We rheumatologists may have inadvertently encouraged this practice. We teach about the prevalence of specific autoantibodies in patients with specific, accurately diagnosed autoimmune disorders as opposed to that in the general population (ie, the test’s sensitivity and specificity). But that is different than using a test to diagnose a specific disease in an ill patient with a heretofore undiagnosed condition (ie, the test’s predictive value). When I ask trainees or nonrheumatologists, “Why order all those tests?” the response I often get is that they thought the rheumatologist would want them when he or she was consulted. The fact that I also see our rheumatology fellows requesting the same tests before fully evaluating the patient clinically suggests that we have not done a great job at explaining the clinical utility and limitations of these tests. A serologic test should be used to strengthen or refute the clinician’s preliminary diagnosis, depending on the test’s specificity and sensitivity. It should not be used to generate a diagnosis.

So with these concerns, why would we invite a paper encouraging the use of the relatively new anti-cyclic citrullinated peptide (anti-CCP) test to evaluate patients with possible rheumatoid arthritis (Bose and Calabrese)?

As discussed in that paper, this test has characteristics that are useful when evaluating patients with polyarthritis compatible with the diagnosis of rheumatoid arthritis. Specifically, this test, unlike the traditional test for rheumatoid factor, can help discern whether the arthritis is a reaction to an infection like hepatitis C or endocarditis. Like rheumatoid factor, anti-CCP may precede the appearance of clinically meaningful arthritis and helps to predict prognosis in established rheumatoid arthritis. But, like other serologic tests, the anti-CCP test cannot supplant the listening ears and examining fingers of the clinician in establishing the pretest likelihood of the diagnosis. Clinical evaluation must precede laboratory testing.

We rheumatologists may have inadvertently encouraged this practice. We teach about the prevalence of specific autoantibodies in patients with specific, accurately diagnosed autoimmune disorders as opposed to that in the general population (ie, the test’s sensitivity and specificity). But that is different than using a test to diagnose a specific disease in an ill patient with a heretofore undiagnosed condition (ie, the test’s predictive value). When I ask trainees or nonrheumatologists, “Why order all those tests?” the response I often get is that they thought the rheumatologist would want them when he or she was consulted. The fact that I also see our rheumatology fellows requesting the same tests before fully evaluating the patient clinically suggests that we have not done a great job at explaining the clinical utility and limitations of these tests. A serologic test should be used to strengthen or refute the clinician’s preliminary diagnosis, depending on the test’s specificity and sensitivity. It should not be used to generate a diagnosis.

So with these concerns, why would we invite a paper encouraging the use of the relatively new anti-cyclic citrullinated peptide (anti-CCP) test to evaluate patients with possible rheumatoid arthritis (Bose and Calabrese)?

As discussed in that paper, this test has characteristics that are useful when evaluating patients with polyarthritis compatible with the diagnosis of rheumatoid arthritis. Specifically, this test, unlike the traditional test for rheumatoid factor, can help discern whether the arthritis is a reaction to an infection like hepatitis C or endocarditis. Like rheumatoid factor, anti-CCP may precede the appearance of clinically meaningful arthritis and helps to predict prognosis in established rheumatoid arthritis. But, like other serologic tests, the anti-CCP test cannot supplant the listening ears and examining fingers of the clinician in establishing the pretest likelihood of the diagnosis. Clinical evaluation must precede laboratory testing.

We rheumatologists may have inadvertently encouraged this practice. We teach about the prevalence of specific autoantibodies in patients with specific, accurately diagnosed autoimmune disorders as opposed to that in the general population (ie, the test’s sensitivity and specificity). But that is different than using a test to diagnose a specific disease in an ill patient with a heretofore undiagnosed condition (ie, the test’s predictive value). When I ask trainees or nonrheumatologists, “Why order all those tests?” the response I often get is that they thought the rheumatologist would want them when he or she was consulted. The fact that I also see our rheumatology fellows requesting the same tests before fully evaluating the patient clinically suggests that we have not done a great job at explaining the clinical utility and limitations of these tests. A serologic test should be used to strengthen or refute the clinician’s preliminary diagnosis, depending on the test’s specificity and sensitivity. It should not be used to generate a diagnosis.

So with these concerns, why would we invite a paper encouraging the use of the relatively new anti-cyclic citrullinated peptide (anti-CCP) test to evaluate patients with possible rheumatoid arthritis (Bose and Calabrese)?

As discussed in that paper, this test has characteristics that are useful when evaluating patients with polyarthritis compatible with the diagnosis of rheumatoid arthritis. Specifically, this test, unlike the traditional test for rheumatoid factor, can help discern whether the arthritis is a reaction to an infection like hepatitis C or endocarditis. Like rheumatoid factor, anti-CCP may precede the appearance of clinically meaningful arthritis and helps to predict prognosis in established rheumatoid arthritis. But, like other serologic tests, the anti-CCP test cannot supplant the listening ears and examining fingers of the clinician in establishing the pretest likelihood of the diagnosis. Clinical evaluation must precede laboratory testing.

Yes. Testing for anti-cyclic citrullinated peptide (anti-CCP) antibody can help diagnose rheumatoid arthritis (RA) because it is a highly specific test.

For many years, the diagnosis of RA has been based on the presentation of symmetrical small- and large-joint polyarthritis that spares the lower spine, further supported by the presence of characteristic joint damage on radiography and an elevated rheumatoid factor while also excluding clinical mimics. However, rheumatoid factor is often not detected early in RA, and detection of rheumatoid factor is not specific for RA. Testing for anti-CCP antibody can provide additional information and, in some cases, enable earlier and more specific diagnosis.

An important advance in our understanding of the pathogenesis of RA and in improving our ability to diagnose it early is the recognition that RA patients often produce autoantibodies directed against proteins and peptides containing the amino acid citrulline. Citrulline is generated in an inflammatory environment by the modification of the amino acid arginine by the enzyme peptidylarginine deiminase. Antibodies against cyclic citrulline are generated by patients with a certain genetic makeup, although citrulline can be detected in inflammatory tissues in conditions other than RA (without the antibody).

Anti-CCP antibody has been found in sera up to 10 years before the onset of joint symptoms in patients who later develop RA and may appear somewhat earlier than rheumatoid factor.¹ From 10% to 15% of RA patients remain seronegative for rheumatoid factor throughout the disease course.

INFORMAL GUIDELINES FOR ANTI-CCP ANTIBODY TESTING

The role of anti-CCP antibody testing in the management of RA is still being defined, but we suggest several informal guidelines.

Anti-CCP antibody testing can help interpret the significance of an inexplicably high rheumatoid factor titer in the absence of classic RA. In such situations, a negative anti-CCP antibody test suggests a nonrheumatic disorder such as hepatitis C virus infection or endocarditis, whereas a positive anti-CCP antibody test is more consistent with early or even preclinical RA since this test, unlike rheumatoid factor testing, is generally negative in the setting of infection.

However, in a patient who has documented RA and who is seropositive for rheumatoid factor, anti-CCP antibody testing has limited value, as the information it provides may be redundant. In a patient with a low to intermediate probability for RA and with a negative or low level of rheumatoid factor, a positive anti-CCP antibody test helps confirm the diagnosis. Rheumatoid factor positivity and anti-CCP antibody positivity are each associated with more severe RA. Neither test varies with the activity of RA.

Finally, in smokers with a particular genotype, the presence of anti-CCP antibody predicts a particularly worse course for RA.

THE ROLE OF RHEUMATOID FACTOR TESTING

Rheumatoid factor, first described in 1940,⁴ is an antibody against the Fc portion of immunoglobulin G. The cutoff value for positivity varies by laboratory but is usually greater than 45 IU/mL by enzyme-linked immunosorbent assay or laser nephelometry, or greater than 1:80 by latex fixation. However, serum titers or serum levels expressed as “IU/mL” cannot accurately be compared between laboratories; instead, when using tests for rheumatoid factor, physicians should refer to specificity and sensitivity measurements for each analyzing laboratory.

Around 50% of patients with RA become positive for rheumatoid factor in the first 6 months, and 85% become positive over the first 2 years. Also, rheumatoid factor testing suffers from low specificity, since it can be detected (although sometimes in low levels) in a variety of infectious and inflammatory conditions, such as bacterial endocarditis, malaria, tuberculosis, osteomyelitis, hepatitis C (with or without cryoglobulinemia), Sjögren syndrome, systemic lupus erythematosus, primary biliary cirrhosis, postvaccination arthropathy, and aging.

Current detection methods cannot differentiate between naturally occurring, transiently induced, and RA-associated rheumatoid factor. The levels are generally higher in RA than in many non-RA disorders, but significant overlap occurs. Rheumatoid factor positivity serves as a marker of poor prognosis, predicting generally more aggressive, erosive disease, and it is correlated with extra-articular manifestations such as rheumatoid nodules and lung involvement.

The classification criteria for RA published in 2010 by the American College of Rheumatology and the European League Against Rheumatism provide references for the measurement of rheumatoid factor: “low-level positive” refers to values less than or equal to three times the upper limit of normal for a particular laboratory; “high-level positive” refers to values more than three times the upper limit of normal.⁵ This is an attempt to provide a clinically useful benchmark for the measurement of rheumatoid factor, the values of which may vary between laboratories.

STUDIES COMPARING THE TWO TESTS

Several studies have evaluated the utility and validity of anti-CCP antibody testing vs rheumatoid factor testing.

In a study of 826 US veterans with RA,⁶ 75% tested positive for anti-CCP antibody and 80% were positive for rheumatoid factor. It was found that a higher anti-CCP antibody titer was associated with increased disease activity and inversely correlated with remission, especially in those also positive for rheumatoid factor.⁶

In another study,¹ in which blood samples from 79 patients with RA who had been blood donors were analyzed, 39 patients (49.4%) were positive for either rheumatoid factor or anti-CCP antibody, or both, a median of 4.5 years (range 0.1 to 13.8 years) before the onset of RA symptoms; 32 patients (40.5%) became positive for anti-CCP antibody before symptom onset.

Whiting et al,⁷ in a systematic review of 151 studies, showed that anti-CCP antibody testing had greater specificity than rheumatoid factor testing (96% vs 86%), with similar sensitivity (56% vs 58%)—most notably in eight cohort studies of patients with early RA.⁷ In the 15 cohort studies analyzed, the test was found to have a positive likelihood ratio of 12.7 and a negative likelihood ratio of 0.45, supporting this as a test of high positive predictive value for RA.

In view of the evidence from these studies, it is not surprising that the 2010 collaborative classification of RA of the American College of Rheumatology and the European League Against Rheumatism places equal weight on anti-CCP antibody testing and rheumatoid factor testing in the early diagnosis of RA.⁵

GENETICS AND THE PROGNOSIS OF RHEUMATOID ARTHRITIS

In recent years, there has been a growing recognition that the pathogenesis of RA in patients who are seropositive for rheumatoid factor or anti-CCP antibody is different from the pathogenesis of RA in patients who are seronegative for rheumatoid factor and anti-CCP antibody. This may help us guide therapy.

Patients positive for rheumatoid factor or anti-CCP antibody who have a specific allelic subset of a region of the immune-response gene DRB1*04 appear to be highly vulnerable to smoking as an environmental trigger or to worsening RA.⁸

Patients positive for anti-CCP antibody tend also to have severe joint destruction and, hence, have a worse prognosis. Kaltenhäuser et al⁹ found that determining the presence of the shared epitope (an RA-specific genetic marker) and positivity for anti-CCP antibody facilitates prediction of the disease course and prognosis.⁹

Studies have shown that patients with confirmed RA who test positive for anti-CCP antibody may also have more-severe extraarticular manifestations. Recent studies have found anti-CCP antibody positivity in 15.7% to 17.5% of patients with psoriatic arthritis and in 85% of patients with RA. Patients with psoriatic arthritis who were positive for anti-CCP antibody had more joints that were tender and swollen, erosive arthritis, deformities, and functional impairment of peripheral joints.^10,11

THE COST DIFFERENCE IS TRIVIAL IN THE LONG RUN

Cost is the major differentiating factor between rheumatoid factor testing and anti-CCP antibody testing. Rheumatoid factor testing costs around $43, and anti-CCP antibody testing costs $102 in the reference laboratory at Cleveland Clinic. However, the difference in cost is trivial, since this is only a one-time cost, whereas the information anti-CCP antibody testing provides can have a major impact on predicting the prognosis and determining the choice of therapy for a disease associated with high direct and indirect costs over a lifetime. Also, Medicare and other insurers would likely reimburse for anti-CCP antibody testing as long as it was associated with a related diagnosis such as arthralgia or arthritis.

Given that there will be a small number of patients with confirmed RA who will be negative for rheumatoid factor yet positive for anti-CCP antibody, one can support ordering both tests in tandem in a patient whom you strongly suspect of having RA. Or, at $100, one could make the argument that it would be cost-effective to order anti-CCP antibody testing only if rheumatoid factor testing is negative.

Testing for rheumatoid factor and anti-CCP antibody should not be done serially to assess treatment response or disease activity in these patients: these markers do not vary with inflammatory activity or disappear with clinical “remission.”

Yes. Testing for anti-cyclic citrullinated peptide (anti-CCP) antibody can help diagnose rheumatoid arthritis (RA) because it is a highly specific test.

For many years, the diagnosis of RA has been based on the presentation of symmetrical small- and large-joint polyarthritis that spares the lower spine, further supported by the presence of characteristic joint damage on radiography and an elevated rheumatoid factor while also excluding clinical mimics. However, rheumatoid factor is often not detected early in RA, and detection of rheumatoid factor is not specific for RA. Testing for anti-CCP antibody can provide additional information and, in some cases, enable earlier and more specific diagnosis.

An important advance in our understanding of the pathogenesis of RA and in improving our ability to diagnose it early is the recognition that RA patients often produce autoantibodies directed against proteins and peptides containing the amino acid citrulline. Citrulline is generated in an inflammatory environment by the modification of the amino acid arginine by the enzyme peptidylarginine deiminase. Antibodies against cyclic citrulline are generated by patients with a certain genetic makeup, although citrulline can be detected in inflammatory tissues in conditions other than RA (without the antibody).

Anti-CCP antibody has been found in sera up to 10 years before the onset of joint symptoms in patients who later develop RA and may appear somewhat earlier than rheumatoid factor.¹ From 10% to 15% of RA patients remain seronegative for rheumatoid factor throughout the disease course.

INFORMAL GUIDELINES FOR ANTI-CCP ANTIBODY TESTING

The role of anti-CCP antibody testing in the management of RA is still being defined, but we suggest several informal guidelines.

Anti-CCP antibody testing can help interpret the significance of an inexplicably high rheumatoid factor titer in the absence of classic RA. In such situations, a negative anti-CCP antibody test suggests a nonrheumatic disorder such as hepatitis C virus infection or endocarditis, whereas a positive anti-CCP antibody test is more consistent with early or even preclinical RA since this test, unlike rheumatoid factor testing, is generally negative in the setting of infection.

However, in a patient who has documented RA and who is seropositive for rheumatoid factor, anti-CCP antibody testing has limited value, as the information it provides may be redundant. In a patient with a low to intermediate probability for RA and with a negative or low level of rheumatoid factor, a positive anti-CCP antibody test helps confirm the diagnosis. Rheumatoid factor positivity and anti-CCP antibody positivity are each associated with more severe RA. Neither test varies with the activity of RA.

Finally, in smokers with a particular genotype, the presence of anti-CCP antibody predicts a particularly worse course for RA.

THE ROLE OF RHEUMATOID FACTOR TESTING

Rheumatoid factor, first described in 1940,⁴ is an antibody against the Fc portion of immunoglobulin G. The cutoff value for positivity varies by laboratory but is usually greater than 45 IU/mL by enzyme-linked immunosorbent assay or laser nephelometry, or greater than 1:80 by latex fixation. However, serum titers or serum levels expressed as “IU/mL” cannot accurately be compared between laboratories; instead, when using tests for rheumatoid factor, physicians should refer to specificity and sensitivity measurements for each analyzing laboratory.

Around 50% of patients with RA become positive for rheumatoid factor in the first 6 months, and 85% become positive over the first 2 years. Also, rheumatoid factor testing suffers from low specificity, since it can be detected (although sometimes in low levels) in a variety of infectious and inflammatory conditions, such as bacterial endocarditis, malaria, tuberculosis, osteomyelitis, hepatitis C (with or without cryoglobulinemia), Sjögren syndrome, systemic lupus erythematosus, primary biliary cirrhosis, postvaccination arthropathy, and aging.

Current detection methods cannot differentiate between naturally occurring, transiently induced, and RA-associated rheumatoid factor. The levels are generally higher in RA than in many non-RA disorders, but significant overlap occurs. Rheumatoid factor positivity serves as a marker of poor prognosis, predicting generally more aggressive, erosive disease, and it is correlated with extra-articular manifestations such as rheumatoid nodules and lung involvement.

The classification criteria for RA published in 2010 by the American College of Rheumatology and the European League Against Rheumatism provide references for the measurement of rheumatoid factor: “low-level positive” refers to values less than or equal to three times the upper limit of normal for a particular laboratory; “high-level positive” refers to values more than three times the upper limit of normal.⁵ This is an attempt to provide a clinically useful benchmark for the measurement of rheumatoid factor, the values of which may vary between laboratories.

STUDIES COMPARING THE TWO TESTS

Several studies have evaluated the utility and validity of anti-CCP antibody testing vs rheumatoid factor testing.

In a study of 826 US veterans with RA,⁶ 75% tested positive for anti-CCP antibody and 80% were positive for rheumatoid factor. It was found that a higher anti-CCP antibody titer was associated with increased disease activity and inversely correlated with remission, especially in those also positive for rheumatoid factor.⁶

In another study,¹ in which blood samples from 79 patients with RA who had been blood donors were analyzed, 39 patients (49.4%) were positive for either rheumatoid factor or anti-CCP antibody, or both, a median of 4.5 years (range 0.1 to 13.8 years) before the onset of RA symptoms; 32 patients (40.5%) became positive for anti-CCP antibody before symptom onset.

Whiting et al,⁷ in a systematic review of 151 studies, showed that anti-CCP antibody testing had greater specificity than rheumatoid factor testing (96% vs 86%), with similar sensitivity (56% vs 58%)—most notably in eight cohort studies of patients with early RA.⁷ In the 15 cohort studies analyzed, the test was found to have a positive likelihood ratio of 12.7 and a negative likelihood ratio of 0.45, supporting this as a test of high positive predictive value for RA.

In view of the evidence from these studies, it is not surprising that the 2010 collaborative classification of RA of the American College of Rheumatology and the European League Against Rheumatism places equal weight on anti-CCP antibody testing and rheumatoid factor testing in the early diagnosis of RA.⁵

GENETICS AND THE PROGNOSIS OF RHEUMATOID ARTHRITIS

In recent years, there has been a growing recognition that the pathogenesis of RA in patients who are seropositive for rheumatoid factor or anti-CCP antibody is different from the pathogenesis of RA in patients who are seronegative for rheumatoid factor and anti-CCP antibody. This may help us guide therapy.

Patients positive for rheumatoid factor or anti-CCP antibody who have a specific allelic subset of a region of the immune-response gene DRB1*04 appear to be highly vulnerable to smoking as an environmental trigger or to worsening RA.⁸

Patients positive for anti-CCP antibody tend also to have severe joint destruction and, hence, have a worse prognosis. Kaltenhäuser et al⁹ found that determining the presence of the shared epitope (an RA-specific genetic marker) and positivity for anti-CCP antibody facilitates prediction of the disease course and prognosis.⁹

Studies have shown that patients with confirmed RA who test positive for anti-CCP antibody may also have more-severe extraarticular manifestations. Recent studies have found anti-CCP antibody positivity in 15.7% to 17.5% of patients with psoriatic arthritis and in 85% of patients with RA. Patients with psoriatic arthritis who were positive for anti-CCP antibody had more joints that were tender and swollen, erosive arthritis, deformities, and functional impairment of peripheral joints.^10,11

THE COST DIFFERENCE IS TRIVIAL IN THE LONG RUN

Cost is the major differentiating factor between rheumatoid factor testing and anti-CCP antibody testing. Rheumatoid factor testing costs around $43, and anti-CCP antibody testing costs $102 in the reference laboratory at Cleveland Clinic. However, the difference in cost is trivial, since this is only a one-time cost, whereas the information anti-CCP antibody testing provides can have a major impact on predicting the prognosis and determining the choice of therapy for a disease associated with high direct and indirect costs over a lifetime. Also, Medicare and other insurers would likely reimburse for anti-CCP antibody testing as long as it was associated with a related diagnosis such as arthralgia or arthritis.

Given that there will be a small number of patients with confirmed RA who will be negative for rheumatoid factor yet positive for anti-CCP antibody, one can support ordering both tests in tandem in a patient whom you strongly suspect of having RA. Or, at $100, one could make the argument that it would be cost-effective to order anti-CCP antibody testing only if rheumatoid factor testing is negative.

Testing for rheumatoid factor and anti-CCP antibody should not be done serially to assess treatment response or disease activity in these patients: these markers do not vary with inflammatory activity or disappear with clinical “remission.”

Yes. Testing for anti-cyclic citrullinated peptide (anti-CCP) antibody can help diagnose rheumatoid arthritis (RA) because it is a highly specific test.

For many years, the diagnosis of RA has been based on the presentation of symmetrical small- and large-joint polyarthritis that spares the lower spine, further supported by the presence of characteristic joint damage on radiography and an elevated rheumatoid factor while also excluding clinical mimics. However, rheumatoid factor is often not detected early in RA, and detection of rheumatoid factor is not specific for RA. Testing for anti-CCP antibody can provide additional information and, in some cases, enable earlier and more specific diagnosis.

An important advance in our understanding of the pathogenesis of RA and in improving our ability to diagnose it early is the recognition that RA patients often produce autoantibodies directed against proteins and peptides containing the amino acid citrulline. Citrulline is generated in an inflammatory environment by the modification of the amino acid arginine by the enzyme peptidylarginine deiminase. Antibodies against cyclic citrulline are generated by patients with a certain genetic makeup, although citrulline can be detected in inflammatory tissues in conditions other than RA (without the antibody).

Anti-CCP antibody has been found in sera up to 10 years before the onset of joint symptoms in patients who later develop RA and may appear somewhat earlier than rheumatoid factor.¹ From 10% to 15% of RA patients remain seronegative for rheumatoid factor throughout the disease course.

INFORMAL GUIDELINES FOR ANTI-CCP ANTIBODY TESTING

The role of anti-CCP antibody testing in the management of RA is still being defined, but we suggest several informal guidelines.

Anti-CCP antibody testing can help interpret the significance of an inexplicably high rheumatoid factor titer in the absence of classic RA. In such situations, a negative anti-CCP antibody test suggests a nonrheumatic disorder such as hepatitis C virus infection or endocarditis, whereas a positive anti-CCP antibody test is more consistent with early or even preclinical RA since this test, unlike rheumatoid factor testing, is generally negative in the setting of infection.

However, in a patient who has documented RA and who is seropositive for rheumatoid factor, anti-CCP antibody testing has limited value, as the information it provides may be redundant. In a patient with a low to intermediate probability for RA and with a negative or low level of rheumatoid factor, a positive anti-CCP antibody test helps confirm the diagnosis. Rheumatoid factor positivity and anti-CCP antibody positivity are each associated with more severe RA. Neither test varies with the activity of RA.

Finally, in smokers with a particular genotype, the presence of anti-CCP antibody predicts a particularly worse course for RA.

THE ROLE OF RHEUMATOID FACTOR TESTING

Rheumatoid factor, first described in 1940,⁴ is an antibody against the Fc portion of immunoglobulin G. The cutoff value for positivity varies by laboratory but is usually greater than 45 IU/mL by enzyme-linked immunosorbent assay or laser nephelometry, or greater than 1:80 by latex fixation. However, serum titers or serum levels expressed as “IU/mL” cannot accurately be compared between laboratories; instead, when using tests for rheumatoid factor, physicians should refer to specificity and sensitivity measurements for each analyzing laboratory.

Around 50% of patients with RA become positive for rheumatoid factor in the first 6 months, and 85% become positive over the first 2 years. Also, rheumatoid factor testing suffers from low specificity, since it can be detected (although sometimes in low levels) in a variety of infectious and inflammatory conditions, such as bacterial endocarditis, malaria, tuberculosis, osteomyelitis, hepatitis C (with or without cryoglobulinemia), Sjögren syndrome, systemic lupus erythematosus, primary biliary cirrhosis, postvaccination arthropathy, and aging.

Current detection methods cannot differentiate between naturally occurring, transiently induced, and RA-associated rheumatoid factor. The levels are generally higher in RA than in many non-RA disorders, but significant overlap occurs. Rheumatoid factor positivity serves as a marker of poor prognosis, predicting generally more aggressive, erosive disease, and it is correlated with extra-articular manifestations such as rheumatoid nodules and lung involvement.

The classification criteria for RA published in 2010 by the American College of Rheumatology and the European League Against Rheumatism provide references for the measurement of rheumatoid factor: “low-level positive” refers to values less than or equal to three times the upper limit of normal for a particular laboratory; “high-level positive” refers to values more than three times the upper limit of normal.⁵ This is an attempt to provide a clinically useful benchmark for the measurement of rheumatoid factor, the values of which may vary between laboratories.

STUDIES COMPARING THE TWO TESTS

Several studies have evaluated the utility and validity of anti-CCP antibody testing vs rheumatoid factor testing.

In a study of 826 US veterans with RA,⁶ 75% tested positive for anti-CCP antibody and 80% were positive for rheumatoid factor. It was found that a higher anti-CCP antibody titer was associated with increased disease activity and inversely correlated with remission, especially in those also positive for rheumatoid factor.⁶

In another study,¹ in which blood samples from 79 patients with RA who had been blood donors were analyzed, 39 patients (49.4%) were positive for either rheumatoid factor or anti-CCP antibody, or both, a median of 4.5 years (range 0.1 to 13.8 years) before the onset of RA symptoms; 32 patients (40.5%) became positive for anti-CCP antibody before symptom onset.

Whiting et al,⁷ in a systematic review of 151 studies, showed that anti-CCP antibody testing had greater specificity than rheumatoid factor testing (96% vs 86%), with similar sensitivity (56% vs 58%)—most notably in eight cohort studies of patients with early RA.⁷ In the 15 cohort studies analyzed, the test was found to have a positive likelihood ratio of 12.7 and a negative likelihood ratio of 0.45, supporting this as a test of high positive predictive value for RA.

In view of the evidence from these studies, it is not surprising that the 2010 collaborative classification of RA of the American College of Rheumatology and the European League Against Rheumatism places equal weight on anti-CCP antibody testing and rheumatoid factor testing in the early diagnosis of RA.⁵

GENETICS AND THE PROGNOSIS OF RHEUMATOID ARTHRITIS

In recent years, there has been a growing recognition that the pathogenesis of RA in patients who are seropositive for rheumatoid factor or anti-CCP antibody is different from the pathogenesis of RA in patients who are seronegative for rheumatoid factor and anti-CCP antibody. This may help us guide therapy.

Patients positive for rheumatoid factor or anti-CCP antibody who have a specific allelic subset of a region of the immune-response gene DRB1*04 appear to be highly vulnerable to smoking as an environmental trigger or to worsening RA.⁸

Patients positive for anti-CCP antibody tend also to have severe joint destruction and, hence, have a worse prognosis. Kaltenhäuser et al⁹ found that determining the presence of the shared epitope (an RA-specific genetic marker) and positivity for anti-CCP antibody facilitates prediction of the disease course and prognosis.⁹

Studies have shown that patients with confirmed RA who test positive for anti-CCP antibody may also have more-severe extraarticular manifestations. Recent studies have found anti-CCP antibody positivity in 15.7% to 17.5% of patients with psoriatic arthritis and in 85% of patients with RA. Patients with psoriatic arthritis who were positive for anti-CCP antibody had more joints that were tender and swollen, erosive arthritis, deformities, and functional impairment of peripheral joints.^10,11

THE COST DIFFERENCE IS TRIVIAL IN THE LONG RUN

Cost is the major differentiating factor between rheumatoid factor testing and anti-CCP antibody testing. Rheumatoid factor testing costs around $43, and anti-CCP antibody testing costs $102 in the reference laboratory at Cleveland Clinic. However, the difference in cost is trivial, since this is only a one-time cost, whereas the information anti-CCP antibody testing provides can have a major impact on predicting the prognosis and determining the choice of therapy for a disease associated with high direct and indirect costs over a lifetime. Also, Medicare and other insurers would likely reimburse for anti-CCP antibody testing as long as it was associated with a related diagnosis such as arthralgia or arthritis.

Given that there will be a small number of patients with confirmed RA who will be negative for rheumatoid factor yet positive for anti-CCP antibody, one can support ordering both tests in tandem in a patient whom you strongly suspect of having RA. Or, at $100, one could make the argument that it would be cost-effective to order anti-CCP antibody testing only if rheumatoid factor testing is negative.

Testing for rheumatoid factor and anti-CCP antibody should not be done serially to assess treatment response or disease activity in these patients: these markers do not vary with inflammatory activity or disappear with clinical “remission.”

In Reply: I thank Dr. Keller for his thoughtful comments. They are most appreciated.

It is true that with availability of generic ropinirole and pramipexole, there are now cheaper alternatives to levodopa. Nonetheless, levodopa remains the cheapest and most efficacious medication for Parkinson disease to date. Whenever levodopa is compared head-to-head with any dopamine agonist, the general results remain consistent: levodopa affords better motor improvement with lesser side effects, but is more likely to lead to motor fluctuations, specifically dyskinesias. Therefore, in general, levodopa is the first choice in elderly patients where tolerability may be an issue, whereas a dopamine agonist may be the initial treatment of choice in younger Parkinson patients, who are able to tolerate the drug better and have a higher likelihood of developing dyskinesias.

It is a tougher task to determine which among the dopamine agonists is superior. The newer dopamine agonists have not been compared head-to-head. Therefore, it is practically a “coin toss” when selecting which dopamine agonist to try. Their mechanism of action (D2 and D3 receptor agonist activity) and frequency of intake (three times per day for generics; once daily for long-acting formulations), cost, and side effect profile are nearly identical, despite minor differences in their half-lives.

Regarding putative neuroprotective agents in Parkinson disease, indeed, isradipine is one of the medications currently undergoing investigation for its potential neuroprotective effect. While I personally have no objection to using it for a Parkinson disease patient who also happens to need an antihypertensive agent, I am more cautious about endorsing it as a neuroprotective agent until results of clinical trials have been released. Similarly, while a large epidemiologic study has shown that people who take ibuprofen are less likely to develop Parkinson disease, there has been no robust human trial that has shown the drug to slow the progression of Parkinson disease among patients who are already suffering from the disorder. Therefore, the current use of ibuprofen in Parkinson disease should be based more on its anti-inflammatory indications rather than its possible neuroprotective effect. Finally, we have shown, in a large, multicenter, global randomized controlled trial with a delayed-start design, that pramipexole is unlikely to possess any meaningful neuroprotective effect. Therefore, I am personally not that optimistic that dexpramipexole would demonstrate such an effect.

While in theory combining the use of catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase (MAO) type B inhibitors can synergistically work to inhibit the breakdown of other catecholamines and lead to adrenergic crisis when taken concomitantly, this has not been our experience. Perhaps it is because at recommended doses, the MAO inhibition is selective to type B (where receptors are more confined to the brain) and not type A (where receptors are more distributed throughout blood vessels, thereby having a higher likelihood of causing a hypertensive crisis as is seen in the use of nonselective MAO inhibitors). Therefore, at our center, we routinely use the two classes of agents concomitantly with minimal safety concerns.

In Reply: I thank Dr. Keller for his thoughtful comments. They are most appreciated.

It is true that with availability of generic ropinirole and pramipexole, there are now cheaper alternatives to levodopa. Nonetheless, levodopa remains the cheapest and most efficacious medication for Parkinson disease to date. Whenever levodopa is compared head-to-head with any dopamine agonist, the general results remain consistent: levodopa affords better motor improvement with lesser side effects, but is more likely to lead to motor fluctuations, specifically dyskinesias. Therefore, in general, levodopa is the first choice in elderly patients where tolerability may be an issue, whereas a dopamine agonist may be the initial treatment of choice in younger Parkinson patients, who are able to tolerate the drug better and have a higher likelihood of developing dyskinesias.

It is a tougher task to determine which among the dopamine agonists is superior. The newer dopamine agonists have not been compared head-to-head. Therefore, it is practically a “coin toss” when selecting which dopamine agonist to try. Their mechanism of action (D2 and D3 receptor agonist activity) and frequency of intake (three times per day for generics; once daily for long-acting formulations), cost, and side effect profile are nearly identical, despite minor differences in their half-lives.

Regarding putative neuroprotective agents in Parkinson disease, indeed, isradipine is one of the medications currently undergoing investigation for its potential neuroprotective effect. While I personally have no objection to using it for a Parkinson disease patient who also happens to need an antihypertensive agent, I am more cautious about endorsing it as a neuroprotective agent until results of clinical trials have been released. Similarly, while a large epidemiologic study has shown that people who take ibuprofen are less likely to develop Parkinson disease, there has been no robust human trial that has shown the drug to slow the progression of Parkinson disease among patients who are already suffering from the disorder. Therefore, the current use of ibuprofen in Parkinson disease should be based more on its anti-inflammatory indications rather than its possible neuroprotective effect. Finally, we have shown, in a large, multicenter, global randomized controlled trial with a delayed-start design, that pramipexole is unlikely to possess any meaningful neuroprotective effect. Therefore, I am personally not that optimistic that dexpramipexole would demonstrate such an effect.

While in theory combining the use of catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase (MAO) type B inhibitors can synergistically work to inhibit the breakdown of other catecholamines and lead to adrenergic crisis when taken concomitantly, this has not been our experience. Perhaps it is because at recommended doses, the MAO inhibition is selective to type B (where receptors are more confined to the brain) and not type A (where receptors are more distributed throughout blood vessels, thereby having a higher likelihood of causing a hypertensive crisis as is seen in the use of nonselective MAO inhibitors). Therefore, at our center, we routinely use the two classes of agents concomitantly with minimal safety concerns.

In Reply: I thank Dr. Keller for his thoughtful comments. They are most appreciated.

It is true that with availability of generic ropinirole and pramipexole, there are now cheaper alternatives to levodopa. Nonetheless, levodopa remains the cheapest and most efficacious medication for Parkinson disease to date. Whenever levodopa is compared head-to-head with any dopamine agonist, the general results remain consistent: levodopa affords better motor improvement with lesser side effects, but is more likely to lead to motor fluctuations, specifically dyskinesias. Therefore, in general, levodopa is the first choice in elderly patients where tolerability may be an issue, whereas a dopamine agonist may be the initial treatment of choice in younger Parkinson patients, who are able to tolerate the drug better and have a higher likelihood of developing dyskinesias.

It is a tougher task to determine which among the dopamine agonists is superior. The newer dopamine agonists have not been compared head-to-head. Therefore, it is practically a “coin toss” when selecting which dopamine agonist to try. Their mechanism of action (D2 and D3 receptor agonist activity) and frequency of intake (three times per day for generics; once daily for long-acting formulations), cost, and side effect profile are nearly identical, despite minor differences in their half-lives.

Regarding putative neuroprotective agents in Parkinson disease, indeed, isradipine is one of the medications currently undergoing investigation for its potential neuroprotective effect. While I personally have no objection to using it for a Parkinson disease patient who also happens to need an antihypertensive agent, I am more cautious about endorsing it as a neuroprotective agent until results of clinical trials have been released. Similarly, while a large epidemiologic study has shown that people who take ibuprofen are less likely to develop Parkinson disease, there has been no robust human trial that has shown the drug to slow the progression of Parkinson disease among patients who are already suffering from the disorder. Therefore, the current use of ibuprofen in Parkinson disease should be based more on its anti-inflammatory indications rather than its possible neuroprotective effect. Finally, we have shown, in a large, multicenter, global randomized controlled trial with a delayed-start design, that pramipexole is unlikely to possess any meaningful neuroprotective effect. Therefore, I am personally not that optimistic that dexpramipexole would demonstrate such an effect.

While in theory combining the use of catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase (MAO) type B inhibitors can synergistically work to inhibit the breakdown of other catecholamines and lead to adrenergic crisis when taken concomitantly, this has not been our experience. Perhaps it is because at recommended doses, the MAO inhibition is selective to type B (where receptors are more confined to the brain) and not type A (where receptors are more distributed throughout blood vessels, thereby having a higher likelihood of causing a hypertensive crisis as is seen in the use of nonselective MAO inhibitors). Therefore, at our center, we routinely use the two classes of agents concomitantly with minimal safety concerns.

To the Editor: I have the following comments and questions regarding the excellent Medical Grand Rounds article on Parkinson disease by Dr. Fernandez in your January 2012 issue.¹

The author mentions that when “cost may be of concern, levodopa is the preferred starting drug.”¹ Generic versions of pramipexole and ropinirole are now available and have made these medications more affordable. For example, the cash price of generic ropinirole 5 mg was recently $66 for 100 tablets, comparable with generic carbidopa/levodopa (25/100 mg priced at $46 for 100 tablets.² And even though the price of generic pramipexole was $240 for 90 tablets, seniors with Medicare Part D drug coverage can usually get any generic medication for a low copay.

When choosing a dopamine agonist, how does Dr. Fernandez decide between ropinirole and pramipexole (aside from the price difference noted above)? Pramipexole has a longer elimination half-life (8 to 12 hours) compared with ropinirole (6 hours).³ Does this imply a significantly longer effective dosing interval for pramipexole? Are there other significant clinical differences between these agents?

Isradipine (DynaCirc CR), a dihydropyridine calcium channel blocker, has shown promise as a neuroprotective agent for slowing the progression of Parkinson disease in epidemiologic and laboratory studies, as noted by the author. In addition, immediate-release isradipine, with its relatively short elimination half-life of 8 hours,³ may be well suited for treating Parkinson patients whose essential hypertension is complicated by episodes of orthostatic hypotension. It should be noted that dihydropyridines that do not cross the blood-brain barrier (such as amlodipine [Norvasc]) have shown no evidence of neuroprotection.

Ibuprofen is another drug that has fairly strong epidemiologic and laboratory evidence that it might be neuroprotective,⁴ although the other nonsteroidal anti-inflammatory drugs (NSAIDs) have proven disappointing as a class.⁵ Lacking any prospective randomized trials, the evidence is not strong enough to recommend ibuprofen solely for neuroprotection. Does Dr. Fernandez, however, consider it reasonable to suggest ibuprofen to Parkinson patients who need to take an NSAID for an approved indication (such as pain)?

Dexpramipexole has recently demonstrated great promise in a phase 3 clinical trial as a neuroprotective agent in amyotrophic lateral sclerosis.⁶ How does this compound relate to pramipexole, and does the author believe it may offer neuroprotection in other neurodegenerative diseases like Parkinson disease?

The author discusses the use of catechol-O-methyltransferase (COMT) inhibitors (such as Comtan and Tasmar) and the monoamine oxidase (MAO) type-B inhibitors rasagiline (Azilect) and selegiline (Eldepryl, Zelapar) for prolonging the effects of levodopa by slowing the breakdown of dopamine. However, it is important to note that it is contraindicated to prescribe both a COMT inhibitor and an MAO-B inhibitor, because these agents also inhibit the breakdown of other catecholamines and can lead to adrenergic crisis when taken concomitantly.

To the Editor: I have the following comments and questions regarding the excellent Medical Grand Rounds article on Parkinson disease by Dr. Fernandez in your January 2012 issue.¹

The author mentions that when “cost may be of concern, levodopa is the preferred starting drug.”¹ Generic versions of pramipexole and ropinirole are now available and have made these medications more affordable. For example, the cash price of generic ropinirole 5 mg was recently $66 for 100 tablets, comparable with generic carbidopa/levodopa (25/100 mg priced at $46 for 100 tablets.² And even though the price of generic pramipexole was $240 for 90 tablets, seniors with Medicare Part D drug coverage can usually get any generic medication for a low copay.

When choosing a dopamine agonist, how does Dr. Fernandez decide between ropinirole and pramipexole (aside from the price difference noted above)? Pramipexole has a longer elimination half-life (8 to 12 hours) compared with ropinirole (6 hours).³ Does this imply a significantly longer effective dosing interval for pramipexole? Are there other significant clinical differences between these agents?

Isradipine (DynaCirc CR), a dihydropyridine calcium channel blocker, has shown promise as a neuroprotective agent for slowing the progression of Parkinson disease in epidemiologic and laboratory studies, as noted by the author. In addition, immediate-release isradipine, with its relatively short elimination half-life of 8 hours,³ may be well suited for treating Parkinson patients whose essential hypertension is complicated by episodes of orthostatic hypotension. It should be noted that dihydropyridines that do not cross the blood-brain barrier (such as amlodipine [Norvasc]) have shown no evidence of neuroprotection.

Ibuprofen is another drug that has fairly strong epidemiologic and laboratory evidence that it might be neuroprotective,⁴ although the other nonsteroidal anti-inflammatory drugs (NSAIDs) have proven disappointing as a class.⁵ Lacking any prospective randomized trials, the evidence is not strong enough to recommend ibuprofen solely for neuroprotection. Does Dr. Fernandez, however, consider it reasonable to suggest ibuprofen to Parkinson patients who need to take an NSAID for an approved indication (such as pain)?

Dexpramipexole has recently demonstrated great promise in a phase 3 clinical trial as a neuroprotective agent in amyotrophic lateral sclerosis.⁶ How does this compound relate to pramipexole, and does the author believe it may offer neuroprotection in other neurodegenerative diseases like Parkinson disease?

The author discusses the use of catechol-O-methyltransferase (COMT) inhibitors (such as Comtan and Tasmar) and the monoamine oxidase (MAO) type-B inhibitors rasagiline (Azilect) and selegiline (Eldepryl, Zelapar) for prolonging the effects of levodopa by slowing the breakdown of dopamine. However, it is important to note that it is contraindicated to prescribe both a COMT inhibitor and an MAO-B inhibitor, because these agents also inhibit the breakdown of other catecholamines and can lead to adrenergic crisis when taken concomitantly.

To the Editor: I have the following comments and questions regarding the excellent Medical Grand Rounds article on Parkinson disease by Dr. Fernandez in your January 2012 issue.¹

The author mentions that when “cost may be of concern, levodopa is the preferred starting drug.”¹ Generic versions of pramipexole and ropinirole are now available and have made these medications more affordable. For example, the cash price of generic ropinirole 5 mg was recently $66 for 100 tablets, comparable with generic carbidopa/levodopa (25/100 mg priced at $46 for 100 tablets.² And even though the price of generic pramipexole was $240 for 90 tablets, seniors with Medicare Part D drug coverage can usually get any generic medication for a low copay.

When choosing a dopamine agonist, how does Dr. Fernandez decide between ropinirole and pramipexole (aside from the price difference noted above)? Pramipexole has a longer elimination half-life (8 to 12 hours) compared with ropinirole (6 hours).³ Does this imply a significantly longer effective dosing interval for pramipexole? Are there other significant clinical differences between these agents?

Isradipine (DynaCirc CR), a dihydropyridine calcium channel blocker, has shown promise as a neuroprotective agent for slowing the progression of Parkinson disease in epidemiologic and laboratory studies, as noted by the author. In addition, immediate-release isradipine, with its relatively short elimination half-life of 8 hours,³ may be well suited for treating Parkinson patients whose essential hypertension is complicated by episodes of orthostatic hypotension. It should be noted that dihydropyridines that do not cross the blood-brain barrier (such as amlodipine [Norvasc]) have shown no evidence of neuroprotection.

Ibuprofen is another drug that has fairly strong epidemiologic and laboratory evidence that it might be neuroprotective,⁴ although the other nonsteroidal anti-inflammatory drugs (NSAIDs) have proven disappointing as a class.⁵ Lacking any prospective randomized trials, the evidence is not strong enough to recommend ibuprofen solely for neuroprotection. Does Dr. Fernandez, however, consider it reasonable to suggest ibuprofen to Parkinson patients who need to take an NSAID for an approved indication (such as pain)?

Dexpramipexole has recently demonstrated great promise in a phase 3 clinical trial as a neuroprotective agent in amyotrophic lateral sclerosis.⁶ How does this compound relate to pramipexole, and does the author believe it may offer neuroprotection in other neurodegenerative diseases like Parkinson disease?

The author discusses the use of catechol-O-methyltransferase (COMT) inhibitors (such as Comtan and Tasmar) and the monoamine oxidase (MAO) type-B inhibitors rasagiline (Azilect) and selegiline (Eldepryl, Zelapar) for prolonging the effects of levodopa by slowing the breakdown of dopamine. However, it is important to note that it is contraindicated to prescribe both a COMT inhibitor and an MAO-B inhibitor, because these agents also inhibit the breakdown of other catecholamines and can lead to adrenergic crisis when taken concomitantly.

In Reply: We agree and thank Dr. Keller for raising this valid point. The two classes of calcium channel blockers are distinct in their actions, and the warning about not combining a calcium channel blocker with a beta-blocker because of the increased risk of developing significant bradycardia applies only to the nondihydropyridine class.

In Reply: We agree and thank Dr. Keller for raising this valid point. The two classes of calcium channel blockers are distinct in their actions, and the warning about not combining a calcium channel blocker with a beta-blocker because of the increased risk of developing significant bradycardia applies only to the nondihydropyridine class.

In Reply: We agree and thank Dr. Keller for raising this valid point. The two classes of calcium channel blockers are distinct in their actions, and the warning about not combining a calcium channel blocker with a beta-blocker because of the increased risk of developing significant bradycardia applies only to the nondihydropyridine class.

To the Editor: In their thorough review of essential tremor,¹Drs. Abboud, Ahmed, and Fernandez make a statement that needs clarification. In their list of absolute contraindications to propranolol (Inderal), the authors include “concurrent use of a calcium channel blocker.” This warning applies only to the nondihydropyridine calcium channel blockers, which are diltiazem (Cardizem) and verapamil (Calan). These two medications slow the heart rate and generally should not be combined with beta-blockers such as propranolol unless the patient requires this combination to control tachycardia. Most calcium channel blockers are dihydropyridines, which include amlodipine (Norvasc), nifedipine (Procardia), felodipine (Plendil), nisoldipine (Sular), isradipine (DynaCirc CR), and nicardipine (Cardene). These agents do not slow the heart rate significantly and therefore can be used freely in combination with propranolol. Of course, the dose of the calcium channel blocker may need to be decreased because of the antihypertensive effect of propranolol.

To the Editor: In their thorough review of essential tremor,¹Drs. Abboud, Ahmed, and Fernandez make a statement that needs clarification. In their list of absolute contraindications to propranolol (Inderal), the authors include “concurrent use of a calcium channel blocker.” This warning applies only to the nondihydropyridine calcium channel blockers, which are diltiazem (Cardizem) and verapamil (Calan). These two medications slow the heart rate and generally should not be combined with beta-blockers such as propranolol unless the patient requires this combination to control tachycardia. Most calcium channel blockers are dihydropyridines, which include amlodipine (Norvasc), nifedipine (Procardia), felodipine (Plendil), nisoldipine (Sular), isradipine (DynaCirc CR), and nicardipine (Cardene). These agents do not slow the heart rate significantly and therefore can be used freely in combination with propranolol. Of course, the dose of the calcium channel blocker may need to be decreased because of the antihypertensive effect of propranolol.

To the Editor: In their thorough review of essential tremor,¹Drs. Abboud, Ahmed, and Fernandez make a statement that needs clarification. In their list of absolute contraindications to propranolol (Inderal), the authors include “concurrent use of a calcium channel blocker.” This warning applies only to the nondihydropyridine calcium channel blockers, which are diltiazem (Cardizem) and verapamil (Calan). These two medications slow the heart rate and generally should not be combined with beta-blockers such as propranolol unless the patient requires this combination to control tachycardia. Most calcium channel blockers are dihydropyridines, which include amlodipine (Norvasc), nifedipine (Procardia), felodipine (Plendil), nisoldipine (Sular), isradipine (DynaCirc CR), and nicardipine (Cardene). These agents do not slow the heart rate significantly and therefore can be used freely in combination with propranolol. Of course, the dose of the calcium channel blocker may need to be decreased because of the antihypertensive effect of propranolol.

In Reply: We thank Drs. Rodríguez-Gutiérrez and Gonzálvez-Gonzálvez and Dr. Keller for their thoughtful comments.

In our paper, we did not elaborate on the low-dose cosyntropin stimulation test. The 1-μg test, in particular, has been shown to have similar or better sensitivity, with similar or lower specificity, compared with the 250-μg dose, depending on the study design. Unfortunately, the administration of the 1-μg dose presents more technical difficulty than the 250-μg dose, thus limiting its use. Cosyntropin (used in the United States) comes in a vial with 250 μg of powder. This must be reconstituted with 250 mL of normal saline, and only 1 mL is to be given. Adherence to the plastic tubing may occur, and more precise timing is needed as the cortisol levels may decrease.^1–3

Responding to Dr. Keller, we were unable to find any systematic reviews comparing inhaled corticosteroids that have a “higher therapeutic index” as a class vs older inhaled corticosteroids. There are several studies, however, comparing individual inhaled corticosteroid preparations with each other in terms of adrenal effects, and we feel that it is beyond the scope of this response to perform a systematic analysis. In addition, the determination of adrenal function used in studies comparing one inhaled corticosteroid with another were varied, including cosyntropin stimulation tests and surrogates such as the urinary cortisolcreatinine ratio, a morning plasma cortisol level less than 5 μg/L, and serum cortisol concentration curves, preventing more definitive conclusions even if the data were to be pooled.^4–6 A double-blind, randomized study comparing the adrenal effects of ciclesonide and fluticasone showed a smaller reduction in the peak serum cortisol level achieved with ciclesonide compared with fluticasone, in both low-dose and high-dose cosyntropin stimulation tests, with the results in the ciclesonide group being similar to placebo.⁷ However, the mean peak serum cortisol levels after exposure to these inhaled corticosteroids were not presented in table format, and the results have to be inferred from the figures and the narrative description of the baseline mean peak cortisol levels⁸ (ie, before exposure to these inhaled corticosteroids). Case reports have suggested that changing the inhaled corticostseroid formulation from fluticasone to ciclesonide allowed for improvement of adrenal function.⁸ The purported mechanism of decreased adrenal effects of ciclesonide is its greater deposition in the lungs and, hence, less entry into the systemic circulation and fewer systemic adverse effects.⁹

In Reply: We thank Drs. Rodríguez-Gutiérrez and Gonzálvez-Gonzálvez and Dr. Keller for their thoughtful comments.

In our paper, we did not elaborate on the low-dose cosyntropin stimulation test. The 1-μg test, in particular, has been shown to have similar or better sensitivity, with similar or lower specificity, compared with the 250-μg dose, depending on the study design. Unfortunately, the administration of the 1-μg dose presents more technical difficulty than the 250-μg dose, thus limiting its use. Cosyntropin (used in the United States) comes in a vial with 250 μg of powder. This must be reconstituted with 250 mL of normal saline, and only 1 mL is to be given. Adherence to the plastic tubing may occur, and more precise timing is needed as the cortisol levels may decrease.^1–3

Responding to Dr. Keller, we were unable to find any systematic reviews comparing inhaled corticosteroids that have a “higher therapeutic index” as a class vs older inhaled corticosteroids. There are several studies, however, comparing individual inhaled corticosteroid preparations with each other in terms of adrenal effects, and we feel that it is beyond the scope of this response to perform a systematic analysis. In addition, the determination of adrenal function used in studies comparing one inhaled corticosteroid with another were varied, including cosyntropin stimulation tests and surrogates such as the urinary cortisolcreatinine ratio, a morning plasma cortisol level less than 5 μg/L, and serum cortisol concentration curves, preventing more definitive conclusions even if the data were to be pooled.^4–6 A double-blind, randomized study comparing the adrenal effects of ciclesonide and fluticasone showed a smaller reduction in the peak serum cortisol level achieved with ciclesonide compared with fluticasone, in both low-dose and high-dose cosyntropin stimulation tests, with the results in the ciclesonide group being similar to placebo.⁷ However, the mean peak serum cortisol levels after exposure to these inhaled corticosteroids were not presented in table format, and the results have to be inferred from the figures and the narrative description of the baseline mean peak cortisol levels⁸ (ie, before exposure to these inhaled corticosteroids). Case reports have suggested that changing the inhaled corticostseroid formulation from fluticasone to ciclesonide allowed for improvement of adrenal function.⁸ The purported mechanism of decreased adrenal effects of ciclesonide is its greater deposition in the lungs and, hence, less entry into the systemic circulation and fewer systemic adverse effects.⁹

In Reply: We thank Drs. Rodríguez-Gutiérrez and Gonzálvez-Gonzálvez and Dr. Keller for their thoughtful comments.

In our paper, we did not elaborate on the low-dose cosyntropin stimulation test. The 1-μg test, in particular, has been shown to have similar or better sensitivity, with similar or lower specificity, compared with the 250-μg dose, depending on the study design. Unfortunately, the administration of the 1-μg dose presents more technical difficulty than the 250-μg dose, thus limiting its use. Cosyntropin (used in the United States) comes in a vial with 250 μg of powder. This must be reconstituted with 250 mL of normal saline, and only 1 mL is to be given. Adherence to the plastic tubing may occur, and more precise timing is needed as the cortisol levels may decrease.^1–3

Responding to Dr. Keller, we were unable to find any systematic reviews comparing inhaled corticosteroids that have a “higher therapeutic index” as a class vs older inhaled corticosteroids. There are several studies, however, comparing individual inhaled corticosteroid preparations with each other in terms of adrenal effects, and we feel that it is beyond the scope of this response to perform a systematic analysis. In addition, the determination of adrenal function used in studies comparing one inhaled corticosteroid with another were varied, including cosyntropin stimulation tests and surrogates such as the urinary cortisolcreatinine ratio, a morning plasma cortisol level less than 5 μg/L, and serum cortisol concentration curves, preventing more definitive conclusions even if the data were to be pooled.^4–6 A double-blind, randomized study comparing the adrenal effects of ciclesonide and fluticasone showed a smaller reduction in the peak serum cortisol level achieved with ciclesonide compared with fluticasone, in both low-dose and high-dose cosyntropin stimulation tests, with the results in the ciclesonide group being similar to placebo.⁷ However, the mean peak serum cortisol levels after exposure to these inhaled corticosteroids were not presented in table format, and the results have to be inferred from the figures and the narrative description of the baseline mean peak cortisol levels⁸ (ie, before exposure to these inhaled corticosteroids). Case reports have suggested that changing the inhaled corticostseroid formulation from fluticasone to ciclesonide allowed for improvement of adrenal function.⁸ The purported mechanism of decreased adrenal effects of ciclesonide is its greater deposition in the lungs and, hence, less entry into the systemic circulation and fewer systemic adverse effects.⁹

To the Editor: Drs. Lansang and Hustak¹ provide a comprehensive and useful review of steroid-induced diabetes and adrenal suppression.

In their section on local steroids, they discuss the side effects of topical and inhaled glucocorticosteroids. Much has been made of the fact that certain steroids, such as mometasone (Elocon, Nasonex) and fluticasone (Flonase), have a higher “therapeutic index” or ratio of local anti-inflammatory effect to systemic side effects, due to extensive hepatic first-pass metabolism, than older agents such as beclomethasone (Qvar) and betamethasone (Diprosone).² Ciclesonide (Alvesco, Omnaris), a newer inhaled steroid, is said to have an enhanced therapeutic index because it is a prodrug that is activated by metabolism in the lungs; it reportedly has an even less suppressive effect on hypothalamic-pituitaryadrenal axis function.³

Are the authors aware of any other evidence that clinical outcome, such as adrenal suppression or hyperglycemia, is improved by the use of steroids with a higher therapeutic index?

To the Editor: Drs. Lansang and Hustak¹ provide a comprehensive and useful review of steroid-induced diabetes and adrenal suppression.

In their section on local steroids, they discuss the side effects of topical and inhaled glucocorticosteroids. Much has been made of the fact that certain steroids, such as mometasone (Elocon, Nasonex) and fluticasone (Flonase), have a higher “therapeutic index” or ratio of local anti-inflammatory effect to systemic side effects, due to extensive hepatic first-pass metabolism, than older agents such as beclomethasone (Qvar) and betamethasone (Diprosone).² Ciclesonide (Alvesco, Omnaris), a newer inhaled steroid, is said to have an enhanced therapeutic index because it is a prodrug that is activated by metabolism in the lungs; it reportedly has an even less suppressive effect on hypothalamic-pituitaryadrenal axis function.³

Are the authors aware of any other evidence that clinical outcome, such as adrenal suppression or hyperglycemia, is improved by the use of steroids with a higher therapeutic index?

To the Editor: Drs. Lansang and Hustak¹ provide a comprehensive and useful review of steroid-induced diabetes and adrenal suppression.

In their section on local steroids, they discuss the side effects of topical and inhaled glucocorticosteroids. Much has been made of the fact that certain steroids, such as mometasone (Elocon, Nasonex) and fluticasone (Flonase), have a higher “therapeutic index” or ratio of local anti-inflammatory effect to systemic side effects, due to extensive hepatic first-pass metabolism, than older agents such as beclomethasone (Qvar) and betamethasone (Diprosone).² Ciclesonide (Alvesco, Omnaris), a newer inhaled steroid, is said to have an enhanced therapeutic index because it is a prodrug that is activated by metabolism in the lungs; it reportedly has an even less suppressive effect on hypothalamic-pituitaryadrenal axis function.³

Are the authors aware of any other evidence that clinical outcome, such as adrenal suppression or hyperglycemia, is improved by the use of steroids with a higher therapeutic index?

To the Editor: We found the article by Drs. Lansang and Kramer¹ on glucocorticoid-induced diabetes and adrenal suppression in the November 2011 issue to be a useful and clinically oriented review. However, we strongly believe there is an issue that should be addressed.

It is well accepted that the short cosyntropin (Cortrosyn) stimulation test is the best screening maneuver for assessing adrenocortical insufficiency. The authors state, however, that 250 μg is preferable to lower doses (10 μg or 1 μg), since these are not yet widely accepted, and refer to an article by Axelrod from 1976.²

Based on studies showing that 250 μg of cosyntropin is a pharmacologic rather than a physiologic stimulus that may overstimulate partially atrophied or mildly dysfunctional adrenal glands, multiple studies in the last 20 years have shown that the low-dose test has an equal or better result than the classic 250-μg dose test.³ Dorin et al,⁴ in a meta-analysis of the diagnosis of adrenocortical insufficiency that included more than 30 studies, found similar sensitivity and specificity in primary and secondary adrenal insufficiency comparing the 250-μg dose vs the low dose. In cases of mild primary adrenal failure, the low-dose test has better performance. A previous investigation in our research center contrasting 250 μg vs 10 μg proved that 10 μg had a better sensitivity than the standard dose, with excellent reproducibility and interchangeability.⁵ Similar findings have been shown by other authors contrasting 1 μg vs 250 μg of cosyntropin.⁶

We believe that the limited use of the low-dose cosyntropin test is not a matter of acceptance or performance but a consequence of the lack of vials containing lower doses of cosyntropin (1 to 10 μg), which makes this test technically challenging.^2,4 The steps needed for one-dose testing and the preservation time of the preparation are strong limitations to its wide use in clinical practice and endocrine laboratories.

To the Editor: We found the article by Drs. Lansang and Kramer¹ on glucocorticoid-induced diabetes and adrenal suppression in the November 2011 issue to be a useful and clinically oriented review. However, we strongly believe there is an issue that should be addressed.

It is well accepted that the short cosyntropin (Cortrosyn) stimulation test is the best screening maneuver for assessing adrenocortical insufficiency. The authors state, however, that 250 μg is preferable to lower doses (10 μg or 1 μg), since these are not yet widely accepted, and refer to an article by Axelrod from 1976.²

Based on studies showing that 250 μg of cosyntropin is a pharmacologic rather than a physiologic stimulus that may overstimulate partially atrophied or mildly dysfunctional adrenal glands, multiple studies in the last 20 years have shown that the low-dose test has an equal or better result than the classic 250-μg dose test.³ Dorin et al,⁴ in a meta-analysis of the diagnosis of adrenocortical insufficiency that included more than 30 studies, found similar sensitivity and specificity in primary and secondary adrenal insufficiency comparing the 250-μg dose vs the low dose. In cases of mild primary adrenal failure, the low-dose test has better performance. A previous investigation in our research center contrasting 250 μg vs 10 μg proved that 10 μg had a better sensitivity than the standard dose, with excellent reproducibility and interchangeability.⁵ Similar findings have been shown by other authors contrasting 1 μg vs 250 μg of cosyntropin.⁶

We believe that the limited use of the low-dose cosyntropin test is not a matter of acceptance or performance but a consequence of the lack of vials containing lower doses of cosyntropin (1 to 10 μg), which makes this test technically challenging.^2,4 The steps needed for one-dose testing and the preservation time of the preparation are strong limitations to its wide use in clinical practice and endocrine laboratories.

To the Editor: We found the article by Drs. Lansang and Kramer¹ on glucocorticoid-induced diabetes and adrenal suppression in the November 2011 issue to be a useful and clinically oriented review. However, we strongly believe there is an issue that should be addressed.

It is well accepted that the short cosyntropin (Cortrosyn) stimulation test is the best screening maneuver for assessing adrenocortical insufficiency. The authors state, however, that 250 μg is preferable to lower doses (10 μg or 1 μg), since these are not yet widely accepted, and refer to an article by Axelrod from 1976.²

Based on studies showing that 250 μg of cosyntropin is a pharmacologic rather than a physiologic stimulus that may overstimulate partially atrophied or mildly dysfunctional adrenal glands, multiple studies in the last 20 years have shown that the low-dose test has an equal or better result than the classic 250-μg dose test.³ Dorin et al,⁴ in a meta-analysis of the diagnosis of adrenocortical insufficiency that included more than 30 studies, found similar sensitivity and specificity in primary and secondary adrenal insufficiency comparing the 250-μg dose vs the low dose. In cases of mild primary adrenal failure, the low-dose test has better performance. A previous investigation in our research center contrasting 250 μg vs 10 μg proved that 10 μg had a better sensitivity than the standard dose, with excellent reproducibility and interchangeability.⁵ Similar findings have been shown by other authors contrasting 1 μg vs 250 μg of cosyntropin.⁶

We believe that the limited use of the low-dose cosyntropin test is not a matter of acceptance or performance but a consequence of the lack of vials containing lower doses of cosyntropin (1 to 10 μg), which makes this test technically challenging.^2,4 The steps needed for one-dose testing and the preservation time of the preparation are strong limitations to its wide use in clinical practice and endocrine laboratories.

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

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

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

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

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

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

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.