blends were safe, legal alternatives to marijuana, and that it was the proprietary blend of herbs that was responsible for the “natural” high. Spice, a specific brand name, was originally trademarked in England as incense and also as an herbal smoking product.⁵

Legal authorities, however, suspected that these herbal blends were adulterated with synthetic substances. In December 2008, the first such substance was found when Austrian authorities isolated a synthetic cannabinoid, JWH-018, from an herbal incense product.⁶ By the end of 2009, five other synthetic cannabinoids—CP-47,497, HU-210, JWH-073, JWH-250, and JWH-398—had been isolated from various herbal incense samples around the world.⁷

The synthetic cannabinoids in herbal incense products are not derived from the hemp plant (Cannabis sativa), but are synthesized in laboratories and are formulated to interact with the endogenous cannabinoid receptors in the brain to produce psychoactive effects.

Synthetic cannabinoids are full agonists; natural THC is only a partial agonist

Two types of cannabinoid receptors have been discovered in humans: CB1 and CB2. Both types are found in the central nervous system, and CB2 is also found extensively in the periphery. CB1 is the receptor responsible for the psychoactive effects of cannabinoids, including altered consciousness, euphoria, relaxation, perceptual disturbances, intensified sensory experiences, cognitive impairment, and increased reaction time.⁶ The physiologic role of CB2 remains uncertain.

The major psychoactive cannabinoid in naturally occurring marijuana is delta-9-tetrahydrocannabinol (THC). The so-called classic cannabinoids, such as HU-210, are analogues of THC and are based on its chemical structure. The rest of the synthetic cannabinoids commonly found in incense products differ in chemical structure from naturally occurring cannabinoids such as THC, but have activity at the CB1 receptor and are thus psychoactive.

Of clinical relevance is that THC is only a partial agonist at the CB1 receptor, while all synthetic cannabinoids commonly found in incense products are full agonists at CB1.⁷ This difference is important because partial agonists bind to receptors but stimulate them only partially and therefore exhibit a plateau effect in terms of dose vs clinical response. In contrast, full agonists have no ceiling on the dose-response relationship and therefore have a greater potential for overdose and severe toxic effects.

Despite uncertainties, use is widespread

Most of the synthetic cannabinoids in herbal incense products were developed for research purposes, and there are almost no reliable scientific data on their effects in humans. Of additional concern is that no research has been conducted on their pyrolytic effects, ie, how these chemicals are transformed when they are burned, such as when consumers smoke them. Furthermore, herbal incense products often vary in their active substances and concentrations, so consumers really do not know what they are getting.

Despite the many uncertainties, the use of these products is widespread. Data submitted to the US Drug Enforcement Administration (DEA) from a major toxicology laboratory indicated that from July through November of 2010, 3,700 samples tested positive for either JWH-018 or JWH-073. This report also indicated that 30% to 35% of specimens submitted by juvenile probation departments were positive for synthetic cannabinoids.⁸

 

MEDICAL CONCERNS OVER SYNTHETIC CANNABINOIDS

Amid the mysteries surrounding synthetic cannabinoids, one thing is clear: users are increasingly seeking medical attention. In 2010, there were 2,906 calls to poison control centers across the United States pertaining to “synthetic marijuana”; in 2011 there were 6,959 calls, and in January 2012, 639 such calls had been placed.⁹

Some of the more common complaints related to the use of synthetic cannabinoids are listed in Table 1 and may be potentially serious.^1,10,11 The greater potency of synthetic cannabinoids and their full-agonist mechanism of action may be to blame for the relatively high number of complaints not typically associated with the use of marijuana.

The duration of the intoxicating effects of synthetic cannabinoids is generally longer than that of THC, but this seems to be variable. JWH-018, for instance, seems to have a shorter duration of action, at around 1 to 2 hours, while a longer, 5- to 6-hour intoxicating effect has been observed with CP-47,497.^7,12

Serious adverse effects

Although the prevalence of serious adverse effects associated with the use of synthetic cannabinoids is not known, a number of serious complications have been recognized.

Seizures. One case of seizure has been reported in association with the use of synthetic cannabinoids, specifically JWH-018.¹² This case involved a previously healthy 48-year-old man who had ingested a powder that was subsequently confirmed to be JWH-018, which he mixed with alcohol. Of further concern in this case is that this individual developed a refractory supraventricular tachycardia that required cardioversion on the first hospital day.

The authors speculated that the seizure may have been due to a dose-response mechanism that resulted in either the release of presynaptic excitatory neurotransmitters or the decreased release of inhibitory neurotransmitters. They further postulated that the supraventricular tachycardia could have been caused by one of two mechanisms previously reported in association with CB1 agonists: an increase in circulating catecholamines or heightened oxidative demands on the myocardium.¹²

Psychosis. The occurrence of psychotic symptoms such as hallucinations and paranoid delusions in association with synthetic cannabinoids is not surprising, given the well-documented link between marijuana use and psychosis.^13,14

A case report of a 25-year-old patient with a 7-year history of recurrent psychosis that was initially triggered by cannabis use indicated that the use of 3 g of herbal incense on three occasions was associated with worsening of previous psychotic symptoms and the emergence of command and paranoid types of auditory hallucination.¹⁰

Semistructured interviews of 15 patients in a forensic rehabilitative service, all of whom had a history of psychotic illness, showed that 69% experienced symptoms consistent with psychotic relapse after smoking an herbal incense product containing JWH-018.¹⁵

It is possible that psychotic symptoms may be more prominent with synthetic cannabinoids than with natural marijuana because not only are synthetic cannabinoids more potent and work as full agonists, but, unlike marijuana, they do not contain cannabidiol, which is thought to have antipsychotic efficacy.^10,16 However, the risk of psychotic symptoms in association with synthetic cannabinoid usage in otherwise healthy people is unknown.

Regulation lags behind

Growing concern over the perceived dangers posed by synthetic cannabinoids has led to a ban on some of the more common ones contained in herbal incense preparations. On March 1, 2011, the US DEA temporarily placed five synthetic cannabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol) under schedule I (banned substances).

Such a ban, however, may be futile because there are an estimated 100 synthetic cannabinoids that have yet to enter the market, and when one is banned, a new one is likely to be introduced immediately as a replacement.⁸

SYNTHETIC STIMULANTS MARKETED AS BATH SALTS

Like the herbal incense products, “bath salts” may likewise not be what they appear to be. They too may be labeled “not for human consumption” in an effort to bypass laws governing mind-altering substances.

Several pharmacologically active substances have been marketed as bath salts. Two of the more common ingredients are 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylcathinone (mephedrone).

MDPV is a dopamine and norepineph-rine reuptake inhibitor that acts as a powerful stimulant. It has no FDA-approved medical use, but it is an analogue of the stimulant pyrovalerone, which was once used to treat chronic fatigue.¹⁷

MDPV seems to be the most common substance found in bath salt products in the United States. A sample of this substance was first seized on the streets by German authorities in 2007. A study in Finland conducted from August 2009 to September 2010 estimated that 5.7% of all arrests for driving under the influence (DUI) unrelated to alcohol consumption involved MDPV intoxication.¹⁷ In 2009, the National Forensic Laboratory Information System of the US DEA had seized only two samples of MDPV, but by 2010 that had increased to 161.¹⁸

Mephedrone is derived from phenethylamine and is closely related to cathinone, the active ingredient in the African khat plant (Catha edulis).¹⁹ Khat has a history of abuse, and the chemical structure of cathinone and its derivatives is similar to that of amphetamine.

Mephedrone, a powerful stimulant, is suspected of working as a monoamine reuptake inhibitor, and it may also directly induce the presynaptic release of monoamines.²⁰ The net effect is an increase in serotonin, norepineph-rine, and dopamine levels at neuronal synapses.

Mephedrone was first described in 1929 by chemist Saem de Burnaga Sanchez, and it remained an obscure research chemical for many years.²¹ It was formally recognized as a drug of abuse in Europe in 2007, and by 2009 it was the sixth most frequently used such drug in Europe.^8,22

Although MDPV and mephedrone are the most common psychoactive ingredients in bath salts, many other synthetic drugs have been found on the market.

A temporary ban

On September 7, 2011, the US government made it illegal to possess or sell any substance containing MDPV, mephedrone, or methy-lone. This temporary restriction was to remain in effect for 1 year to give the DEA time to collect data to support a move to permanently control these substances.³

Like synthetic cannabinoids, however, synthetic stimulants are very difficult to regulate because they are a large group of substances. As soon as one substance is outlawed, another synthetic stimulant will likely take its place.

 

MEDICAL CONCERNS REGARDING SYNTHETIC STIMULANTS

The medical and psychiatric sequelae that are associated with the use of bath salts have sent an increasing number of people to emergency rooms. The number of bath-salt-related calls to US poison control centers increased dramatically from 303 in 2010 to 4,720 by August 31, 2011. Most of these calls were related to tachycardia, agitation, hallucinations, extreme paranoia, delusions, and elevations in blood pressure.³

A report of 35 cases of people who had used bath salts and who had reported to Michigan emergency rooms between November 13, 2010, and March 31, 2011, indicated that agitation was present in 66%, tachycardia in 63%, delusions and hallucinations in 40%, seizure or tremor in 29%, hypertension in 23%, drowsiness in 23%, paranoia in 20%, and mydriasis in 20%; one patient was dead on arrival. Of the 34 patients who were alive on arrival, 17 (50%) were hospitalized, 15 were released, and 2 left against medical advice. In the patients in this study, 63% had injected the drug, 26% snorted it, and 11% ingested it orally.² Toxicology results obtained during an autopsy on the one person who died revealed a high level of MDPV, and the coroner ruled that MDPV toxicity was the primary cause of death.²

In some instances, more data are available on the presenting signs and symptoms of some of the specific substances contained in bath salts. For example, several studies reported the effects on those who specifically used mephedrone either alone or in combination with alcohol (Table 2).^23–27

Though the pharmacokinetic properties of mephedrone are unknown, James et al²⁴ noted that an interesting feature is that its clinical effects seem to persist for more than 24 hours after the last exposure to the drug, which would not be expected based on the rapid elimination of other similar cathinones.

Sympathomimetic toxicity. Many of the symptoms listed in Table 2 are consistent with a sympathomimetic syndrome. In a case series reported by Regan et al,²⁶ most of the 57 patients exhibited cardiovascular findings consistent with sympathomimetic toxicity.

In the study by James et al,²⁴ one of the patients with chest pain had electrocardiographic changes consistent with acute myocardial infarction. Though it is not possible to conclude from a single case that mephedrone poses a risk of myocardial infarction, such a risk has been reported with khat.²⁸ More research is needed to determine whether mephedrone poses a risk of cardiac events when used by people with or without an underlying cardiac condition.

Seizure also seems to be a relatively common feature associated with mephedrone use in case series of emergency room presentations. The US Centers for Disease Control and Prevention l² reported that of 35 patients who had used bath salts, 40% experienced seizures or “tremors.” A recent case series²⁷ of 15 patients presenting to an emergency department after mephedrone use reported that 20% had experienced seizures. In the study by James et al,²⁴ four patients (3% of the total group) experienced seizures after using mephedrone. It should be noted that, aside from people presenting to emergency rooms, seizures are rarely reported in the wider population of mephedrone users.

Psychotic symptoms are also quite common in users of synthetic stimulants who present to emergency rooms, occurring, as previously stated, in 14% to 40% of cases.^2,24

In a small case series, Penders and Gestring²⁹ pointed out some common features in three patients who had used MDPV and had presented with psychosis: sleep problems, inattention, vivid hallucinations of intruders, fearfulness, and inability to remember many of the events surrounding their drug use. The authors concluded that the psychotic syndrome present in their three patients was indicative of a short-term delirium rather than a substance-induced psychosis based on the presence of attention deficits and memory problems. The patients in this series responded well to brief hospitalization and antipsychotic medications.

As with seizure, extreme presentations such as psychosis are infrequently mentioned except in people requiring treatment at a hospital. There are simply no data regarding the prevalence of psychotic symptoms in the larger group of all synthetic stimulant users.

SUSPECT SLID INTOXICATION IN ‘PSYCHIATRIC’ PATIENTS

Despite the temporary ban on the more common substances found in Spice and bath salts, it is premature for the medical community to breath a sigh of relief. Producers of these products are already likely bringing to market new ones containing similar but as yet nonbanned substances. Furthermore, such bans will do little to affect Internet commerce; rather than go to a head shop, consumers will order the products online.

Doctors in urgent care centers, emergency rooms, and on general medical floors should pay close attention to any patient without a known psychiatric history who is acting in a bizarre fashion. Most SLID-intoxicated patients will present with anxiety, agitation, and psychosis. Rather than assume that they are psychiatric patients, one should consider the possibility of SLID intoxication and pay close attention to the possible medical sequelae associated with SLID use, such as elevated blood pressure, tachycardia, and seizure.

Benzodiazepines, especially lorazepam (Ativan), have been the agents most commonly used to treat both agitation and seizures associated with SLID intoxication.

Antipsychotics should be used judiciously because of their propensity to lower the seizure threshold, and patients with synthetic stimulant toxicity are already at increased risk of seizure.

A psychiatric consult should be considered in the event of any suspected toxicity or for any patient whose behavior is difficult to manage.

Restraints may be needed in some circumstances when agitation cannot be controlled with benzodiazepines alone, to ensure safety for the patient as well as that of others in the emergency department.

Routine laboratory tests should be part of the workup of patients suspected of being under the influence of SLIDs. These include a complete blood cell count, complete metabolic panel, and urine toxicology (Table 3).^23,25 A routine urine toxicology study will likely be negative, but either the patient or collateral information may give you a general idea of what the patient used, in which case the sample could be sent out for special tests for the more common substances found in herbal incense or bath salt products.

Electroencephalography may be indicated if there is any question as to whether the patient may have suffered a seizure. There should be a low threshold to order electrocardiography, especially in the case of synthetic stimulant intoxication.

Serial cardiac enzymes may be warranted if a patient with synthetic-stimulant intoxicated has chest pain.

Education, addiction treatment. Much is unknown about the risk of SLIDs, but given the adverse events reported in the literature, it seems likely that those with underlying cardiac or psychiatric issues may be at higher risk for the most serious drug-related consequences. With regard to synthetic stimulants, Winstock et al²⁰ recommend a harm-reduction approach involving educating patients about avoiding the development of tolerance, not engaging in polydrug use, not injecting, and paying special attention to remaining cool and well hydrated.

Experience shows that once SLID patients get through their acute crisis and are no longer psychotic, they tend to be forthright in divulging what they used to get high. At that point, consideration should be given to consulting an addiction treatment specialist for further evaluation of the patient’s drug use history and for formulation of a treatment plan to help ensure that the patient doesn’t return to using these drugs.

 

SLIDs POSE A REAL CHALLENGE

SLIDs present a real challenge to law enforcement, governments, the public, and the addiction treatment community. There is currently no way to routinely test for these substances. Furthermore, any tests that are developed or laws that are enacted will be easily evaded, as there are many more synthetic substances waiting in the wings to be released.

Don’t be lulled into thinking that SLIDs are gone with the recent bans against some of the more common substances. More SLIDs are coming, and more morbidity should be expected in medical settings.

Doctors in emergency departments and other settings need to be prepared for the agitated and often psychotic presentation of SLID-intoxicated patients and should be ready with benzodiazepines, restraints, and a calm and reassuring manner. And for patients who present with psychotic symptoms, medical staff should also be ready to consider involuntary short-term commitment to an inpatient psychiatric unit.

Once they recover, patients need to be educated about the dangers of substances such as SLIDs that, because of their novelty, may be perceived as less dangerous alternatives to traditional illicit drugs.

Over the past year, it has been hard to avoid news reports involving people getting high on “bath salts” and “incense” (also known as “Spice” or “K2”). Addiction treatment professionals have been overwhelmed by questions regarding why one would want to “snort bath salts” or “smoke incense.”

These substances are not what they appear to be. They are sold as bath salts and incense and are labeled “not for human consumption” simply to avoid regulation by the US Food and Drug Administration (FDA). In reality, they are powerful psychoactive drugs, with effects that mimic those of more commonly abused drugs such as amphetamines and marijuana. Until recently, they were legally available over the counter at quick-marts, head shops, and on the Internet. Because they are relatively new, they may not be detectable on routine urine drug screens, and users may be unaware of the specific chemicals contained in them.

These drugs, which we have collectively termed synthetic legal intoxicating drugs (SLIDs), are increasing dramatically in use.^1–3 A survey of youths at a rave party indicated that 21% had used one of them on at least one occasion.⁴ The general impression held by the drug-using public is that SLIDs are relatively cheap, are not detected on standard urine drug screens, can produce a powerful high, and, until recently, were readily available through legitimate sources.

Physicians need to be aware of SLIDs in order to recognize and manage the intoxication syndromes associated with these substances when encountered in clinical practice, and in order to educate patients about their potential dangers.

SYNTHETIC CANNABINOIDS MARKETED AS INCENSE

Herbal incense products that could be smoked as an alternative to marijuana started appearing on the Internet in Europe in 2004. By 2008, when such products first appeared in the United States, their use in Europe was already widespread.

Initially, consumers were led to believe that such herbal smoking blends were safe, legal alternatives to marijuana, and that it was the proprietary blend of herbs that was responsible for the “natural” high. Spice, a specific brand name, was originally trademarked in England as incense and also as an herbal smoking product.⁵

Legal authorities, however, suspected that these herbal blends were adulterated with synthetic substances. In December 2008, the first such substance was found when Austrian authorities isolated a synthetic cannabinoid, JWH-018, from an herbal incense product.⁶ By the end of 2009, five other synthetic cannabinoids—CP-47,497, HU-210, JWH-073, JWH-250, and JWH-398—had been isolated from various herbal incense samples around the world.⁷

The synthetic cannabinoids in herbal incense products are not derived from the hemp plant (Cannabis sativa), but are synthesized in laboratories and are formulated to interact with the endogenous cannabinoid receptors in the brain to produce psychoactive effects.

Synthetic cannabinoids are full agonists; natural THC is only a partial agonist

Two types of cannabinoid receptors have been discovered in humans: CB1 and CB2. Both types are found in the central nervous system, and CB2 is also found extensively in the periphery. CB1 is the receptor responsible for the psychoactive effects of cannabinoids, including altered consciousness, euphoria, relaxation, perceptual disturbances, intensified sensory experiences, cognitive impairment, and increased reaction time.⁶ The physiologic role of CB2 remains uncertain.

The major psychoactive cannabinoid in naturally occurring marijuana is delta-9-tetrahydrocannabinol (THC). The so-called classic cannabinoids, such as HU-210, are analogues of THC and are based on its chemical structure. The rest of the synthetic cannabinoids commonly found in incense products differ in chemical structure from naturally occurring cannabinoids such as THC, but have activity at the CB1 receptor and are thus psychoactive.

Of clinical relevance is that THC is only a partial agonist at the CB1 receptor, while all synthetic cannabinoids commonly found in incense products are full agonists at CB1.⁷ This difference is important because partial agonists bind to receptors but stimulate them only partially and therefore exhibit a plateau effect in terms of dose vs clinical response. In contrast, full agonists have no ceiling on the dose-response relationship and therefore have a greater potential for overdose and severe toxic effects.

Despite uncertainties, use is widespread

Most of the synthetic cannabinoids in herbal incense products were developed for research purposes, and there are almost no reliable scientific data on their effects in humans. Of additional concern is that no research has been conducted on their pyrolytic effects, ie, how these chemicals are transformed when they are burned, such as when consumers smoke them. Furthermore, herbal incense products often vary in their active substances and concentrations, so consumers really do not know what they are getting.

Despite the many uncertainties, the use of these products is widespread. Data submitted to the US Drug Enforcement Administration (DEA) from a major toxicology laboratory indicated that from July through November of 2010, 3,700 samples tested positive for either JWH-018 or JWH-073. This report also indicated that 30% to 35% of specimens submitted by juvenile probation departments were positive for synthetic cannabinoids.⁸

 

MEDICAL CONCERNS OVER SYNTHETIC CANNABINOIDS

Amid the mysteries surrounding synthetic cannabinoids, one thing is clear: users are increasingly seeking medical attention. In 2010, there were 2,906 calls to poison control centers across the United States pertaining to “synthetic marijuana”; in 2011 there were 6,959 calls, and in January 2012, 639 such calls had been placed.⁹

Some of the more common complaints related to the use of synthetic cannabinoids are listed in Table 1 and may be potentially serious.^1,10,11 The greater potency of synthetic cannabinoids and their full-agonist mechanism of action may be to blame for the relatively high number of complaints not typically associated with the use of marijuana.

The duration of the intoxicating effects of synthetic cannabinoids is generally longer than that of THC, but this seems to be variable. JWH-018, for instance, seems to have a shorter duration of action, at around 1 to 2 hours, while a longer, 5- to 6-hour intoxicating effect has been observed with CP-47,497.^7,12

Serious adverse effects

Although the prevalence of serious adverse effects associated with the use of synthetic cannabinoids is not known, a number of serious complications have been recognized.

Seizures. One case of seizure has been reported in association with the use of synthetic cannabinoids, specifically JWH-018.¹² This case involved a previously healthy 48-year-old man who had ingested a powder that was subsequently confirmed to be JWH-018, which he mixed with alcohol. Of further concern in this case is that this individual developed a refractory supraventricular tachycardia that required cardioversion on the first hospital day.

The authors speculated that the seizure may have been due to a dose-response mechanism that resulted in either the release of presynaptic excitatory neurotransmitters or the decreased release of inhibitory neurotransmitters. They further postulated that the supraventricular tachycardia could have been caused by one of two mechanisms previously reported in association with CB1 agonists: an increase in circulating catecholamines or heightened oxidative demands on the myocardium.¹²

Psychosis. The occurrence of psychotic symptoms such as hallucinations and paranoid delusions in association with synthetic cannabinoids is not surprising, given the well-documented link between marijuana use and psychosis.^13,14

A case report of a 25-year-old patient with a 7-year history of recurrent psychosis that was initially triggered by cannabis use indicated that the use of 3 g of herbal incense on three occasions was associated with worsening of previous psychotic symptoms and the emergence of command and paranoid types of auditory hallucination.¹⁰

Semistructured interviews of 15 patients in a forensic rehabilitative service, all of whom had a history of psychotic illness, showed that 69% experienced symptoms consistent with psychotic relapse after smoking an herbal incense product containing JWH-018.¹⁵

It is possible that psychotic symptoms may be more prominent with synthetic cannabinoids than with natural marijuana because not only are synthetic cannabinoids more potent and work as full agonists, but, unlike marijuana, they do not contain cannabidiol, which is thought to have antipsychotic efficacy.^10,16 However, the risk of psychotic symptoms in association with synthetic cannabinoid usage in otherwise healthy people is unknown.

Regulation lags behind

Growing concern over the perceived dangers posed by synthetic cannabinoids has led to a ban on some of the more common ones contained in herbal incense preparations. On March 1, 2011, the US DEA temporarily placed five synthetic cannabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol) under schedule I (banned substances).

Such a ban, however, may be futile because there are an estimated 100 synthetic cannabinoids that have yet to enter the market, and when one is banned, a new one is likely to be introduced immediately as a replacement.⁸

SYNTHETIC STIMULANTS MARKETED AS BATH SALTS

Like the herbal incense products, “bath salts” may likewise not be what they appear to be. They too may be labeled “not for human consumption” in an effort to bypass laws governing mind-altering substances.

Several pharmacologically active substances have been marketed as bath salts. Two of the more common ingredients are 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylcathinone (mephedrone).

MDPV is a dopamine and norepineph-rine reuptake inhibitor that acts as a powerful stimulant. It has no FDA-approved medical use, but it is an analogue of the stimulant pyrovalerone, which was once used to treat chronic fatigue.¹⁷

MDPV seems to be the most common substance found in bath salt products in the United States. A sample of this substance was first seized on the streets by German authorities in 2007. A study in Finland conducted from August 2009 to September 2010 estimated that 5.7% of all arrests for driving under the influence (DUI) unrelated to alcohol consumption involved MDPV intoxication.¹⁷ In 2009, the National Forensic Laboratory Information System of the US DEA had seized only two samples of MDPV, but by 2010 that had increased to 161.¹⁸

Mephedrone is derived from phenethylamine and is closely related to cathinone, the active ingredient in the African khat plant (Catha edulis).¹⁹ Khat has a history of abuse, and the chemical structure of cathinone and its derivatives is similar to that of amphetamine.

Mephedrone, a powerful stimulant, is suspected of working as a monoamine reuptake inhibitor, and it may also directly induce the presynaptic release of monoamines.²⁰ The net effect is an increase in serotonin, norepineph-rine, and dopamine levels at neuronal synapses.

Mephedrone was first described in 1929 by chemist Saem de Burnaga Sanchez, and it remained an obscure research chemical for many years.²¹ It was formally recognized as a drug of abuse in Europe in 2007, and by 2009 it was the sixth most frequently used such drug in Europe.^8,22

Although MDPV and mephedrone are the most common psychoactive ingredients in bath salts, many other synthetic drugs have been found on the market.

A temporary ban

On September 7, 2011, the US government made it illegal to possess or sell any substance containing MDPV, mephedrone, or methy-lone. This temporary restriction was to remain in effect for 1 year to give the DEA time to collect data to support a move to permanently control these substances.³

Like synthetic cannabinoids, however, synthetic stimulants are very difficult to regulate because they are a large group of substances. As soon as one substance is outlawed, another synthetic stimulant will likely take its place.

 

MEDICAL CONCERNS REGARDING SYNTHETIC STIMULANTS

The medical and psychiatric sequelae that are associated with the use of bath salts have sent an increasing number of people to emergency rooms. The number of bath-salt-related calls to US poison control centers increased dramatically from 303 in 2010 to 4,720 by August 31, 2011. Most of these calls were related to tachycardia, agitation, hallucinations, extreme paranoia, delusions, and elevations in blood pressure.³

A report of 35 cases of people who had used bath salts and who had reported to Michigan emergency rooms between November 13, 2010, and March 31, 2011, indicated that agitation was present in 66%, tachycardia in 63%, delusions and hallucinations in 40%, seizure or tremor in 29%, hypertension in 23%, drowsiness in 23%, paranoia in 20%, and mydriasis in 20%; one patient was dead on arrival. Of the 34 patients who were alive on arrival, 17 (50%) were hospitalized, 15 were released, and 2 left against medical advice. In the patients in this study, 63% had injected the drug, 26% snorted it, and 11% ingested it orally.² Toxicology results obtained during an autopsy on the one person who died revealed a high level of MDPV, and the coroner ruled that MDPV toxicity was the primary cause of death.²

In some instances, more data are available on the presenting signs and symptoms of some of the specific substances contained in bath salts. For example, several studies reported the effects on those who specifically used mephedrone either alone or in combination with alcohol (Table 2).^23–27

Though the pharmacokinetic properties of mephedrone are unknown, James et al²⁴ noted that an interesting feature is that its clinical effects seem to persist for more than 24 hours after the last exposure to the drug, which would not be expected based on the rapid elimination of other similar cathinones.

Sympathomimetic toxicity. Many of the symptoms listed in Table 2 are consistent with a sympathomimetic syndrome. In a case series reported by Regan et al,²⁶ most of the 57 patients exhibited cardiovascular findings consistent with sympathomimetic toxicity.

In the study by James et al,²⁴ one of the patients with chest pain had electrocardiographic changes consistent with acute myocardial infarction. Though it is not possible to conclude from a single case that mephedrone poses a risk of myocardial infarction, such a risk has been reported with khat.²⁸ More research is needed to determine whether mephedrone poses a risk of cardiac events when used by people with or without an underlying cardiac condition.

Seizure also seems to be a relatively common feature associated with mephedrone use in case series of emergency room presentations. The US Centers for Disease Control and Prevention l² reported that of 35 patients who had used bath salts, 40% experienced seizures or “tremors.” A recent case series²⁷ of 15 patients presenting to an emergency department after mephedrone use reported that 20% had experienced seizures. In the study by James et al,²⁴ four patients (3% of the total group) experienced seizures after using mephedrone. It should be noted that, aside from people presenting to emergency rooms, seizures are rarely reported in the wider population of mephedrone users.

Psychotic symptoms are also quite common in users of synthetic stimulants who present to emergency rooms, occurring, as previously stated, in 14% to 40% of cases.^2,24

In a small case series, Penders and Gestring²⁹ pointed out some common features in three patients who had used MDPV and had presented with psychosis: sleep problems, inattention, vivid hallucinations of intruders, fearfulness, and inability to remember many of the events surrounding their drug use. The authors concluded that the psychotic syndrome present in their three patients was indicative of a short-term delirium rather than a substance-induced psychosis based on the presence of attention deficits and memory problems. The patients in this series responded well to brief hospitalization and antipsychotic medications.

As with seizure, extreme presentations such as psychosis are infrequently mentioned except in people requiring treatment at a hospital. There are simply no data regarding the prevalence of psychotic symptoms in the larger group of all synthetic stimulant users.

SUSPECT SLID INTOXICATION IN ‘PSYCHIATRIC’ PATIENTS

Despite the temporary ban on the more common substances found in Spice and bath salts, it is premature for the medical community to breath a sigh of relief. Producers of these products are already likely bringing to market new ones containing similar but as yet nonbanned substances. Furthermore, such bans will do little to affect Internet commerce; rather than go to a head shop, consumers will order the products online.

Doctors in urgent care centers, emergency rooms, and on general medical floors should pay close attention to any patient without a known psychiatric history who is acting in a bizarre fashion. Most SLID-intoxicated patients will present with anxiety, agitation, and psychosis. Rather than assume that they are psychiatric patients, one should consider the possibility of SLID intoxication and pay close attention to the possible medical sequelae associated with SLID use, such as elevated blood pressure, tachycardia, and seizure.

Benzodiazepines, especially lorazepam (Ativan), have been the agents most commonly used to treat both agitation and seizures associated with SLID intoxication.

Antipsychotics should be used judiciously because of their propensity to lower the seizure threshold, and patients with synthetic stimulant toxicity are already at increased risk of seizure.

A psychiatric consult should be considered in the event of any suspected toxicity or for any patient whose behavior is difficult to manage.

Restraints may be needed in some circumstances when agitation cannot be controlled with benzodiazepines alone, to ensure safety for the patient as well as that of others in the emergency department.

Routine laboratory tests should be part of the workup of patients suspected of being under the influence of SLIDs. These include a complete blood cell count, complete metabolic panel, and urine toxicology (Table 3).^23,25 A routine urine toxicology study will likely be negative, but either the patient or collateral information may give you a general idea of what the patient used, in which case the sample could be sent out for special tests for the more common substances found in herbal incense or bath salt products.

Electroencephalography may be indicated if there is any question as to whether the patient may have suffered a seizure. There should be a low threshold to order electrocardiography, especially in the case of synthetic stimulant intoxication.

Serial cardiac enzymes may be warranted if a patient with synthetic-stimulant intoxicated has chest pain.

Education, addiction treatment. Much is unknown about the risk of SLIDs, but given the adverse events reported in the literature, it seems likely that those with underlying cardiac or psychiatric issues may be at higher risk for the most serious drug-related consequences. With regard to synthetic stimulants, Winstock et al²⁰ recommend a harm-reduction approach involving educating patients about avoiding the development of tolerance, not engaging in polydrug use, not injecting, and paying special attention to remaining cool and well hydrated.

Experience shows that once SLID patients get through their acute crisis and are no longer psychotic, they tend to be forthright in divulging what they used to get high. At that point, consideration should be given to consulting an addiction treatment specialist for further evaluation of the patient’s drug use history and for formulation of a treatment plan to help ensure that the patient doesn’t return to using these drugs.

 

SLIDs POSE A REAL CHALLENGE

SLIDs present a real challenge to law enforcement, governments, the public, and the addiction treatment community. There is currently no way to routinely test for these substances. Furthermore, any tests that are developed or laws that are enacted will be easily evaded, as there are many more synthetic substances waiting in the wings to be released.

Don’t be lulled into thinking that SLIDs are gone with the recent bans against some of the more common substances. More SLIDs are coming, and more morbidity should be expected in medical settings.

Doctors in emergency departments and other settings need to be prepared for the agitated and often psychotic presentation of SLID-intoxicated patients and should be ready with benzodiazepines, restraints, and a calm and reassuring manner. And for patients who present with psychotic symptoms, medical staff should also be ready to consider involuntary short-term commitment to an inpatient psychiatric unit.

Once they recover, patients need to be educated about the dangers of substances such as SLIDs that, because of their novelty, may be perceived as less dangerous alternatives to traditional illicit drugs.

Helping hospitalized geriatric patients maintain an appropriate sleep-wake cycle can be a challenge. Older patients’ circadian rhythm may be affected by several factors—eg, obstructive sleep apnea and restless leg syndrome—that contribute to disrupted sleep and daytime fatigue. Some patients may have dementing illnesses that could dysregulate sleep. Many older patients experience delirium during hospitalization, of which sleep-wake cycle disturbances are a hallmark. Finally, geriatric patients’ natural sleep pattern often does not mimic a hospital’s typical schedule.

Sleep medication side effects

Medications used to promote sleep can cause side effects in geriatric patients. Benzodiazepine use by older adults is discouraged because these medications could cause falls or contribute to delirium. Non-benzodiazepine hypnotics such as zolpidem, zaleplon, and eszopiclone pose a similar risk. Medications containing diphenhydramine predispose patients to deliriogenic effects via their anticholinergic properties. Tricyclic antidepressants carry risks, such as delirium secondary to anticholinergic effects, orthostatic hypotension, falls from α-1 blockade, and cardiac arrythmias.

Atypical antipsychotics sometimes are used off-label to help initiate sleep, but they carry a “black-box” warning regarding sudden death from cardiovascular events in geriatric patients with dementia. Hydroxyzine and trazodone also are associated with side effects such as orthostatic hypotension and daytime sedation, and are not always effective.

Melatonin is a hormone secreted by the pineal gland in response to darkness, under the control of the suprachiasmatic nucleus (SCN), and is thought to promote sleep via synchronizing effects on the SCN.¹ Melatonin is available as an over-the-counter dietary supplement and via prescription in dosages of 1 or 3 mg. The typical effective dose is 3 to 9 mg.¹ Patients should take melatonin in the mid-evening, ideally between 7 pm and 8 pm, and effects become evident after a few days. Side effects are rare; the most common are headache and nausea. Daytime sedation and vivid dreams also have been reported. Melatonin can be used safely in conjunction with other sleep aids and its major drug-drug interactions involve enhancing the effects of other sedatives.²

We have found melatonin to be effective for treating sleep disturbances in older hospitalized patients. Its effectiveness may stem from the high incidence of dysregulated or calcified pineal glands in geriatric patients, which leads to a marked reduction in melatonin secretion.³ Recent evidence also suggests melatonin may reduce the incidence of delirium in older adults, and it has been proposed as a delirium treatment in post-operative and intensive care unit settings.⁴

Disclosure

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

Helping hospitalized geriatric patients maintain an appropriate sleep-wake cycle can be a challenge. Older patients’ circadian rhythm may be affected by several factors—eg, obstructive sleep apnea and restless leg syndrome—that contribute to disrupted sleep and daytime fatigue. Some patients may have dementing illnesses that could dysregulate sleep. Many older patients experience delirium during hospitalization, of which sleep-wake cycle disturbances are a hallmark. Finally, geriatric patients’ natural sleep pattern often does not mimic a hospital’s typical schedule.

Sleep medication side effects

Medications used to promote sleep can cause side effects in geriatric patients. Benzodiazepine use by older adults is discouraged because these medications could cause falls or contribute to delirium. Non-benzodiazepine hypnotics such as zolpidem, zaleplon, and eszopiclone pose a similar risk. Medications containing diphenhydramine predispose patients to deliriogenic effects via their anticholinergic properties. Tricyclic antidepressants carry risks, such as delirium secondary to anticholinergic effects, orthostatic hypotension, falls from α-1 blockade, and cardiac arrythmias.

Atypical antipsychotics sometimes are used off-label to help initiate sleep, but they carry a “black-box” warning regarding sudden death from cardiovascular events in geriatric patients with dementia. Hydroxyzine and trazodone also are associated with side effects such as orthostatic hypotension and daytime sedation, and are not always effective.

Melatonin is a hormone secreted by the pineal gland in response to darkness, under the control of the suprachiasmatic nucleus (SCN), and is thought to promote sleep via synchronizing effects on the SCN.¹ Melatonin is available as an over-the-counter dietary supplement and via prescription in dosages of 1 or 3 mg. The typical effective dose is 3 to 9 mg.¹ Patients should take melatonin in the mid-evening, ideally between 7 pm and 8 pm, and effects become evident after a few days. Side effects are rare; the most common are headache and nausea. Daytime sedation and vivid dreams also have been reported. Melatonin can be used safely in conjunction with other sleep aids and its major drug-drug interactions involve enhancing the effects of other sedatives.²

We have found melatonin to be effective for treating sleep disturbances in older hospitalized patients. Its effectiveness may stem from the high incidence of dysregulated or calcified pineal glands in geriatric patients, which leads to a marked reduction in melatonin secretion.³ Recent evidence also suggests melatonin may reduce the incidence of delirium in older adults, and it has been proposed as a delirium treatment in post-operative and intensive care unit settings.⁴

Disclosure

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

Helping hospitalized geriatric patients maintain an appropriate sleep-wake cycle can be a challenge. Older patients’ circadian rhythm may be affected by several factors—eg, obstructive sleep apnea and restless leg syndrome—that contribute to disrupted sleep and daytime fatigue. Some patients may have dementing illnesses that could dysregulate sleep. Many older patients experience delirium during hospitalization, of which sleep-wake cycle disturbances are a hallmark. Finally, geriatric patients’ natural sleep pattern often does not mimic a hospital’s typical schedule.

Sleep medication side effects

Medications used to promote sleep can cause side effects in geriatric patients. Benzodiazepine use by older adults is discouraged because these medications could cause falls or contribute to delirium. Non-benzodiazepine hypnotics such as zolpidem, zaleplon, and eszopiclone pose a similar risk. Medications containing diphenhydramine predispose patients to deliriogenic effects via their anticholinergic properties. Tricyclic antidepressants carry risks, such as delirium secondary to anticholinergic effects, orthostatic hypotension, falls from α-1 blockade, and cardiac arrythmias.

Atypical antipsychotics sometimes are used off-label to help initiate sleep, but they carry a “black-box” warning regarding sudden death from cardiovascular events in geriatric patients with dementia. Hydroxyzine and trazodone also are associated with side effects such as orthostatic hypotension and daytime sedation, and are not always effective.

Melatonin is a hormone secreted by the pineal gland in response to darkness, under the control of the suprachiasmatic nucleus (SCN), and is thought to promote sleep via synchronizing effects on the SCN.¹ Melatonin is available as an over-the-counter dietary supplement and via prescription in dosages of 1 or 3 mg. The typical effective dose is 3 to 9 mg.¹ Patients should take melatonin in the mid-evening, ideally between 7 pm and 8 pm, and effects become evident after a few days. Side effects are rare; the most common are headache and nausea. Daytime sedation and vivid dreams also have been reported. Melatonin can be used safely in conjunction with other sleep aids and its major drug-drug interactions involve enhancing the effects of other sedatives.²

We have found melatonin to be effective for treating sleep disturbances in older hospitalized patients. Its effectiveness may stem from the high incidence of dysregulated or calcified pineal glands in geriatric patients, which leads to a marked reduction in melatonin secretion.³ Recent evidence also suggests melatonin may reduce the incidence of delirium in older adults, and it has been proposed as a delirium treatment in post-operative and intensive care unit settings.⁴

Disclosure

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