Pain

The numbers are stunning: 1,643% increase in rates of deaths involving synthetic opioids. A 915% increase for heroin, 830% for benzodiazepines. Even more stunning: Those are the increases only in overdose death rates for women aged 30 to 64 years.

According to CDC data, between 1999 and 2010, the largest percentage change in the rates of overall drug overdose deaths was among women aged between 45 and 64 years. But that research did not account for trends in specific drugs or consider changes in age group distributions, say researchers from the CDC’s National Center for Injury Prevention and Control.

They examined overdose death rates among women aged 30 to 64 years between 1999 and 2017. The unadjusted death rate jumped 260%, from 4,314 deaths to 18,110 deaths. Among women aged 55 to 59 years, the number of deaths involving antidepressants increased approximately 300%; among women aged 60 to 64 years, nearly 400%. The crude rate of deaths involving prescription opioids skyrocketed > 1,000%.

The drug epidemic is “evolving,” the researchers note. In 1999, overdose death rates were highest among women aged 40 to 44 years. In 2017, they were highest among women aged 50 to 54 years. And as demographics shift, prevention programs need to shift as well. As women age, the researchers say, individual experiences can change the type of substance used or misused and in the experiences of pain that might result in an opioid prescription.

The researchers note that “substantial work” has focused on informing women of childbearing age about the risks and benefits of certain drugs. The current analysis demonstrates “the remaining need” to consider middle-aged women who are at risk.

Targeted efforts are needed, and the researchers suggest interventions: Medicaid and other health insurance programs can review records of controlled substance prescribing. States and local communities can expand capacity of drug use disorder treatments and links to care, particularly adding “gender-responsive” substance use disorder treatment centers.

A “multifaceted approach involving the full spectrum of care services is likely necessary,” the researchers say. Health care practitioners who treat women for pain, depression, or anxiety can discuss treatment options that consider the unique biopsychosocial needs of women.

Health care practitioners also can consider implementing the CDC Guideline for Prescribing Opioids for Chronic Pain, which says “Opioids are not first-line or routine therapy for chronic pain.” The guideline also says before starting and periodically during opioid therapy, clinicians should discuss with patients the “known risks and realistic benefits of opioid therapy.”  In other words, listen to the women and prescribe carefully.

The numbers are stunning: 1,643% increase in rates of deaths involving synthetic opioids. A 915% increase for heroin, 830% for benzodiazepines. Even more stunning: Those are the increases only in overdose death rates for women aged 30 to 64 years.

According to CDC data, between 1999 and 2010, the largest percentage change in the rates of overall drug overdose deaths was among women aged between 45 and 64 years. But that research did not account for trends in specific drugs or consider changes in age group distributions, say researchers from the CDC’s National Center for Injury Prevention and Control.

They examined overdose death rates among women aged 30 to 64 years between 1999 and 2017. The unadjusted death rate jumped 260%, from 4,314 deaths to 18,110 deaths. Among women aged 55 to 59 years, the number of deaths involving antidepressants increased approximately 300%; among women aged 60 to 64 years, nearly 400%. The crude rate of deaths involving prescription opioids skyrocketed > 1,000%.

The drug epidemic is “evolving,” the researchers note. In 1999, overdose death rates were highest among women aged 40 to 44 years. In 2017, they were highest among women aged 50 to 54 years. And as demographics shift, prevention programs need to shift as well. As women age, the researchers say, individual experiences can change the type of substance used or misused and in the experiences of pain that might result in an opioid prescription.

The researchers note that “substantial work” has focused on informing women of childbearing age about the risks and benefits of certain drugs. The current analysis demonstrates “the remaining need” to consider middle-aged women who are at risk.

Targeted efforts are needed, and the researchers suggest interventions: Medicaid and other health insurance programs can review records of controlled substance prescribing. States and local communities can expand capacity of drug use disorder treatments and links to care, particularly adding “gender-responsive” substance use disorder treatment centers.

A “multifaceted approach involving the full spectrum of care services is likely necessary,” the researchers say. Health care practitioners who treat women for pain, depression, or anxiety can discuss treatment options that consider the unique biopsychosocial needs of women.

Health care practitioners also can consider implementing the CDC Guideline for Prescribing Opioids for Chronic Pain, which says “Opioids are not first-line or routine therapy for chronic pain.” The guideline also says before starting and periodically during opioid therapy, clinicians should discuss with patients the “known risks and realistic benefits of opioid therapy.”  In other words, listen to the women and prescribe carefully.

The numbers are stunning: 1,643% increase in rates of deaths involving synthetic opioids. A 915% increase for heroin, 830% for benzodiazepines. Even more stunning: Those are the increases only in overdose death rates for women aged 30 to 64 years.

According to CDC data, between 1999 and 2010, the largest percentage change in the rates of overall drug overdose deaths was among women aged between 45 and 64 years. But that research did not account for trends in specific drugs or consider changes in age group distributions, say researchers from the CDC’s National Center for Injury Prevention and Control.

They examined overdose death rates among women aged 30 to 64 years between 1999 and 2017. The unadjusted death rate jumped 260%, from 4,314 deaths to 18,110 deaths. Among women aged 55 to 59 years, the number of deaths involving antidepressants increased approximately 300%; among women aged 60 to 64 years, nearly 400%. The crude rate of deaths involving prescription opioids skyrocketed > 1,000%.

The drug epidemic is “evolving,” the researchers note. In 1999, overdose death rates were highest among women aged 40 to 44 years. In 2017, they were highest among women aged 50 to 54 years. And as demographics shift, prevention programs need to shift as well. As women age, the researchers say, individual experiences can change the type of substance used or misused and in the experiences of pain that might result in an opioid prescription.

The researchers note that “substantial work” has focused on informing women of childbearing age about the risks and benefits of certain drugs. The current analysis demonstrates “the remaining need” to consider middle-aged women who are at risk.

Targeted efforts are needed, and the researchers suggest interventions: Medicaid and other health insurance programs can review records of controlled substance prescribing. States and local communities can expand capacity of drug use disorder treatments and links to care, particularly adding “gender-responsive” substance use disorder treatment centers.

A “multifaceted approach involving the full spectrum of care services is likely necessary,” the researchers say. Health care practitioners who treat women for pain, depression, or anxiety can discuss treatment options that consider the unique biopsychosocial needs of women.

Health care practitioners also can consider implementing the CDC Guideline for Prescribing Opioids for Chronic Pain, which says “Opioids are not first-line or routine therapy for chronic pain.” The guideline also says before starting and periodically during opioid therapy, clinicians should discuss with patients the “known risks and realistic benefits of opioid therapy.”  In other words, listen to the women and prescribe carefully.

More people are using medical cannabis as it becomes legal in more states, but the lack of standardization in states’ data collection hindered investigators’ efforts to track that use.

Legalized medical cannabis is now available in 33 states and the District of Columbia, and the number of users has risen from just over 72,000 in 2009 to almost 814,000 in 2017. That 814,000, however, covers only 16 states and D.C., since 1 state (Connecticut) does not publish reports on medical cannabis use, 12 did not have statistics available, 2 (New York and Vermont) didn’t report data for 2017, and 2 (California and Maine) have voluntary registries that are unlikely to be accurate, according to Kevin F. Boehnke, PhD, of the University of Michigan, Ann Arbor, and his associates.

Michigan had the largest reported number of patients enrolled in its medical cannabis program in 2017, almost 270,000. California – the state with the oldest medical cannabis legislation (passed in 1996) and the largest overall population but a voluntary cannabis registry – reported its highest number of enrollees, 12,659, in 2009-2010, the investigators said. Colorado had more than 116,000 patients in its medical cannabis program in 2010 (Health Aff. 2019;38[2]:295-302).

The “many inconsistencies in data quality across states [suggest] the need for further standardization of data collection. Such standardization would add transparency to understanding how medical cannabis programs are used, which would help guide both research and policy needs,” Dr. Boehnke and his associates wrote.

More consistency was seen in the reasons for using medical cannabis. Chronic pain made up 62.2% of all qualifying conditions reported by patients during 1999-2016, with the annual average varying between 33.3% and 73%. Multiple sclerosis spasticity symptoms had the second-highest number of reports over the study period, followed by chemotherapy-induced nausea and vomiting, posttraumatic stress disorder, and cancer, they reported.

The investigators also looked at the appropriateness of cannabis and determined that its use in 85.5% of patient-reported conditions was “supported by conclusive or substantial evidence of therapeutic effectiveness, according to the 2017 National Academies report” on the health effects of cannabis.

“We believe not only that it is inappropriate for cannabis to remain a Schedule I substance, but also that state and federal policy makers should begin evaluating evidence-based ways for safely integrating cannabis research and products into the health care system,” they concluded.

[email protected]

SOURCE: Boehnke KF et al. Health Aff. 2019;38(2):295-302.
 

More people are using medical cannabis as it becomes legal in more states, but the lack of standardization in states’ data collection hindered investigators’ efforts to track that use.

Legalized medical cannabis is now available in 33 states and the District of Columbia, and the number of users has risen from just over 72,000 in 2009 to almost 814,000 in 2017. That 814,000, however, covers only 16 states and D.C., since 1 state (Connecticut) does not publish reports on medical cannabis use, 12 did not have statistics available, 2 (New York and Vermont) didn’t report data for 2017, and 2 (California and Maine) have voluntary registries that are unlikely to be accurate, according to Kevin F. Boehnke, PhD, of the University of Michigan, Ann Arbor, and his associates.

Michigan had the largest reported number of patients enrolled in its medical cannabis program in 2017, almost 270,000. California – the state with the oldest medical cannabis legislation (passed in 1996) and the largest overall population but a voluntary cannabis registry – reported its highest number of enrollees, 12,659, in 2009-2010, the investigators said. Colorado had more than 116,000 patients in its medical cannabis program in 2010 (Health Aff. 2019;38[2]:295-302).

The “many inconsistencies in data quality across states [suggest] the need for further standardization of data collection. Such standardization would add transparency to understanding how medical cannabis programs are used, which would help guide both research and policy needs,” Dr. Boehnke and his associates wrote.

More consistency was seen in the reasons for using medical cannabis. Chronic pain made up 62.2% of all qualifying conditions reported by patients during 1999-2016, with the annual average varying between 33.3% and 73%. Multiple sclerosis spasticity symptoms had the second-highest number of reports over the study period, followed by chemotherapy-induced nausea and vomiting, posttraumatic stress disorder, and cancer, they reported.

The investigators also looked at the appropriateness of cannabis and determined that its use in 85.5% of patient-reported conditions was “supported by conclusive or substantial evidence of therapeutic effectiveness, according to the 2017 National Academies report” on the health effects of cannabis.

“We believe not only that it is inappropriate for cannabis to remain a Schedule I substance, but also that state and federal policy makers should begin evaluating evidence-based ways for safely integrating cannabis research and products into the health care system,” they concluded.

[email protected]

SOURCE: Boehnke KF et al. Health Aff. 2019;38(2):295-302.
 

More people are using medical cannabis as it becomes legal in more states, but the lack of standardization in states’ data collection hindered investigators’ efforts to track that use.

Legalized medical cannabis is now available in 33 states and the District of Columbia, and the number of users has risen from just over 72,000 in 2009 to almost 814,000 in 2017. That 814,000, however, covers only 16 states and D.C., since 1 state (Connecticut) does not publish reports on medical cannabis use, 12 did not have statistics available, 2 (New York and Vermont) didn’t report data for 2017, and 2 (California and Maine) have voluntary registries that are unlikely to be accurate, according to Kevin F. Boehnke, PhD, of the University of Michigan, Ann Arbor, and his associates.

Michigan had the largest reported number of patients enrolled in its medical cannabis program in 2017, almost 270,000. California – the state with the oldest medical cannabis legislation (passed in 1996) and the largest overall population but a voluntary cannabis registry – reported its highest number of enrollees, 12,659, in 2009-2010, the investigators said. Colorado had more than 116,000 patients in its medical cannabis program in 2010 (Health Aff. 2019;38[2]:295-302).

The “many inconsistencies in data quality across states [suggest] the need for further standardization of data collection. Such standardization would add transparency to understanding how medical cannabis programs are used, which would help guide both research and policy needs,” Dr. Boehnke and his associates wrote.

More consistency was seen in the reasons for using medical cannabis. Chronic pain made up 62.2% of all qualifying conditions reported by patients during 1999-2016, with the annual average varying between 33.3% and 73%. Multiple sclerosis spasticity symptoms had the second-highest number of reports over the study period, followed by chemotherapy-induced nausea and vomiting, posttraumatic stress disorder, and cancer, they reported.

The investigators also looked at the appropriateness of cannabis and determined that its use in 85.5% of patient-reported conditions was “supported by conclusive or substantial evidence of therapeutic effectiveness, according to the 2017 National Academies report” on the health effects of cannabis.

“We believe not only that it is inappropriate for cannabis to remain a Schedule I substance, but also that state and federal policy makers should begin evaluating evidence-based ways for safely integrating cannabis research and products into the health care system,” they concluded.

[email protected]

SOURCE: Boehnke KF et al. Health Aff. 2019;38(2):295-302.
 

Most patients with psoriatic arthritis first present with psoriasis only. Their skin disorder precedes any joint involvement, often by several years. That suggests targeting interventions to patients with psoriasis to prevent or slow their progression to psoriatic arthritis, as well as following psoriatic patients closely to diagnose psoriatic arthritis quickly when it first appears. It’s a simple and attractive management premise that’s been challenging to apply in practice.

It’s not that clinicians aren’t motivated to diagnose psoriatic arthritis (PsA) in patients early, hopefully as soon as it appears. The susceptibility of patients with psoriasis to develop PsA is well described, with an annual progression rate of about 3%, and adverse consequences result from even a 6-month delay in diagnosis.

“Some physicians still don’t ask psoriasis patients about joint pain, or their symptoms are misinterpreted as something else,” said Lihi Eder, MD, a rheumatologist at Women’s College Research Institute, Toronto, and the University of Toronto. “Although there is increased awareness about PsA, there are still delays in diagnosis,” she said in an interview.

“Often there is a massive delay in diagnosis, and we know from a number of studies that longer duration of symptoms before diagnosis is associated with poorer outcomes,” said Laura C. Coates, MBChB, PhD, a rheumatologist at the University of Oxford (England). The delay to PsA diagnosis is generally “longer than for equivalent rheumatoid arthritis patients. PsA patients take longer to ask a primary care physician for help, longer to get a referral to a rheumatologist, and longer to get a diagnosis” from a rheumatologist. “We need to educate patients with psoriasis about their risk so that they seek help, educate GPs about whom to refer, and educate rheumatologists about diagnosis,” Dr. Coates said.

“It is very important to diagnose PsA as early as possible. We know that a delay in diagnosis and treatment can lead to worse outcomes and joint damage,” said Soumya M. Reddy, MD, codirector of the Psoriasis and Psoriatic Arthritis Center at New York University Langone Health in New York. “The heterogeneity of clinical manifestations of PsA can make it difficult to diagnose, and in some cases this leads to delayed diagnosis.”

“We are increasingly interested in the concept of preventing PsA. Psoriasis is a unique disease state in which we have an at-risk population where 30% will develop an inflammatory and potentially damaging arthritis. This may become important as our skin treatments may also treat musculoskeletal components of the disease,” said Joseph F. Merola, MD, director of the Center for Skin and Related Musculoskeletal Diseases at Brigham and Women’s Hospital in Boston and double board certified in dermatology and rheumatology.

Focusing on patients with psoriasis

Treatment of psoriasis makes sense to address several quality-of-life issues, but controlling the severity of psoriatic skin manifestations gives patients no guarantees about their possible progression to PsA.

“So many people have mild psoriasis that, although they are less likely, proportionately, to get PsA, we still see many in the clinic,” said Dr. Coates. “Patients with severe skin involvement have a good reason to get treatment, which could help test whether a drug slows progression to arthritis. But it’s unethical to not treat severe psoriasis just to have a comparison group.” Aside from skin psoriasis, “we don’t have any other good markers,” Dr. Coates noted.

PsA can develop in patients who had psoriasis in the past but without currently active disease. “At the level of individual patients you can’t say someone is protected from developing PsA because their psoriasis is inactive,” Dr. Eder said. “No study has looked at whether treatment of psoriasis reduces the risk for progression to PsA. We don’t know whether any treatments that reduce inflammation in psoriasis also reduce progression to PsA.” Regardless, treating psoriasis is important because it improves quality of life and may have a beneficial, long-term effects on possible cardiovascular disease effects from psoriasis, Dr. Eder said.

“The risk of developing PsA increases as the severity of skin psoriasis increases, measured by percentage of body surface area affected. However, there is only a weak correlation between the severity of skin disease and the severity of PsA,” said Joel M. Gelfand, MD, professor of dermatology at the University of Pennsylvania in Philadelphia.
 

Widening the PsA diagnostic net

What’s elusive is some other parameter to identify the 3% of psoriasis patients who will develop PsA during the next year – or at least a better way to find patients as soon as they have what is identifiably PsA.

The diagnostic definition for PsA that many experts now accept is actually a set of classification criteria, CASPAR (Classification Criteria for Psoriatic Arthritis) (Arthritis Rheum. 2006 Aug;54[8]:2665-73). But in actual practice, diagnosing PsA relies heavily on clinical skill, case recognition, and ruling out mimickers.

“The CASPAR criteria were developed as classification criteria to use in studies, but they are also quite helpful in diagnosing PsA. It is the agreed on definition of PsA at the moment,” said Alexis Ogdie, MD, director of the psoriatic arthritis clinic at the University of Pennsylvania.

“CASPAR fills the role at present for clinical trials, but the diagnosis remains clinical, based on history, physical findings, and supported by lab and radiology findings,” Dr. Merola said. “A clinical prediction tool and a proper biomarker would be of great value.”

“We certainly use CASPAR criteria in the clinic, but they do not include all PsA patients; sometimes we diagnose PsA in patients who don’t meet the CASPAR criteria,” Dr. Coates said.

“In practice, rheumatologists mostly use their clinical judgment: a patient with history and findings typical of PsA after ruling out other causes. But distinguishing inflammatory from noninflammatory arthritis – like osteoarthritis or fibromyalgia – can be quite difficult; that’s the main challenge,” Dr. Eder said. “Rheumatologists rely on their clinical skill and experience. PsA can be difficult to diagnose. There is no biomarker for it. PsA is complex [to diagnose], and that’s why it’s diagnosed later. A primary care physician might get a negative result on a rheumatoid factor test and think that rules out PsA, but it doesn’t.”

Dr. Eder and others suggest that ultrasound may be a useful tool for earlier diagnosis of PsA. Ultrasound is more sensitive than a physical examination and can detect inflammation in joints and entheses, she noted. Another effective method may be more systematic use of screening questionnaires, Dr. Coates said, or simply more systematic questioning of patients.

“Questionnaires are not a high priority for a primary care physician who may have only a few patients with psoriasis. Even some dermatologists may not use the questionnaires because they take time to administer and assess. But just asking a psoriasis patient whether they have joint symptoms is enough,” Dr. Eder said. All clinicians who encounter patients with psoriasis should ask about musculoskeletal symptoms and refer when appropriate to a rheumatologist, Dr. Reddy said.
 

The earliest indicators of PsA

Evidence supporting ultrasound’s value for early PsA diagnosis came in a report at the most recent annual meeting of the American College of Rheumatology in Chicago in October 2018. Researchers from the University of Rochester (New York) used ultrasound to examine 78 patients with psoriasis but without PsA or musculoskeletal symptoms and 25 healthy controls. They found ultrasound abnormalities in almost half of the patients with psoriasis, significantly more than in the controls (Thiele R et al. Arthritis Rheumatol. 2018;70[suppl 10]: Abstract 2904).

Another report at the ACR annual meeting last October looked at the incidence of physician visits for nonspecific musculoskeletal symptoms during each of the 5 years preceding diagnosis of PsA. A prior report from Dr. Eder and her associates had documented in an observational cohort of 410 patients with psoriasis that, prior to development of PsA, patients often had nonspecific musculoskeletal symptoms of joint pain, fatigue, and stiffness that constituted a “preclinical” phase (Arthritis Rheumatol. 2017 March;69[3]:622-9).

In October, Dr. Eder reported how the appearance of musculoskeletal symptoms played out in terms of physician visits. She and her associates analyzed data from an Ontario health insurance database that included about 430,000 Ontario patients seen by 466 primary care physicians, which included 462 patients with a new diagnosis of PsA and 2,310 matched controls. The results showed that, in every year during the 5 years preceding diagnosis of PsA, the patients who would wind up getting diagnosed had roughly twice the number of visits to a primary care physician each year for nonspecific musculoskeletal issues. A similar pattern of doubled visits occurred for people prior to their PsA diagnosis going to physicians who specialize in musculoskeletal conditions, and when the analysis focused on visits to rheumatologists, patients who went on to get diagnosed with PsA had a nearly sevenfold increased rate of these visits, compared with controls, for each of the 5 years preceding their PsA diagnosis (Eder L et al. Arthritis Rheumatol. 2018;70[suppl 10]: Abstract 967).

These results “highlight that in many patients PsA is not an acute disease that starts suddenly. In many patients, there is a period when the patient experiences musculoskeletal symptoms and sees a primary care physician or rheumatologist and may be diagnosed with something that is not PsA. That means that the delay in diagnosis [of PsA] may have happened because the patients were misdiagnosed. It reinforces the need for better diagnostic tools,” Dr. Eder said. “We have focused on getting these patients to see a rheumatologist earlier, but that may not be enough. These patients may not receive routine follow-up; we need to do more follow-up on patients like these.” Diagnosing PsA early means earlier treatment, a better chance of reaching remission, less chance of permanent joint damage, and better quality of life.

The challenges of making an early diagnosis were also documented in a study reported by Dr. Ogdie during the June 2018 annual congress of the European League Against Rheumatism. Dr. Ogdie reported on the survey responses of 203 patients who said they had been diagnosed with PsA whose index diagnosis was a median of 6 years before they completed the survey. A total of 195 of these patients, or 96%, said that they had received at least one misdiagnosis prior to their PsA diagnosis (Odgie A et al. Ann Rheum Dis. 2018;77[Suppl 2]:163. Abstract THU0292). The most common misdiagnoses were psychosomatic disease, reported by 27% of the patients; osteoarthritis in 22%; anxiety or depression in 18%; and an orthopedic problem in 18%. (Patients could report more than one type of misdiagnosis.)

The results “showed that patients often had substantial delays and misdiagnoses before they received a PsA diagnosis,” Dr. Ogdie and her associates concluded. Although the CASPAR classification criteria may be the agreed on PsA definition, recent findings suggest a pre-PsA stage exists with musculoskeletal and other abnormalities. “How may we diagnose ‘pre-PsA’? How might we capture this transition phase from psoriasis to PsA before the CASPAR criteria are fulfilled,” she wondered in an interview. “If we could stop PsA before it is clinically relevant, that could dramatically change the course of the disease. This is a big need in the field right now.”

Weight loss and other interventions

Aside from treating psoriasis and perhaps putting a patient with psoriasis in a PsA-prevention trial, one of the best ways to prevent PsA may be weight loss.

Penn Medicine

Results from “some studies suggest that being overweight increases the risk for developing PsA. Obesity also exacerbates skin psoriasis, makes treatment less effective, and further increases the risk of cardiometabolic diseases associated with psoriasis,” Dr. Gelfand said. “All patients with psoriatic disease should be educated about the importance of maintaining a healthy body weight.”

“Several studies suggest that obesity is a risk factor for developing PsA. Obesity likely plays a role in driving or contributing to inflammation in psoriatic disease,” said Dr. Reddy, who noted that other PsA risk factors include nail psoriasis and first-degree relatives with PsA. Dr. Ogdie also cited uveitis and prior joint trauma as other risk factors.

“Strong observational data link obesity and PsA incidence. I talk to psoriasis patients about weight control, and selected patients could even consider bariatric surgery,” Dr. Eder said. Losing at least 5% of body mass index can make a difference, she added.

At the 2018 annual meeting of the American College of Rheumatology, researchers from the University of Bath (England) reported results from a retrospective, observational study of more than 90,000 people with recent-onset psoriasis; they found that people with an obese BMI had twice the rate of progression to PsA when compared with people with a normal BMI. Overweight people had a nearly 80% higher rate of incident PsA (Green A et al. Arthritis Rheumatol. 2018;70[Suppl 10]: Abstract 2134).

Hints have also emerged that new approaches to treating psoriasis also could help to keep PsA precursors at bay. One recent example from researchers at the University of Leeds (England) was a phase 2 study of 73 patients with moderate to severe psoriasis but no PsA who underwent ultrasound screening of their entheses for signs of inflammatory changes. The 23 patients underwent 52 weeks of treatment with the drug ustekinumab (Stelara), an antagonist of interleukin-12 and -23 that is approved for U.S. marketing to treat both psoriasis and PsA. After 24 weeks on treatment, their mean inflammation scores had dropped by more than 40%, and the effect persisted through 52 weeks of treatment (Arthritis Rheum. 2018 Nov 22. doi: 10.1002/art.40778).

Despite this promise, the researchers “haven’t looked long enough or in enough people to see whether this actually stops patients from developing PsA,” Dr. Coates commented. It also remains unclear whether this or another ultrasound abnormality detectable in joints or entheses is a reliable predictor of PsA, she noted.

“We still have a lot to learn about how to classify patients as high risk” for PsA, Dr. Ogdie concluded.

Dr. Eder has received research and educational grants from AbbVie, Amgen, Celgene, Lilly, Novartis, and UCB. Dr. Coates has received honoraria, research funding, or both from more than a dozen companies. Dr. Reddy has been a consultant to AbbVie, Novartis, Pfizer, and UCB. Dr. Merola has been a consultant to AbbVie, Celgene, GlaxoSmithKline, Janssen, Lilly, Novartis, Samumed, Sanofi, and UCB and has received research grants from Aclaris, Biogen, Incyte, Novartis, Pfizer, and Sanofi. Dr. Gelfand has been a consultant, adviser, or both to more than a dozen companies. Dr. Ogdie has been a consultant to AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Corrona, Lilly, Novartis, Pfizer, and Takeda.

[email protected]

Most patients with psoriatic arthritis first present with psoriasis only. Their skin disorder precedes any joint involvement, often by several years. That suggests targeting interventions to patients with psoriasis to prevent or slow their progression to psoriatic arthritis, as well as following psoriatic patients closely to diagnose psoriatic arthritis quickly when it first appears. It’s a simple and attractive management premise that’s been challenging to apply in practice.

It’s not that clinicians aren’t motivated to diagnose psoriatic arthritis (PsA) in patients early, hopefully as soon as it appears. The susceptibility of patients with psoriasis to develop PsA is well described, with an annual progression rate of about 3%, and adverse consequences result from even a 6-month delay in diagnosis.

“Some physicians still don’t ask psoriasis patients about joint pain, or their symptoms are misinterpreted as something else,” said Lihi Eder, MD, a rheumatologist at Women’s College Research Institute, Toronto, and the University of Toronto. “Although there is increased awareness about PsA, there are still delays in diagnosis,” she said in an interview.

“Often there is a massive delay in diagnosis, and we know from a number of studies that longer duration of symptoms before diagnosis is associated with poorer outcomes,” said Laura C. Coates, MBChB, PhD, a rheumatologist at the University of Oxford (England). The delay to PsA diagnosis is generally “longer than for equivalent rheumatoid arthritis patients. PsA patients take longer to ask a primary care physician for help, longer to get a referral to a rheumatologist, and longer to get a diagnosis” from a rheumatologist. “We need to educate patients with psoriasis about their risk so that they seek help, educate GPs about whom to refer, and educate rheumatologists about diagnosis,” Dr. Coates said.

“It is very important to diagnose PsA as early as possible. We know that a delay in diagnosis and treatment can lead to worse outcomes and joint damage,” said Soumya M. Reddy, MD, codirector of the Psoriasis and Psoriatic Arthritis Center at New York University Langone Health in New York. “The heterogeneity of clinical manifestations of PsA can make it difficult to diagnose, and in some cases this leads to delayed diagnosis.”

“We are increasingly interested in the concept of preventing PsA. Psoriasis is a unique disease state in which we have an at-risk population where 30% will develop an inflammatory and potentially damaging arthritis. This may become important as our skin treatments may also treat musculoskeletal components of the disease,” said Joseph F. Merola, MD, director of the Center for Skin and Related Musculoskeletal Diseases at Brigham and Women’s Hospital in Boston and double board certified in dermatology and rheumatology.

Focusing on patients with psoriasis

Treatment of psoriasis makes sense to address several quality-of-life issues, but controlling the severity of psoriatic skin manifestations gives patients no guarantees about their possible progression to PsA.

“So many people have mild psoriasis that, although they are less likely, proportionately, to get PsA, we still see many in the clinic,” said Dr. Coates. “Patients with severe skin involvement have a good reason to get treatment, which could help test whether a drug slows progression to arthritis. But it’s unethical to not treat severe psoriasis just to have a comparison group.” Aside from skin psoriasis, “we don’t have any other good markers,” Dr. Coates noted.

PsA can develop in patients who had psoriasis in the past but without currently active disease. “At the level of individual patients you can’t say someone is protected from developing PsA because their psoriasis is inactive,” Dr. Eder said. “No study has looked at whether treatment of psoriasis reduces the risk for progression to PsA. We don’t know whether any treatments that reduce inflammation in psoriasis also reduce progression to PsA.” Regardless, treating psoriasis is important because it improves quality of life and may have a beneficial, long-term effects on possible cardiovascular disease effects from psoriasis, Dr. Eder said.

“The risk of developing PsA increases as the severity of skin psoriasis increases, measured by percentage of body surface area affected. However, there is only a weak correlation between the severity of skin disease and the severity of PsA,” said Joel M. Gelfand, MD, professor of dermatology at the University of Pennsylvania in Philadelphia.
 

Widening the PsA diagnostic net

What’s elusive is some other parameter to identify the 3% of psoriasis patients who will develop PsA during the next year – or at least a better way to find patients as soon as they have what is identifiably PsA.

The diagnostic definition for PsA that many experts now accept is actually a set of classification criteria, CASPAR (Classification Criteria for Psoriatic Arthritis) (Arthritis Rheum. 2006 Aug;54[8]:2665-73). But in actual practice, diagnosing PsA relies heavily on clinical skill, case recognition, and ruling out mimickers.

“The CASPAR criteria were developed as classification criteria to use in studies, but they are also quite helpful in diagnosing PsA. It is the agreed on definition of PsA at the moment,” said Alexis Ogdie, MD, director of the psoriatic arthritis clinic at the University of Pennsylvania.

“CASPAR fills the role at present for clinical trials, but the diagnosis remains clinical, based on history, physical findings, and supported by lab and radiology findings,” Dr. Merola said. “A clinical prediction tool and a proper biomarker would be of great value.”

“We certainly use CASPAR criteria in the clinic, but they do not include all PsA patients; sometimes we diagnose PsA in patients who don’t meet the CASPAR criteria,” Dr. Coates said.

“In practice, rheumatologists mostly use their clinical judgment: a patient with history and findings typical of PsA after ruling out other causes. But distinguishing inflammatory from noninflammatory arthritis – like osteoarthritis or fibromyalgia – can be quite difficult; that’s the main challenge,” Dr. Eder said. “Rheumatologists rely on their clinical skill and experience. PsA can be difficult to diagnose. There is no biomarker for it. PsA is complex [to diagnose], and that’s why it’s diagnosed later. A primary care physician might get a negative result on a rheumatoid factor test and think that rules out PsA, but it doesn’t.”

Dr. Eder and others suggest that ultrasound may be a useful tool for earlier diagnosis of PsA. Ultrasound is more sensitive than a physical examination and can detect inflammation in joints and entheses, she noted. Another effective method may be more systematic use of screening questionnaires, Dr. Coates said, or simply more systematic questioning of patients.

“Questionnaires are not a high priority for a primary care physician who may have only a few patients with psoriasis. Even some dermatologists may not use the questionnaires because they take time to administer and assess. But just asking a psoriasis patient whether they have joint symptoms is enough,” Dr. Eder said. All clinicians who encounter patients with psoriasis should ask about musculoskeletal symptoms and refer when appropriate to a rheumatologist, Dr. Reddy said.
 

The earliest indicators of PsA

Evidence supporting ultrasound’s value for early PsA diagnosis came in a report at the most recent annual meeting of the American College of Rheumatology in Chicago in October 2018. Researchers from the University of Rochester (New York) used ultrasound to examine 78 patients with psoriasis but without PsA or musculoskeletal symptoms and 25 healthy controls. They found ultrasound abnormalities in almost half of the patients with psoriasis, significantly more than in the controls (Thiele R et al. Arthritis Rheumatol. 2018;70[suppl 10]: Abstract 2904).

Another report at the ACR annual meeting last October looked at the incidence of physician visits for nonspecific musculoskeletal symptoms during each of the 5 years preceding diagnosis of PsA. A prior report from Dr. Eder and her associates had documented in an observational cohort of 410 patients with psoriasis that, prior to development of PsA, patients often had nonspecific musculoskeletal symptoms of joint pain, fatigue, and stiffness that constituted a “preclinical” phase (Arthritis Rheumatol. 2017 March;69[3]:622-9).

In October, Dr. Eder reported how the appearance of musculoskeletal symptoms played out in terms of physician visits. She and her associates analyzed data from an Ontario health insurance database that included about 430,000 Ontario patients seen by 466 primary care physicians, which included 462 patients with a new diagnosis of PsA and 2,310 matched controls. The results showed that, in every year during the 5 years preceding diagnosis of PsA, the patients who would wind up getting diagnosed had roughly twice the number of visits to a primary care physician each year for nonspecific musculoskeletal issues. A similar pattern of doubled visits occurred for people prior to their PsA diagnosis going to physicians who specialize in musculoskeletal conditions, and when the analysis focused on visits to rheumatologists, patients who went on to get diagnosed with PsA had a nearly sevenfold increased rate of these visits, compared with controls, for each of the 5 years preceding their PsA diagnosis (Eder L et al. Arthritis Rheumatol. 2018;70[suppl 10]: Abstract 967).

These results “highlight that in many patients PsA is not an acute disease that starts suddenly. In many patients, there is a period when the patient experiences musculoskeletal symptoms and sees a primary care physician or rheumatologist and may be diagnosed with something that is not PsA. That means that the delay in diagnosis [of PsA] may have happened because the patients were misdiagnosed. It reinforces the need for better diagnostic tools,” Dr. Eder said. “We have focused on getting these patients to see a rheumatologist earlier, but that may not be enough. These patients may not receive routine follow-up; we need to do more follow-up on patients like these.” Diagnosing PsA early means earlier treatment, a better chance of reaching remission, less chance of permanent joint damage, and better quality of life.

The challenges of making an early diagnosis were also documented in a study reported by Dr. Ogdie during the June 2018 annual congress of the European League Against Rheumatism. Dr. Ogdie reported on the survey responses of 203 patients who said they had been diagnosed with PsA whose index diagnosis was a median of 6 years before they completed the survey. A total of 195 of these patients, or 96%, said that they had received at least one misdiagnosis prior to their PsA diagnosis (Odgie A et al. Ann Rheum Dis. 2018;77[Suppl 2]:163. Abstract THU0292). The most common misdiagnoses were psychosomatic disease, reported by 27% of the patients; osteoarthritis in 22%; anxiety or depression in 18%; and an orthopedic problem in 18%. (Patients could report more than one type of misdiagnosis.)

The results “showed that patients often had substantial delays and misdiagnoses before they received a PsA diagnosis,” Dr. Ogdie and her associates concluded. Although the CASPAR classification criteria may be the agreed on PsA definition, recent findings suggest a pre-PsA stage exists with musculoskeletal and other abnormalities. “How may we diagnose ‘pre-PsA’? How might we capture this transition phase from psoriasis to PsA before the CASPAR criteria are fulfilled,” she wondered in an interview. “If we could stop PsA before it is clinically relevant, that could dramatically change the course of the disease. This is a big need in the field right now.”

Weight loss and other interventions

Aside from treating psoriasis and perhaps putting a patient with psoriasis in a PsA-prevention trial, one of the best ways to prevent PsA may be weight loss.

Penn Medicine

Results from “some studies suggest that being overweight increases the risk for developing PsA. Obesity also exacerbates skin psoriasis, makes treatment less effective, and further increases the risk of cardiometabolic diseases associated with psoriasis,” Dr. Gelfand said. “All patients with psoriatic disease should be educated about the importance of maintaining a healthy body weight.”

“Several studies suggest that obesity is a risk factor for developing PsA. Obesity likely plays a role in driving or contributing to inflammation in psoriatic disease,” said Dr. Reddy, who noted that other PsA risk factors include nail psoriasis and first-degree relatives with PsA. Dr. Ogdie also cited uveitis and prior joint trauma as other risk factors.

“Strong observational data link obesity and PsA incidence. I talk to psoriasis patients about weight control, and selected patients could even consider bariatric surgery,” Dr. Eder said. Losing at least 5% of body mass index can make a difference, she added.

At the 2018 annual meeting of the American College of Rheumatology, researchers from the University of Bath (England) reported results from a retrospective, observational study of more than 90,000 people with recent-onset psoriasis; they found that people with an obese BMI had twice the rate of progression to PsA when compared with people with a normal BMI. Overweight people had a nearly 80% higher rate of incident PsA (Green A et al. Arthritis Rheumatol. 2018;70[Suppl 10]: Abstract 2134).

Hints have also emerged that new approaches to treating psoriasis also could help to keep PsA precursors at bay. One recent example from researchers at the University of Leeds (England) was a phase 2 study of 73 patients with moderate to severe psoriasis but no PsA who underwent ultrasound screening of their entheses for signs of inflammatory changes. The 23 patients underwent 52 weeks of treatment with the drug ustekinumab (Stelara), an antagonist of interleukin-12 and -23 that is approved for U.S. marketing to treat both psoriasis and PsA. After 24 weeks on treatment, their mean inflammation scores had dropped by more than 40%, and the effect persisted through 52 weeks of treatment (Arthritis Rheum. 2018 Nov 22. doi: 10.1002/art.40778).

Despite this promise, the researchers “haven’t looked long enough or in enough people to see whether this actually stops patients from developing PsA,” Dr. Coates commented. It also remains unclear whether this or another ultrasound abnormality detectable in joints or entheses is a reliable predictor of PsA, she noted.

“We still have a lot to learn about how to classify patients as high risk” for PsA, Dr. Ogdie concluded.

Dr. Eder has received research and educational grants from AbbVie, Amgen, Celgene, Lilly, Novartis, and UCB. Dr. Coates has received honoraria, research funding, or both from more than a dozen companies. Dr. Reddy has been a consultant to AbbVie, Novartis, Pfizer, and UCB. Dr. Merola has been a consultant to AbbVie, Celgene, GlaxoSmithKline, Janssen, Lilly, Novartis, Samumed, Sanofi, and UCB and has received research grants from Aclaris, Biogen, Incyte, Novartis, Pfizer, and Sanofi. Dr. Gelfand has been a consultant, adviser, or both to more than a dozen companies. Dr. Ogdie has been a consultant to AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Corrona, Lilly, Novartis, Pfizer, and Takeda.

[email protected]

Most patients with psoriatic arthritis first present with psoriasis only. Their skin disorder precedes any joint involvement, often by several years. That suggests targeting interventions to patients with psoriasis to prevent or slow their progression to psoriatic arthritis, as well as following psoriatic patients closely to diagnose psoriatic arthritis quickly when it first appears. It’s a simple and attractive management premise that’s been challenging to apply in practice.

It’s not that clinicians aren’t motivated to diagnose psoriatic arthritis (PsA) in patients early, hopefully as soon as it appears. The susceptibility of patients with psoriasis to develop PsA is well described, with an annual progression rate of about 3%, and adverse consequences result from even a 6-month delay in diagnosis.

“Some physicians still don’t ask psoriasis patients about joint pain, or their symptoms are misinterpreted as something else,” said Lihi Eder, MD, a rheumatologist at Women’s College Research Institute, Toronto, and the University of Toronto. “Although there is increased awareness about PsA, there are still delays in diagnosis,” she said in an interview.

“Often there is a massive delay in diagnosis, and we know from a number of studies that longer duration of symptoms before diagnosis is associated with poorer outcomes,” said Laura C. Coates, MBChB, PhD, a rheumatologist at the University of Oxford (England). The delay to PsA diagnosis is generally “longer than for equivalent rheumatoid arthritis patients. PsA patients take longer to ask a primary care physician for help, longer to get a referral to a rheumatologist, and longer to get a diagnosis” from a rheumatologist. “We need to educate patients with psoriasis about their risk so that they seek help, educate GPs about whom to refer, and educate rheumatologists about diagnosis,” Dr. Coates said.

“It is very important to diagnose PsA as early as possible. We know that a delay in diagnosis and treatment can lead to worse outcomes and joint damage,” said Soumya M. Reddy, MD, codirector of the Psoriasis and Psoriatic Arthritis Center at New York University Langone Health in New York. “The heterogeneity of clinical manifestations of PsA can make it difficult to diagnose, and in some cases this leads to delayed diagnosis.”

“We are increasingly interested in the concept of preventing PsA. Psoriasis is a unique disease state in which we have an at-risk population where 30% will develop an inflammatory and potentially damaging arthritis. This may become important as our skin treatments may also treat musculoskeletal components of the disease,” said Joseph F. Merola, MD, director of the Center for Skin and Related Musculoskeletal Diseases at Brigham and Women’s Hospital in Boston and double board certified in dermatology and rheumatology.

Focusing on patients with psoriasis

Treatment of psoriasis makes sense to address several quality-of-life issues, but controlling the severity of psoriatic skin manifestations gives patients no guarantees about their possible progression to PsA.

“So many people have mild psoriasis that, although they are less likely, proportionately, to get PsA, we still see many in the clinic,” said Dr. Coates. “Patients with severe skin involvement have a good reason to get treatment, which could help test whether a drug slows progression to arthritis. But it’s unethical to not treat severe psoriasis just to have a comparison group.” Aside from skin psoriasis, “we don’t have any other good markers,” Dr. Coates noted.

PsA can develop in patients who had psoriasis in the past but without currently active disease. “At the level of individual patients you can’t say someone is protected from developing PsA because their psoriasis is inactive,” Dr. Eder said. “No study has looked at whether treatment of psoriasis reduces the risk for progression to PsA. We don’t know whether any treatments that reduce inflammation in psoriasis also reduce progression to PsA.” Regardless, treating psoriasis is important because it improves quality of life and may have a beneficial, long-term effects on possible cardiovascular disease effects from psoriasis, Dr. Eder said.

“The risk of developing PsA increases as the severity of skin psoriasis increases, measured by percentage of body surface area affected. However, there is only a weak correlation between the severity of skin disease and the severity of PsA,” said Joel M. Gelfand, MD, professor of dermatology at the University of Pennsylvania in Philadelphia.
 

Widening the PsA diagnostic net

What’s elusive is some other parameter to identify the 3% of psoriasis patients who will develop PsA during the next year – or at least a better way to find patients as soon as they have what is identifiably PsA.

The diagnostic definition for PsA that many experts now accept is actually a set of classification criteria, CASPAR (Classification Criteria for Psoriatic Arthritis) (Arthritis Rheum. 2006 Aug;54[8]:2665-73). But in actual practice, diagnosing PsA relies heavily on clinical skill, case recognition, and ruling out mimickers.

“The CASPAR criteria were developed as classification criteria to use in studies, but they are also quite helpful in diagnosing PsA. It is the agreed on definition of PsA at the moment,” said Alexis Ogdie, MD, director of the psoriatic arthritis clinic at the University of Pennsylvania.

“CASPAR fills the role at present for clinical trials, but the diagnosis remains clinical, based on history, physical findings, and supported by lab and radiology findings,” Dr. Merola said. “A clinical prediction tool and a proper biomarker would be of great value.”

“We certainly use CASPAR criteria in the clinic, but they do not include all PsA patients; sometimes we diagnose PsA in patients who don’t meet the CASPAR criteria,” Dr. Coates said.

“In practice, rheumatologists mostly use their clinical judgment: a patient with history and findings typical of PsA after ruling out other causes. But distinguishing inflammatory from noninflammatory arthritis – like osteoarthritis or fibromyalgia – can be quite difficult; that’s the main challenge,” Dr. Eder said. “Rheumatologists rely on their clinical skill and experience. PsA can be difficult to diagnose. There is no biomarker for it. PsA is complex [to diagnose], and that’s why it’s diagnosed later. A primary care physician might get a negative result on a rheumatoid factor test and think that rules out PsA, but it doesn’t.”

Dr. Eder and others suggest that ultrasound may be a useful tool for earlier diagnosis of PsA. Ultrasound is more sensitive than a physical examination and can detect inflammation in joints and entheses, she noted. Another effective method may be more systematic use of screening questionnaires, Dr. Coates said, or simply more systematic questioning of patients.

“Questionnaires are not a high priority for a primary care physician who may have only a few patients with psoriasis. Even some dermatologists may not use the questionnaires because they take time to administer and assess. But just asking a psoriasis patient whether they have joint symptoms is enough,” Dr. Eder said. All clinicians who encounter patients with psoriasis should ask about musculoskeletal symptoms and refer when appropriate to a rheumatologist, Dr. Reddy said.
 

The earliest indicators of PsA

Evidence supporting ultrasound’s value for early PsA diagnosis came in a report at the most recent annual meeting of the American College of Rheumatology in Chicago in October 2018. Researchers from the University of Rochester (New York) used ultrasound to examine 78 patients with psoriasis but without PsA or musculoskeletal symptoms and 25 healthy controls. They found ultrasound abnormalities in almost half of the patients with psoriasis, significantly more than in the controls (Thiele R et al. Arthritis Rheumatol. 2018;70[suppl 10]: Abstract 2904).

Another report at the ACR annual meeting last October looked at the incidence of physician visits for nonspecific musculoskeletal symptoms during each of the 5 years preceding diagnosis of PsA. A prior report from Dr. Eder and her associates had documented in an observational cohort of 410 patients with psoriasis that, prior to development of PsA, patients often had nonspecific musculoskeletal symptoms of joint pain, fatigue, and stiffness that constituted a “preclinical” phase (Arthritis Rheumatol. 2017 March;69[3]:622-9).

In October, Dr. Eder reported how the appearance of musculoskeletal symptoms played out in terms of physician visits. She and her associates analyzed data from an Ontario health insurance database that included about 430,000 Ontario patients seen by 466 primary care physicians, which included 462 patients with a new diagnosis of PsA and 2,310 matched controls. The results showed that, in every year during the 5 years preceding diagnosis of PsA, the patients who would wind up getting diagnosed had roughly twice the number of visits to a primary care physician each year for nonspecific musculoskeletal issues. A similar pattern of doubled visits occurred for people prior to their PsA diagnosis going to physicians who specialize in musculoskeletal conditions, and when the analysis focused on visits to rheumatologists, patients who went on to get diagnosed with PsA had a nearly sevenfold increased rate of these visits, compared with controls, for each of the 5 years preceding their PsA diagnosis (Eder L et al. Arthritis Rheumatol. 2018;70[suppl 10]: Abstract 967).

These results “highlight that in many patients PsA is not an acute disease that starts suddenly. In many patients, there is a period when the patient experiences musculoskeletal symptoms and sees a primary care physician or rheumatologist and may be diagnosed with something that is not PsA. That means that the delay in diagnosis [of PsA] may have happened because the patients were misdiagnosed. It reinforces the need for better diagnostic tools,” Dr. Eder said. “We have focused on getting these patients to see a rheumatologist earlier, but that may not be enough. These patients may not receive routine follow-up; we need to do more follow-up on patients like these.” Diagnosing PsA early means earlier treatment, a better chance of reaching remission, less chance of permanent joint damage, and better quality of life.

The challenges of making an early diagnosis were also documented in a study reported by Dr. Ogdie during the June 2018 annual congress of the European League Against Rheumatism. Dr. Ogdie reported on the survey responses of 203 patients who said they had been diagnosed with PsA whose index diagnosis was a median of 6 years before they completed the survey. A total of 195 of these patients, or 96%, said that they had received at least one misdiagnosis prior to their PsA diagnosis (Odgie A et al. Ann Rheum Dis. 2018;77[Suppl 2]:163. Abstract THU0292). The most common misdiagnoses were psychosomatic disease, reported by 27% of the patients; osteoarthritis in 22%; anxiety or depression in 18%; and an orthopedic problem in 18%. (Patients could report more than one type of misdiagnosis.)

The results “showed that patients often had substantial delays and misdiagnoses before they received a PsA diagnosis,” Dr. Ogdie and her associates concluded. Although the CASPAR classification criteria may be the agreed on PsA definition, recent findings suggest a pre-PsA stage exists with musculoskeletal and other abnormalities. “How may we diagnose ‘pre-PsA’? How might we capture this transition phase from psoriasis to PsA before the CASPAR criteria are fulfilled,” she wondered in an interview. “If we could stop PsA before it is clinically relevant, that could dramatically change the course of the disease. This is a big need in the field right now.”

Weight loss and other interventions

Aside from treating psoriasis and perhaps putting a patient with psoriasis in a PsA-prevention trial, one of the best ways to prevent PsA may be weight loss.

Penn Medicine

Results from “some studies suggest that being overweight increases the risk for developing PsA. Obesity also exacerbates skin psoriasis, makes treatment less effective, and further increases the risk of cardiometabolic diseases associated with psoriasis,” Dr. Gelfand said. “All patients with psoriatic disease should be educated about the importance of maintaining a healthy body weight.”

“Several studies suggest that obesity is a risk factor for developing PsA. Obesity likely plays a role in driving or contributing to inflammation in psoriatic disease,” said Dr. Reddy, who noted that other PsA risk factors include nail psoriasis and first-degree relatives with PsA. Dr. Ogdie also cited uveitis and prior joint trauma as other risk factors.

“Strong observational data link obesity and PsA incidence. I talk to psoriasis patients about weight control, and selected patients could even consider bariatric surgery,” Dr. Eder said. Losing at least 5% of body mass index can make a difference, she added.

At the 2018 annual meeting of the American College of Rheumatology, researchers from the University of Bath (England) reported results from a retrospective, observational study of more than 90,000 people with recent-onset psoriasis; they found that people with an obese BMI had twice the rate of progression to PsA when compared with people with a normal BMI. Overweight people had a nearly 80% higher rate of incident PsA (Green A et al. Arthritis Rheumatol. 2018;70[Suppl 10]: Abstract 2134).

Hints have also emerged that new approaches to treating psoriasis also could help to keep PsA precursors at bay. One recent example from researchers at the University of Leeds (England) was a phase 2 study of 73 patients with moderate to severe psoriasis but no PsA who underwent ultrasound screening of their entheses for signs of inflammatory changes. The 23 patients underwent 52 weeks of treatment with the drug ustekinumab (Stelara), an antagonist of interleukin-12 and -23 that is approved for U.S. marketing to treat both psoriasis and PsA. After 24 weeks on treatment, their mean inflammation scores had dropped by more than 40%, and the effect persisted through 52 weeks of treatment (Arthritis Rheum. 2018 Nov 22. doi: 10.1002/art.40778).

Despite this promise, the researchers “haven’t looked long enough or in enough people to see whether this actually stops patients from developing PsA,” Dr. Coates commented. It also remains unclear whether this or another ultrasound abnormality detectable in joints or entheses is a reliable predictor of PsA, she noted.

“We still have a lot to learn about how to classify patients as high risk” for PsA, Dr. Ogdie concluded.

Dr. Eder has received research and educational grants from AbbVie, Amgen, Celgene, Lilly, Novartis, and UCB. Dr. Coates has received honoraria, research funding, or both from more than a dozen companies. Dr. Reddy has been a consultant to AbbVie, Novartis, Pfizer, and UCB. Dr. Merola has been a consultant to AbbVie, Celgene, GlaxoSmithKline, Janssen, Lilly, Novartis, Samumed, Sanofi, and UCB and has received research grants from Aclaris, Biogen, Incyte, Novartis, Pfizer, and Sanofi. Dr. Gelfand has been a consultant, adviser, or both to more than a dozen companies. Dr. Ogdie has been a consultant to AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Corrona, Lilly, Novartis, Pfizer, and Takeda.

[email protected]

Specially formulated topical pain creams are no better than placebo creams for relieving localized chronic pain, according to results from a double-blind, randomized, placebo-controlled trial.

nebari/ThinkStock

Study authors led by Robert E. Brutcher, PharmD, PhD, of Walter Reed National Military Medical Center in Bethesda, Md., said their findings published Feb. 4 in Annals of Internal Medicine suggest compounded pain creams should not be routinely used for chronic pain conditions.

The researchers noted that the use of compounded topical pain creams has increased dramatically despite “weak evidence” supporting their efficacy to treat localized pain, and this is particularly the case in military personnel, where the authors said treatments without central effect may be particularly beneficial because “opioid therapy may render a service member nondeployable and medications that affect the central nervous system may have a negative effect on judgment and motor skills.”

They noted a report from the U.S. Government Accountability Office that showed Tricare’s pharmacy benefits program paid $259 million for compounded medications in the 2013 fiscal year, a figure that increased to $746 million in 2014.

“The soaring costs, coupled with sparse efficacy data prompted the Defense Health Agency to evaluate this issue,” they wrote.

The objectives of the current study were to assess the efficacy of compounded pain creams for chronic pain conditions and determine whether efficacy differed for the various pain classifications.

“We hypothesized that, compared with placebo, compounded topical pain creams would provide greater pain relief and functional improvement,” they said.

The randomized trial involved 133 patients diagnosed with neuropathic pain, 133 with nociceptive pain, and 133 with mixed pain who had attended pain clinics at Walter Reed. Patients were aged between 18 and 90 years and had localized pain in the face, back or buttocks, neck, abdomen, chest, groin, or in up to two extremities. To be included in the study, they were also required to have an average pain score of 4 or greater on a 0- to 10-point numerical rating scale during the preceding week and have symptoms lasting longer than 6 weeks.

Patients in all three pain subgroups were randomized in a 1:1 ratio to receive either a compounded pain cream or a placebo cream. The authors noted that their “pain cream formulations were selected on the basis of accepted systemic indications for neuropathic and nociceptive pain.”

The formulation given to participants with neuropathic pain (n = 68) contained 10% ketamine, 6% gabapentin, 0.2% clonidine, and 2% lidocaine. The patients with nociceptive pain (n = 66) received a cream with 10% ketoprofen, 2% baclofen, 2% cyclobenzaprine, and 2% lidocaine. Those with mixed pain (n = 68) were given a cream containing 10% ketamine, 6% gabapentin, 3% diclofenac, 2% baclofen, 2% cyclobenzaprine, and 2% lidocaine. The authors said the concentrations of individual medications were based on previous trials that evaluated topical use.

The patients, who had a mean age across the groups that ranged from 48 to 57 years, applied cream to affected areas three times per day, with the amount dispensed determined by the size of the area experiencing pain. About half of the patients were women.

The primary outcome measures were an average pain score 1 month after treatment. A positive categorical response was a reduction in pain score of 2 or more points coupled with a score above 3 on a 5-point satisfaction scale. Secondary outcomes included Short Form-36 Health Survey scores, satisfaction, and categorical response. Participants with a positive outcome were followed to 3 months.

Change in the primary outcome of average pain score at 1 month did not differ between the active cream and placebo groups for any type of pain classification. The change was only –0.1 points (95% confidence interval, –0.8 to 0.5 points) for neuropathic pain, –0.3 points (95% CI, –0.9 to 0.2 points) for nociceptive pain, and –0.3 points (95% CI, –0.9 to 0.2 points) for mixed pain.

Among all patients combined, an overall change in average pain scores of –0.3 points (95% CI, –0.6 to 0.1 points) that favored the active-ingredient cream also did not differ between the treatment and placebo groups.

“The lower 95% confidence bounds for the 1-month between-group differences were all 0.9 points or less and excluded clinically meaningful benefits with the compounded topical pain cream,” the authors wrote.

Secondary outcomes also did not differ between the two study groups for any type of pain classification or for the entire cohort.

“Although participants in both treatment and control groups had improvement in their pain throughout the study, no significant differences were observed in pain scores, functional improvement, or satisfaction in the cohort or in any subgroup,” the authors concluded.

They noted that their findings were consistent with previous studies that also showed a lack of efficacy for most topical pain creams.

While some randomized trials have suggested positive findings for capsaicin, lidocaine, and NSAIDs, the authors noted that they did not find a similar benefit in their study population.

“Administered as stand-alone agents, lidocaine and NSAIDs may alleviate pain, although the effect size is small and the number needed to treat is large,” they wrote.

“Considering the increased costs of using a non–FDA-approved and regulated compounded cream rather than a single agent, we caution against routine use of compounded creams for chronic pain,” they wrote.

They noted that their study had several limitations, including that conventional treatments had failed in some of the participants before they enrolled in the study, increasing the likelihood that subsequent therapy would not be effective.

The authors suggested that future studies should aim to establish whether targeting specific types of pain or adding other agents like dimethyl sulfoxide would result in better outcomes.

The Centers for Rehabilitation Sciences Research in the U.S. Department of Defense’s Defense Health Agency funded the study. Two authors reported receiving grants and personal fees from several pharmaceutical companies.

SOURCE: Brutcher RE et al. Ann Intern Med. 2019 Feb 4. doi: 10.7326/M18-2736.

Specially formulated topical pain creams are no better than placebo creams for relieving localized chronic pain, according to results from a double-blind, randomized, placebo-controlled trial.

nebari/ThinkStock

Study authors led by Robert E. Brutcher, PharmD, PhD, of Walter Reed National Military Medical Center in Bethesda, Md., said their findings published Feb. 4 in Annals of Internal Medicine suggest compounded pain creams should not be routinely used for chronic pain conditions.

The researchers noted that the use of compounded topical pain creams has increased dramatically despite “weak evidence” supporting their efficacy to treat localized pain, and this is particularly the case in military personnel, where the authors said treatments without central effect may be particularly beneficial because “opioid therapy may render a service member nondeployable and medications that affect the central nervous system may have a negative effect on judgment and motor skills.”

They noted a report from the U.S. Government Accountability Office that showed Tricare’s pharmacy benefits program paid $259 million for compounded medications in the 2013 fiscal year, a figure that increased to $746 million in 2014.

“The soaring costs, coupled with sparse efficacy data prompted the Defense Health Agency to evaluate this issue,” they wrote.

The objectives of the current study were to assess the efficacy of compounded pain creams for chronic pain conditions and determine whether efficacy differed for the various pain classifications.

“We hypothesized that, compared with placebo, compounded topical pain creams would provide greater pain relief and functional improvement,” they said.

The randomized trial involved 133 patients diagnosed with neuropathic pain, 133 with nociceptive pain, and 133 with mixed pain who had attended pain clinics at Walter Reed. Patients were aged between 18 and 90 years and had localized pain in the face, back or buttocks, neck, abdomen, chest, groin, or in up to two extremities. To be included in the study, they were also required to have an average pain score of 4 or greater on a 0- to 10-point numerical rating scale during the preceding week and have symptoms lasting longer than 6 weeks.

Patients in all three pain subgroups were randomized in a 1:1 ratio to receive either a compounded pain cream or a placebo cream. The authors noted that their “pain cream formulations were selected on the basis of accepted systemic indications for neuropathic and nociceptive pain.”

The formulation given to participants with neuropathic pain (n = 68) contained 10% ketamine, 6% gabapentin, 0.2% clonidine, and 2% lidocaine. The patients with nociceptive pain (n = 66) received a cream with 10% ketoprofen, 2% baclofen, 2% cyclobenzaprine, and 2% lidocaine. Those with mixed pain (n = 68) were given a cream containing 10% ketamine, 6% gabapentin, 3% diclofenac, 2% baclofen, 2% cyclobenzaprine, and 2% lidocaine. The authors said the concentrations of individual medications were based on previous trials that evaluated topical use.

The patients, who had a mean age across the groups that ranged from 48 to 57 years, applied cream to affected areas three times per day, with the amount dispensed determined by the size of the area experiencing pain. About half of the patients were women.

The primary outcome measures were an average pain score 1 month after treatment. A positive categorical response was a reduction in pain score of 2 or more points coupled with a score above 3 on a 5-point satisfaction scale. Secondary outcomes included Short Form-36 Health Survey scores, satisfaction, and categorical response. Participants with a positive outcome were followed to 3 months.

Change in the primary outcome of average pain score at 1 month did not differ between the active cream and placebo groups for any type of pain classification. The change was only –0.1 points (95% confidence interval, –0.8 to 0.5 points) for neuropathic pain, –0.3 points (95% CI, –0.9 to 0.2 points) for nociceptive pain, and –0.3 points (95% CI, –0.9 to 0.2 points) for mixed pain.

Among all patients combined, an overall change in average pain scores of –0.3 points (95% CI, –0.6 to 0.1 points) that favored the active-ingredient cream also did not differ between the treatment and placebo groups.

“The lower 95% confidence bounds for the 1-month between-group differences were all 0.9 points or less and excluded clinically meaningful benefits with the compounded topical pain cream,” the authors wrote.

Secondary outcomes also did not differ between the two study groups for any type of pain classification or for the entire cohort.

“Although participants in both treatment and control groups had improvement in their pain throughout the study, no significant differences were observed in pain scores, functional improvement, or satisfaction in the cohort or in any subgroup,” the authors concluded.

They noted that their findings were consistent with previous studies that also showed a lack of efficacy for most topical pain creams.

While some randomized trials have suggested positive findings for capsaicin, lidocaine, and NSAIDs, the authors noted that they did not find a similar benefit in their study population.

“Administered as stand-alone agents, lidocaine and NSAIDs may alleviate pain, although the effect size is small and the number needed to treat is large,” they wrote.

“Considering the increased costs of using a non–FDA-approved and regulated compounded cream rather than a single agent, we caution against routine use of compounded creams for chronic pain,” they wrote.

They noted that their study had several limitations, including that conventional treatments had failed in some of the participants before they enrolled in the study, increasing the likelihood that subsequent therapy would not be effective.

The authors suggested that future studies should aim to establish whether targeting specific types of pain or adding other agents like dimethyl sulfoxide would result in better outcomes.

The Centers for Rehabilitation Sciences Research in the U.S. Department of Defense’s Defense Health Agency funded the study. Two authors reported receiving grants and personal fees from several pharmaceutical companies.

SOURCE: Brutcher RE et al. Ann Intern Med. 2019 Feb 4. doi: 10.7326/M18-2736.

Specially formulated topical pain creams are no better than placebo creams for relieving localized chronic pain, according to results from a double-blind, randomized, placebo-controlled trial.

nebari/ThinkStock

Study authors led by Robert E. Brutcher, PharmD, PhD, of Walter Reed National Military Medical Center in Bethesda, Md., said their findings published Feb. 4 in Annals of Internal Medicine suggest compounded pain creams should not be routinely used for chronic pain conditions.

The researchers noted that the use of compounded topical pain creams has increased dramatically despite “weak evidence” supporting their efficacy to treat localized pain, and this is particularly the case in military personnel, where the authors said treatments without central effect may be particularly beneficial because “opioid therapy may render a service member nondeployable and medications that affect the central nervous system may have a negative effect on judgment and motor skills.”

They noted a report from the U.S. Government Accountability Office that showed Tricare’s pharmacy benefits program paid $259 million for compounded medications in the 2013 fiscal year, a figure that increased to $746 million in 2014.

“The soaring costs, coupled with sparse efficacy data prompted the Defense Health Agency to evaluate this issue,” they wrote.

The objectives of the current study were to assess the efficacy of compounded pain creams for chronic pain conditions and determine whether efficacy differed for the various pain classifications.

“We hypothesized that, compared with placebo, compounded topical pain creams would provide greater pain relief and functional improvement,” they said.

The randomized trial involved 133 patients diagnosed with neuropathic pain, 133 with nociceptive pain, and 133 with mixed pain who had attended pain clinics at Walter Reed. Patients were aged between 18 and 90 years and had localized pain in the face, back or buttocks, neck, abdomen, chest, groin, or in up to two extremities. To be included in the study, they were also required to have an average pain score of 4 or greater on a 0- to 10-point numerical rating scale during the preceding week and have symptoms lasting longer than 6 weeks.

Patients in all three pain subgroups were randomized in a 1:1 ratio to receive either a compounded pain cream or a placebo cream. The authors noted that their “pain cream formulations were selected on the basis of accepted systemic indications for neuropathic and nociceptive pain.”

The formulation given to participants with neuropathic pain (n = 68) contained 10% ketamine, 6% gabapentin, 0.2% clonidine, and 2% lidocaine. The patients with nociceptive pain (n = 66) received a cream with 10% ketoprofen, 2% baclofen, 2% cyclobenzaprine, and 2% lidocaine. Those with mixed pain (n = 68) were given a cream containing 10% ketamine, 6% gabapentin, 3% diclofenac, 2% baclofen, 2% cyclobenzaprine, and 2% lidocaine. The authors said the concentrations of individual medications were based on previous trials that evaluated topical use.

The patients, who had a mean age across the groups that ranged from 48 to 57 years, applied cream to affected areas three times per day, with the amount dispensed determined by the size of the area experiencing pain. About half of the patients were women.

The primary outcome measures were an average pain score 1 month after treatment. A positive categorical response was a reduction in pain score of 2 or more points coupled with a score above 3 on a 5-point satisfaction scale. Secondary outcomes included Short Form-36 Health Survey scores, satisfaction, and categorical response. Participants with a positive outcome were followed to 3 months.

Change in the primary outcome of average pain score at 1 month did not differ between the active cream and placebo groups for any type of pain classification. The change was only –0.1 points (95% confidence interval, –0.8 to 0.5 points) for neuropathic pain, –0.3 points (95% CI, –0.9 to 0.2 points) for nociceptive pain, and –0.3 points (95% CI, –0.9 to 0.2 points) for mixed pain.

Among all patients combined, an overall change in average pain scores of –0.3 points (95% CI, –0.6 to 0.1 points) that favored the active-ingredient cream also did not differ between the treatment and placebo groups.

“The lower 95% confidence bounds for the 1-month between-group differences were all 0.9 points or less and excluded clinically meaningful benefits with the compounded topical pain cream,” the authors wrote.

Secondary outcomes also did not differ between the two study groups for any type of pain classification or for the entire cohort.

“Although participants in both treatment and control groups had improvement in their pain throughout the study, no significant differences were observed in pain scores, functional improvement, or satisfaction in the cohort or in any subgroup,” the authors concluded.

They noted that their findings were consistent with previous studies that also showed a lack of efficacy for most topical pain creams.

While some randomized trials have suggested positive findings for capsaicin, lidocaine, and NSAIDs, the authors noted that they did not find a similar benefit in their study population.

“Administered as stand-alone agents, lidocaine and NSAIDs may alleviate pain, although the effect size is small and the number needed to treat is large,” they wrote.

“Considering the increased costs of using a non–FDA-approved and regulated compounded cream rather than a single agent, we caution against routine use of compounded creams for chronic pain,” they wrote.

They noted that their study had several limitations, including that conventional treatments had failed in some of the participants before they enrolled in the study, increasing the likelihood that subsequent therapy would not be effective.

The authors suggested that future studies should aim to establish whether targeting specific types of pain or adding other agents like dimethyl sulfoxide would result in better outcomes.

The Centers for Rehabilitation Sciences Research in the U.S. Department of Defense’s Defense Health Agency funded the study. Two authors reported receiving grants and personal fees from several pharmaceutical companies.

SOURCE: Brutcher RE et al. Ann Intern Med. 2019 Feb 4. doi: 10.7326/M18-2736.

What makes us pull a hand away from a hot stove or flinch at a pinprick? Researchers from the National Center for Complementary and Integrative Health say they have identified activity in the brain that governs these reactions.

Alexander Chesler, PhD, senior author of the study, says we already know a lot about local spinal cord circuits for simple reflexive responses, but “the mechanisms underlying more complex behaviors remain poorly understood.”

Using heat as the source of discomfort in their experiments, the researchers found a predictable sequence of behaviors—likened to the sequence of responding to walking cautiously on a hot beach, then hopping as the heat intensifies, then running to a water source. “This kind of ‘feed-forward’ circuitry is unique because it is an upward spiral,” says Arnab Barik, PhD, one of the study authors. “The more this pathway is activated by harmful activity, the more it reacts, leading to dramatic behavioral responses.”

The experiments showed that the parts of the brainstem involved in this circuit are the parabrachial nucleus (PBNI) and the dorsal reticular formation in the medulla (MdD). Standing on a hot surface activated a group of nerve cells in the PBNI, triggering escape responses through connections to the MdD. Interestingly, the PBNI cells express a gene that codes for substances that also contribute to multiple disease processes.

“Our data provide evidence that the PBNI produces streams of information with distinct functional significance,” says Arnab Barik, PhD, one of the study authors. “The brainstem-spinal cord pathway identified in this study selectively controls pain response and elicits appropriate behaviors based on sensory input.”

Further investigation, the researchers say, can help us understand how pain is encoded in the brain. The study findings may also offer opportunities to understand how the body becomes dysregulated during chronic pain.

What makes us pull a hand away from a hot stove or flinch at a pinprick? Researchers from the National Center for Complementary and Integrative Health say they have identified activity in the brain that governs these reactions.

Alexander Chesler, PhD, senior author of the study, says we already know a lot about local spinal cord circuits for simple reflexive responses, but “the mechanisms underlying more complex behaviors remain poorly understood.”

Using heat as the source of discomfort in their experiments, the researchers found a predictable sequence of behaviors—likened to the sequence of responding to walking cautiously on a hot beach, then hopping as the heat intensifies, then running to a water source. “This kind of ‘feed-forward’ circuitry is unique because it is an upward spiral,” says Arnab Barik, PhD, one of the study authors. “The more this pathway is activated by harmful activity, the more it reacts, leading to dramatic behavioral responses.”

The experiments showed that the parts of the brainstem involved in this circuit are the parabrachial nucleus (PBNI) and the dorsal reticular formation in the medulla (MdD). Standing on a hot surface activated a group of nerve cells in the PBNI, triggering escape responses through connections to the MdD. Interestingly, the PBNI cells express a gene that codes for substances that also contribute to multiple disease processes.

“Our data provide evidence that the PBNI produces streams of information with distinct functional significance,” says Arnab Barik, PhD, one of the study authors. “The brainstem-spinal cord pathway identified in this study selectively controls pain response and elicits appropriate behaviors based on sensory input.”

Further investigation, the researchers say, can help us understand how pain is encoded in the brain. The study findings may also offer opportunities to understand how the body becomes dysregulated during chronic pain.

What makes us pull a hand away from a hot stove or flinch at a pinprick? Researchers from the National Center for Complementary and Integrative Health say they have identified activity in the brain that governs these reactions.

Alexander Chesler, PhD, senior author of the study, says we already know a lot about local spinal cord circuits for simple reflexive responses, but “the mechanisms underlying more complex behaviors remain poorly understood.”

Using heat as the source of discomfort in their experiments, the researchers found a predictable sequence of behaviors—likened to the sequence of responding to walking cautiously on a hot beach, then hopping as the heat intensifies, then running to a water source. “This kind of ‘feed-forward’ circuitry is unique because it is an upward spiral,” says Arnab Barik, PhD, one of the study authors. “The more this pathway is activated by harmful activity, the more it reacts, leading to dramatic behavioral responses.”

The experiments showed that the parts of the brainstem involved in this circuit are the parabrachial nucleus (PBNI) and the dorsal reticular formation in the medulla (MdD). Standing on a hot surface activated a group of nerve cells in the PBNI, triggering escape responses through connections to the MdD. Interestingly, the PBNI cells express a gene that codes for substances that also contribute to multiple disease processes.

“Our data provide evidence that the PBNI produces streams of information with distinct functional significance,” says Arnab Barik, PhD, one of the study authors. “The brainstem-spinal cord pathway identified in this study selectively controls pain response and elicits appropriate behaviors based on sensory input.”

Further investigation, the researchers say, can help us understand how pain is encoded in the brain. The study findings may also offer opportunities to understand how the body becomes dysregulated during chronic pain.

SAN DIEGO – There are many potential treatments for fibromyalgia, but a large number of them – NSAIDs, opioids, cannabis and more – come with caveats and nothing beats an old stand-by: physical rehabilitation.

With exercise, “we’re getting the muscles moving, and we’re getting [patients] used to stimulation that will hopefully deaden that pain response over time,” David E.J. Bazzo, MD, said at Pain Care for Primary Care. Still, “it’s going to take multiple things to best treat your patients.”

Fibromyalgia is unique, said Dr. Bazzo, professor of family medicine and public health at the University of California, San Diego. Diagnosis is based on self-reported symptoms since no laboratory tests are available. For diagnostic criteria, he recommends those released by the American College of Rheumatology in 2010 and 2011 and updated in 2016. The criteria, he said, recognize the importance of cognitive symptoms, unrefreshing sleep, fatigue, and certain somatic symptoms (Semin Arthritis Rheum. 2016;46[3]:319-29).

Poor sleep is an especially important problem in fibromyalgia, Dr. Bazzo said, although it’s “a bit of a chicken-and-egg discussion.” It’s not clear which comes first, but “we know that both happen hand-in-hand. We need to work on people’s sleep as one of the primary targets.”

When it comes to treatment, “you have to validate this person’s symptoms and say, ‘Yes, I believe you. I know that you are suffering, and that you’re having pain,’ ” Dr. Bazzo said at the meeting held by the American Pain Society and Global Academy for Medical Education. He advised clinicians to keep in mind conditions that can accompany fibromyalgia, such as depression, that may require other treatment options.

Dr. Bazzo offered advice about these approaches to treatment:

• Exercise. Research supports treadmill and cycle ergometry (BMJ 2002;325:185).
• Opioids. “There’s no convincing evidence that opioids have a role in treating fibromyalgia initially. If you’ve tried everything and patients have had problems, are just not responsive or had side effects, you could consider opioids. But that should be at the tail end of everything because the data is not there,” he said.
• Tramadol. “It’s like an opioid with potential for addiction,” he said. “Don’t just use it willy-nilly. Make sure you have a reason and a good plan. Would it be my first thing? No. Is it something that I keep in my back pocket when other things aren’t working? Perhaps. Would I use it before an opioid? For sure.”
• Second-line therapies. According to Dr. Bazzo, these include antiepileptics such as gabapentin and pregabalin, low-dose cyclobenzaprine, and dual reuptake inhibitors such as duloxetine. There are many other second-line options, he said, from behavioral approaches to yoga to guided physical therapy.
• NSAIDs. Not helpful.
• Cannabis. May interact with other medications.
• Pain clinics. Make sure you refer patients to a pain clinic that embraces a multidisciplinary approach, he said, not one that only offers “pain pills or shots.”

Dr. Bazzo reported no relevant conflicts of interest. The Global Academy for Medical Education and this news organization are owned by the same parent company.

SAN DIEGO – There are many potential treatments for fibromyalgia, but a large number of them – NSAIDs, opioids, cannabis and more – come with caveats and nothing beats an old stand-by: physical rehabilitation.

With exercise, “we’re getting the muscles moving, and we’re getting [patients] used to stimulation that will hopefully deaden that pain response over time,” David E.J. Bazzo, MD, said at Pain Care for Primary Care. Still, “it’s going to take multiple things to best treat your patients.”

Fibromyalgia is unique, said Dr. Bazzo, professor of family medicine and public health at the University of California, San Diego. Diagnosis is based on self-reported symptoms since no laboratory tests are available. For diagnostic criteria, he recommends those released by the American College of Rheumatology in 2010 and 2011 and updated in 2016. The criteria, he said, recognize the importance of cognitive symptoms, unrefreshing sleep, fatigue, and certain somatic symptoms (Semin Arthritis Rheum. 2016;46[3]:319-29).

Poor sleep is an especially important problem in fibromyalgia, Dr. Bazzo said, although it’s “a bit of a chicken-and-egg discussion.” It’s not clear which comes first, but “we know that both happen hand-in-hand. We need to work on people’s sleep as one of the primary targets.”

When it comes to treatment, “you have to validate this person’s symptoms and say, ‘Yes, I believe you. I know that you are suffering, and that you’re having pain,’ ” Dr. Bazzo said at the meeting held by the American Pain Society and Global Academy for Medical Education. He advised clinicians to keep in mind conditions that can accompany fibromyalgia, such as depression, that may require other treatment options.

Dr. Bazzo offered advice about these approaches to treatment:

• Exercise. Research supports treadmill and cycle ergometry (BMJ 2002;325:185).
• Opioids. “There’s no convincing evidence that opioids have a role in treating fibromyalgia initially. If you’ve tried everything and patients have had problems, are just not responsive or had side effects, you could consider opioids. But that should be at the tail end of everything because the data is not there,” he said.
• Tramadol. “It’s like an opioid with potential for addiction,” he said. “Don’t just use it willy-nilly. Make sure you have a reason and a good plan. Would it be my first thing? No. Is it something that I keep in my back pocket when other things aren’t working? Perhaps. Would I use it before an opioid? For sure.”
• Second-line therapies. According to Dr. Bazzo, these include antiepileptics such as gabapentin and pregabalin, low-dose cyclobenzaprine, and dual reuptake inhibitors such as duloxetine. There are many other second-line options, he said, from behavioral approaches to yoga to guided physical therapy.
• NSAIDs. Not helpful.
• Cannabis. May interact with other medications.
• Pain clinics. Make sure you refer patients to a pain clinic that embraces a multidisciplinary approach, he said, not one that only offers “pain pills or shots.”

Dr. Bazzo reported no relevant conflicts of interest. The Global Academy for Medical Education and this news organization are owned by the same parent company.

SAN DIEGO – There are many potential treatments for fibromyalgia, but a large number of them – NSAIDs, opioids, cannabis and more – come with caveats and nothing beats an old stand-by: physical rehabilitation.

With exercise, “we’re getting the muscles moving, and we’re getting [patients] used to stimulation that will hopefully deaden that pain response over time,” David E.J. Bazzo, MD, said at Pain Care for Primary Care. Still, “it’s going to take multiple things to best treat your patients.”

Fibromyalgia is unique, said Dr. Bazzo, professor of family medicine and public health at the University of California, San Diego. Diagnosis is based on self-reported symptoms since no laboratory tests are available. For diagnostic criteria, he recommends those released by the American College of Rheumatology in 2010 and 2011 and updated in 2016. The criteria, he said, recognize the importance of cognitive symptoms, unrefreshing sleep, fatigue, and certain somatic symptoms (Semin Arthritis Rheum. 2016;46[3]:319-29).

Poor sleep is an especially important problem in fibromyalgia, Dr. Bazzo said, although it’s “a bit of a chicken-and-egg discussion.” It’s not clear which comes first, but “we know that both happen hand-in-hand. We need to work on people’s sleep as one of the primary targets.”

When it comes to treatment, “you have to validate this person’s symptoms and say, ‘Yes, I believe you. I know that you are suffering, and that you’re having pain,’ ” Dr. Bazzo said at the meeting held by the American Pain Society and Global Academy for Medical Education. He advised clinicians to keep in mind conditions that can accompany fibromyalgia, such as depression, that may require other treatment options.

Dr. Bazzo offered advice about these approaches to treatment:

• Exercise. Research supports treadmill and cycle ergometry (BMJ 2002;325:185).
• Opioids. “There’s no convincing evidence that opioids have a role in treating fibromyalgia initially. If you’ve tried everything and patients have had problems, are just not responsive or had side effects, you could consider opioids. But that should be at the tail end of everything because the data is not there,” he said.
• Tramadol. “It’s like an opioid with potential for addiction,” he said. “Don’t just use it willy-nilly. Make sure you have a reason and a good plan. Would it be my first thing? No. Is it something that I keep in my back pocket when other things aren’t working? Perhaps. Would I use it before an opioid? For sure.”
• Second-line therapies. According to Dr. Bazzo, these include antiepileptics such as gabapentin and pregabalin, low-dose cyclobenzaprine, and dual reuptake inhibitors such as duloxetine. There are many other second-line options, he said, from behavioral approaches to yoga to guided physical therapy.
• NSAIDs. Not helpful.
• Cannabis. May interact with other medications.
• Pain clinics. Make sure you refer patients to a pain clinic that embraces a multidisciplinary approach, he said, not one that only offers “pain pills or shots.”

Dr. Bazzo reported no relevant conflicts of interest. The Global Academy for Medical Education and this news organization are owned by the same parent company.

Approximately 55 years ago, tricyclic antidepressants (TCAs) began to be used to treat neuropathic pain.¹ Eventually, clinical trials emerged suggesting the utility of TCAs for other chronic pain conditions, such as fibromyalgia (FM) and migraine prophylaxis. However, despite TCAs’ effectiveness in mitigating painful conditions, their adverse effects limited their use.

Pharmacologic advancements have led to the development of other antidepressant classes, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), and the use of these agents has come to eclipse that of TCAs. In the realm of pain management, such developments have raised the hope of possible alternative co-analgesic agents that could avoid the adverse effects associated with TCAs. Some of these agents have demonstrated efficacy for managing chronic pain states, while others have demonstrated only limited utility.

This article provides a synopsis of systematic reviews and meta-analyses examining the role of antidepressant therapy for managing several chronic pain conditions, including pain associated with neuropathy, FM, headache, and irritable bowel syndrome (IBS). Because the literature base is rapidly evolving, it is necessary to revisit the information gleaned from clinical data with respect to treatment effectiveness, and to clarify how antidepressants might be positioned in the management of chronic pain.

The effectiveness of antidepressants for pain

The pathophysiologic processes that precipitate and maintain chronic pain conditions are complex (Box 1^2-10). The pain-mitigating effects of antidepressants can be thought of in terms of direct analgesic effects and indirect effects (Box 2^{2,3,8,10,11-33}).

Box 1

During the last several decades, anti­depressants have been used to address—and have demonstrated clinical utility for—a variety of chronic pain states. However, antidepressants are not a panacea; some chronic pain conditions are more responsive to antidepressants than are others. The chronic painful states most amenable to antidepressants are those that result primarily from a process of neural sensitization, as opposed to acute somatic or visceral nociception. Hence, several meta-analyses and evidence-based reviews have long suggested the usefulness of antidepressants for mitigating pain associated with neuropathy,^34,35 FM,^36,37 headache,³⁸ and IBS.^39,40

Box 2

Continue to: Neuropathic pain

Several treatment guidelines advocate for the use of antidepressants for neuropathic pain.^41-44 For decades, TCAs have been employed off-label to successfully treat many patients with neuropathic pain states. Early investigations suggested that TCAs were robustly efficacious in managing patients with neuropathy.^45-48 Calculated number-needed-to-treat (NNT) values for TCAs were quite low (ie, reflecting that few patients would need to be treated to yield a positive response in one patient compared with placebo), and were comparable to, if not slightly better than, the NNTs generated for anticonvulsants and α2-δ ligands, such as gabapentin or pregabalin.^45-48

Unfortunately, early studies involving TCAs conducted many years ago do not meet contemporary standards of methodological rigor; they featured relatively small samples of patients assessed for brief post-treatment intervals with variable outcome measures. Thus, the NNT values obtained in meta-analyses based on these studies may overestimate treatment benefits.⁴⁹ Further, NNT values derived from meta-analyses tended to combine all drugs within a particular antidepressant class (eg, amitriptyline, nortriptyline, desipramine, and imipramine among the TCAs) employed at diverse doses. Taken together, these limitations raise questions about the results of those meta-analyses.

Subsequent meta-analyses, which employed strict criteria to eliminate data from studies with potential sources of bias and used a primary outcome of frequencies of patients reporting at least 30% pain reduction compared with a placebo-controlled sample, suggest that the effectiveness of TCAs as a class for treating neuropathic pain is not as compelling as once was thought. Meta-analyses of studies employing specific TCAs revealed that there was little evidence to support the use of desipramine,⁵⁰ imipramine,⁵¹ or nortriptyline⁵² in managing diabetic neuropathy or postherpetic neuralgia. Studies evaluating amitriptyline (dose range 12.5 to 150 mg/d), found low-level evidence of effectiveness; the benefit was expected to be present for a small subset (approximately 25%) of patients with neuropathic pain.⁵³

There is moderate-quality evidence that duloxetine (60 to 120 mg/d) can produce a ≥50% improvement in pain severity ratings among patients with diabetic peripheral neuropathy.⁵⁴ Although head-to-head studies with other antidepressants are limited, it appears that duloxetine and amitriptyline have comparable efficacy, even though the NNTs for amitriptyline were derived from lower-quality studies than those for duloxetine. Duloxetine is the only antidepressant to receive FDA approval for managing diabetic neuropathy. By contrast, studies assessing the utility of venlafaxine in neuropathic pain comprised small samples for brief durations, which limits the ability to draw clear (unbiased) support for its usefulness.⁵⁵

Given the diversity of pathophysiologic processes underlying the disturbances that cause neuropathic pain disorders, it is unsurprising that the effectiveness of amitriptyline and duloxetine were not generalizable to all neuropathic pain states. Although amitriptyline produced pain-mitigating effects in patients with diabetic neuropathy and post-herpetic neuralgia, and duloxetine mitigated pain among patients with diabetic neuropathy, there was no evidence to suggest their effectiveness in phantom limb pain or human immunodeficiency virus-related and spinal cord-related neuropathies.^{35,53,54,56-58}

Continue to: Fibromyalgia

As with the issues encountered in interpreting the effectiveness of antidepressants in neuropathic pain, interpreting results gleaned from clinical trials of antidepressants for treating FM are fraught with similar difficulties. Although amitriptyline has been a first-line treatment for FM for many years, the evidence upon which such recommendations were based consisted of low-level studies that had a significant potential for bias.⁵⁹ Large randomized trials would offer more compelling data regarding the efficacy of amitriptyline, but the prohibitive costs of such studies makes it unlikely they will be conducted. Amitriptyline (25 to 50 mg/d) was effective in mitigating FM-related pain in a small percentage of patients studied, with an estimated NNT of 4.⁵⁹ Adverse effects, often contributing to treatment discontinuation, were encountered more frequently among patients who received amitriptyline compared with placebo.

Selective serotonin reuptake inhibitors failed to demonstrate significant pain relief (estimated NNT of 10), or improvement in fatigue or sleep problems, even though the studies upon which such conclusions were based were low-level studies with a high potential for bias.⁶⁰ Although SSRIs have limited utility for mitigating pain, they are still quite useful for reducing depression among patients with FM.⁶⁰

By contrast, the SNRIs duloxetine and milnacipran provided clinically relevant benefit over placebo in the frequency of patients reporting pain relief of ≥30%, as well as patients’ global impression of change.⁶¹ These agents, however, failed to provide clinically relevant benefit over placebo in improving health-related quality of life, reducing sleep problems, or improving fatigue. Nonetheless, duloxetine and milnacipran are FDA-approved for managing pain in FM. Studies assessing the efficacy of venlafaxine in the treatment of FM to date have been limited by small sample sizes, inconsistent dosing, lack of a placebo control, and lack of blinding, which limits the ability to clearly delineate the role of venlafaxine in managing FM.⁶²

Mirtazapine (15 to 45 mg/d) showed a clinically relevant benefit compared with placebo for participant-reported pain relief of ≥30% and sleep disturbances. There was no benefit in terms of participant-reported improvement of quality of life, fatigue, or negative mood.⁶³ The evidence was considered to be of low quality overall.

Headache

Amitriptyline has been employed off-label to address headache prophylaxis since 1964.⁶⁴ Compared with placebo, it is efficacious in ameliorating migraine frequency and intensity as well as the frequency of tension headache.^65,66 However, SSRIs and SNRIs (venlafaxine) failed to produce significant reductions in migraine frequency or severity or the frequencies of tension headache when compared with placebo.^67,68

Continue to: Irritable bowel syndrome

Early studies addressing antidepressant efficacy in IBS reveal inconsistencies. For example, whereas some suggest that TCAs are effective in mitigating chronic, severe abdominal pain,^39,40 others concluded that TCAs failed to demonstrate a significant analgesic benefit.⁶⁹ A recent meta-analysis that restricted analysis of efficacy to randomized controlled trials (RCTs) with more rigorous methodological adherence found that pain relief in IBS is possible with both TCAs as well as SSRIs. However, adverse effects were more commonly encountered with TCAs than with SSRIs. Some of the inconsistencies in treatment efficacy reported in early studies may be due to variations in responsiveness of subsets of IBS patients. Specifically, the utility of TCAs appears to be best among patients with diarrheal-type (as opposed to constipation-type) IBS, presumably due to TCAs’ anticholinergic effects, whereas SSRIs may provide more of a benefit for patients with predominantly constipation-type IBS.^40,70

Other chronic pain conditions

Antidepressants have been used to assist in the management of several other pain conditions, including oral-facial pain, interstitial cystitis, non-cardiac chest pain, and others. The role of antidepressants for such conditions remains unclear due to limitations in the prevailing empirical work, such as few trials, small sample sizes, variations in outcome measures, and insufficient randomization and blinding.^71-76 The interpretation of results from systematic reviews and meta-analyses is limited because of these shortcomings.⁷⁷ Hence, it has not always been possible to determine whether, and to what extent, patients with such conditions may benefit from antidepressants.

Neuromodulatory effects and efficacy for pain

The interplay of norepinephrine (NE) and serotonin (5-HT) neurotransmitter systems and cellular mechanisms involved in the descending modulation of pain pathways is complex. Experimental animal models of pain modulation suggest that 5-HT can both inhibit as well as promote pain perception by different physiological mechanisms, in contrast to NE, which is predominately inhibitory. While 5-HT in the descending modulating system can inhibit pain transmission ascending to the brain from the periphery, it appears that an intact noradrenergic system is necessary for the inhibitory influences of the serotonergic system to be appreciated.^16,78,79 Deficiencies in one or both of these neurotransmitter systems may contribute to hyperactive pain processing, and thereby precipitate or maintain chronic pain.

Pain mitigation may be achieved best by enhancing both neurotransmitters simultaneously, less so by enhancing NE alone, and least by enhancing 5-HT alone.⁶ The ability to impact pain modulation would, therefore, depend on the degree to which an antidepressant capitalizes on both noradrenergic and serotonergic neurotransmission. Antidepressants commonly employed to manage pain are presented in Table 1^{47,60,68,80-88} according to their primary neurotransmitter effects. Thus, the literature summarized above suggests that antidepressants that influence both NE and 5-HT transmission have greater analgesic effects than antidepressants with more specific effects, such as influencing 5-HT reuptake alone.^80-85 It is unsurprising, therefore, that the SSRIs have not been demonstrated to be as consistently analgesic.^{47,60,68,80,86-88}

Similarly, pharmacodynamic and pharmacokinetic differences within antidepressant classes may influence analgesic effectiveness. Simultaneous effects on NE and 5-HT are achieved at low doses with duloxetine and milnacipran. By contrast, 5-HT effects predominate at low doses for venlafaxine. To achieve pain-mitigating effects, higher doses of venlafaxine generally are required.⁸⁹ Therefore, inconsistencies across studies regarding the analgesic benefits of venlafaxine may be attributable to variability in dosing; patients treated with lower doses may not have experienced sufficient NE effects to garner positive results.

Continue to: The differences in analgesic efficacy...

The differences in analgesic efficacy among specific TCAs may be understood in a similar fashion. Specifically, tertiary TCAs (imipramine and amitriptyline) inhibit both 5-HT and NE reuptake.^6,90 Secondary amines (desipramine and nortriptyline) predominantly impact NE reuptake, possibly accounting for the lesser pain-mitigating benefit achieved with these agents, such as for treating neuro­pathic pain. Further, in vivo imipramine and amitriptyline are rapidly metabolized to secondary amines that are potent and selective NE reuptake inhibitors. In this way, the secondary amines may substantially lose the ability to modulate pain transmission because of the loss of concurrent 5-HT influences.⁹⁰

Clinical pearls

The following practical points can help guide clinicians regarding the usefulness of antidepressants for pain management:

• Antidepressants can alleviate symptoms of depression and pain. The pain-mitigating effects of antidepressants are possible even among chronic pain patients who are not depressed. Antidepressants may confer benefits for chronic pain patients with depression and other comorbid conditions, such as somatic symptom and related disorders.
• Antidepressants are useful for select chronic pain states. Although the noradrenergic and serotonergic antidepressants (SNRIs and, to some extent, amitriptyline) appear to have efficacy for neuropathic pain and FM, the benefits of SSRIs appear to be less robust. On the other hand, SSRIs and TCAs may have potential benefit for patients with IBS. However, the results of meta-analyses are limited in the ability to provide information about which patients will best respond to which specific antidepressant or how well. Future research directed at identifying characteristics that can predict which patients are likely to benefit from one antidepressant vs another would help inform how best to tailor treatment to individual needs.
• The pain-mitigating effects of antidepressants often emerge early in the course of treatment (often before mood-elevating effects are observed). For example, in the case of amitriptyline, pain relief may be possible for some patients at doses generally lower than those required for mood-elevating effects. To date, there is limited information in the literature to determine what constitutes a sufficient duration of treatment, or when treatment should be modified.
• Failure to reduce pain should raise questions about whether the dose should be increased, an alternative agent should be tried, or combinations with other analgesic agents should be considered. Failure to achieve pain-mitigating effects with one antidepressant does not mean failure with others. Hence, failure to achieve desired effects with one agent might warrant an empirical trial with another agent. Presently, too few double-blind RCTs have been conducted to assess the pain-mitigating effects of other antidepressants (eg, bupropion and newer SNRIs such as desvenlafaxine and levomilnacipran). Meta-analysis of the analgesic effectiveness of these agents or comparisons to the efficacy of other antidepressant classes is, therefore, impossible at this time.

Because many chronic pain states are complex, patients will seldom experience clinically relevant benefit from any one intervention.⁵³ The bigger implication for clinical research is to determine whether there is a sequence or combination of medication use that will provide overall better clinical effectiveness.⁵³ Only limited data are available exploring the utility of combining pharmacologic approaches to address pain.⁹¹ For example, preliminary evidence suggests that combinations of complementary strategies, such as duloxetine combined with pregabalin, may result in significantly greater numbers of FM patients achieving ≥30% pain reduction compared with monotherapy with either agent alone or placebo.⁹²

• Antidepressant selection may need to be based on medication-related adverse effect profiles and the potential for drug interactions. These factors are useful to consider in delineating multimodal treatment regimens for chronic pain in light of patients’ comorbidities and co-medication regimen. For example, the adverse effects of TCAs (anticholinergic and alpha-adrenergic influences) limit their utility for treating pain. Some of these effects can be more problematic in select populations, such as older adults or those with orthostatic difficulties, among others. TCAs are contraindicated in patients with closed-angle glaucoma, recent myocardial infarction, cardiac arrhythmias, poorly controlled seizures, or severe benign prostatic hypertrophy. Although the pain-mitigating effects of SNRIs have not been demonstrated to significantly exceed those of TCAs,^68,93,94 SNRIs would offer an advantage of greater tolerability of adverse effects and relative safety in patients with comorbid medical conditions that would otherwise preclude TCA use. The adverse effects and common drug interactions associated with antidepressants are summarized in Table 2⁹⁵.

Conclusion

Chronic, nonmalignant pain conditions afflict many patients and significantly impair their ability to function. Because of heightened concerns related to the appropriateness of, and restricting inordinate access to, long-term opioid analgesics, clinicians need to explore the usefulness of co-analgesic agents, such as antidepressants. Significant comorbidities exist between psychiatric disorders and chronic pain, and psychiatrists are uniquely positioned to diagnose and treat psychiatric comorbidities, as well as pain, among their patients, especially since they understand the kinetics and dynamics of antidepressants.

Bottom Line

Antidepressants can alleviate symptoms of depression and pain. Noradrenergic and serotonergic antidepressants appear to have efficacy for pain associated with neuropathy and fibromyalgia, while selective serotonin reuptake inhibitors and tricyclic antidepressants may have benefit for patients with irritable bowel syndrome. However, evidence regarding which patients will best respond to which specific antidepressant is limited.

Continue to: Related Resources

• Williams AM, Knox ED. When to prescribe antidepressants to treat comorbid depression and pain disorders. Current Psychiatry. 2017;16(1):55-58.
• Maletic V, Demuri B. Chronic pain and depression: treatment of 2 culprits in common. Current Psychiatry. 2016;15(3):41,47-50,52.

Drug Brand Names

Amitriptyline • Elavil, Endep
Bupropion • Wellbutrin, Zyban
Carisoprodol • Rela, Soma
Cyclobenzaprine • Amrix, Flexeril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Fluoxetine • Prozac
Gabapentin • Horizant, Neurontin
Imipramine • Tofranil
Levomilnacipran • Fetzima
Methadone • Dolophine, Methadose
Milnacipran • Savella
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Pregabalin • Lyrica, Lyrica CR
Tapentadol • Nucynta
Tramadol • Ultram
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Warfarin • Coumadin, Jantoven

Approximately 55 years ago, tricyclic antidepressants (TCAs) began to be used to treat neuropathic pain.¹ Eventually, clinical trials emerged suggesting the utility of TCAs for other chronic pain conditions, such as fibromyalgia (FM) and migraine prophylaxis. However, despite TCAs’ effectiveness in mitigating painful conditions, their adverse effects limited their use.

Pharmacologic advancements have led to the development of other antidepressant classes, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), and the use of these agents has come to eclipse that of TCAs. In the realm of pain management, such developments have raised the hope of possible alternative co-analgesic agents that could avoid the adverse effects associated with TCAs. Some of these agents have demonstrated efficacy for managing chronic pain states, while others have demonstrated only limited utility.

This article provides a synopsis of systematic reviews and meta-analyses examining the role of antidepressant therapy for managing several chronic pain conditions, including pain associated with neuropathy, FM, headache, and irritable bowel syndrome (IBS). Because the literature base is rapidly evolving, it is necessary to revisit the information gleaned from clinical data with respect to treatment effectiveness, and to clarify how antidepressants might be positioned in the management of chronic pain.

The effectiveness of antidepressants for pain

The pathophysiologic processes that precipitate and maintain chronic pain conditions are complex (Box 1^2-10). The pain-mitigating effects of antidepressants can be thought of in terms of direct analgesic effects and indirect effects (Box 2^{2,3,8,10,11-33}).

Box 1

During the last several decades, anti­depressants have been used to address—and have demonstrated clinical utility for—a variety of chronic pain states. However, antidepressants are not a panacea; some chronic pain conditions are more responsive to antidepressants than are others. The chronic painful states most amenable to antidepressants are those that result primarily from a process of neural sensitization, as opposed to acute somatic or visceral nociception. Hence, several meta-analyses and evidence-based reviews have long suggested the usefulness of antidepressants for mitigating pain associated with neuropathy,^34,35 FM,^36,37 headache,³⁸ and IBS.^39,40

Box 2

Continue to: Neuropathic pain

Several treatment guidelines advocate for the use of antidepressants for neuropathic pain.^41-44 For decades, TCAs have been employed off-label to successfully treat many patients with neuropathic pain states. Early investigations suggested that TCAs were robustly efficacious in managing patients with neuropathy.^45-48 Calculated number-needed-to-treat (NNT) values for TCAs were quite low (ie, reflecting that few patients would need to be treated to yield a positive response in one patient compared with placebo), and were comparable to, if not slightly better than, the NNTs generated for anticonvulsants and α2-δ ligands, such as gabapentin or pregabalin.^45-48

Unfortunately, early studies involving TCAs conducted many years ago do not meet contemporary standards of methodological rigor; they featured relatively small samples of patients assessed for brief post-treatment intervals with variable outcome measures. Thus, the NNT values obtained in meta-analyses based on these studies may overestimate treatment benefits.⁴⁹ Further, NNT values derived from meta-analyses tended to combine all drugs within a particular antidepressant class (eg, amitriptyline, nortriptyline, desipramine, and imipramine among the TCAs) employed at diverse doses. Taken together, these limitations raise questions about the results of those meta-analyses.

Subsequent meta-analyses, which employed strict criteria to eliminate data from studies with potential sources of bias and used a primary outcome of frequencies of patients reporting at least 30% pain reduction compared with a placebo-controlled sample, suggest that the effectiveness of TCAs as a class for treating neuropathic pain is not as compelling as once was thought. Meta-analyses of studies employing specific TCAs revealed that there was little evidence to support the use of desipramine,⁵⁰ imipramine,⁵¹ or nortriptyline⁵² in managing diabetic neuropathy or postherpetic neuralgia. Studies evaluating amitriptyline (dose range 12.5 to 150 mg/d), found low-level evidence of effectiveness; the benefit was expected to be present for a small subset (approximately 25%) of patients with neuropathic pain.⁵³

There is moderate-quality evidence that duloxetine (60 to 120 mg/d) can produce a ≥50% improvement in pain severity ratings among patients with diabetic peripheral neuropathy.⁵⁴ Although head-to-head studies with other antidepressants are limited, it appears that duloxetine and amitriptyline have comparable efficacy, even though the NNTs for amitriptyline were derived from lower-quality studies than those for duloxetine. Duloxetine is the only antidepressant to receive FDA approval for managing diabetic neuropathy. By contrast, studies assessing the utility of venlafaxine in neuropathic pain comprised small samples for brief durations, which limits the ability to draw clear (unbiased) support for its usefulness.⁵⁵

Given the diversity of pathophysiologic processes underlying the disturbances that cause neuropathic pain disorders, it is unsurprising that the effectiveness of amitriptyline and duloxetine were not generalizable to all neuropathic pain states. Although amitriptyline produced pain-mitigating effects in patients with diabetic neuropathy and post-herpetic neuralgia, and duloxetine mitigated pain among patients with diabetic neuropathy, there was no evidence to suggest their effectiveness in phantom limb pain or human immunodeficiency virus-related and spinal cord-related neuropathies.^{35,53,54,56-58}

Continue to: Fibromyalgia

As with the issues encountered in interpreting the effectiveness of antidepressants in neuropathic pain, interpreting results gleaned from clinical trials of antidepressants for treating FM are fraught with similar difficulties. Although amitriptyline has been a first-line treatment for FM for many years, the evidence upon which such recommendations were based consisted of low-level studies that had a significant potential for bias.⁵⁹ Large randomized trials would offer more compelling data regarding the efficacy of amitriptyline, but the prohibitive costs of such studies makes it unlikely they will be conducted. Amitriptyline (25 to 50 mg/d) was effective in mitigating FM-related pain in a small percentage of patients studied, with an estimated NNT of 4.⁵⁹ Adverse effects, often contributing to treatment discontinuation, were encountered more frequently among patients who received amitriptyline compared with placebo.

Selective serotonin reuptake inhibitors failed to demonstrate significant pain relief (estimated NNT of 10), or improvement in fatigue or sleep problems, even though the studies upon which such conclusions were based were low-level studies with a high potential for bias.⁶⁰ Although SSRIs have limited utility for mitigating pain, they are still quite useful for reducing depression among patients with FM.⁶⁰

By contrast, the SNRIs duloxetine and milnacipran provided clinically relevant benefit over placebo in the frequency of patients reporting pain relief of ≥30%, as well as patients’ global impression of change.⁶¹ These agents, however, failed to provide clinically relevant benefit over placebo in improving health-related quality of life, reducing sleep problems, or improving fatigue. Nonetheless, duloxetine and milnacipran are FDA-approved for managing pain in FM. Studies assessing the efficacy of venlafaxine in the treatment of FM to date have been limited by small sample sizes, inconsistent dosing, lack of a placebo control, and lack of blinding, which limits the ability to clearly delineate the role of venlafaxine in managing FM.⁶²

Mirtazapine (15 to 45 mg/d) showed a clinically relevant benefit compared with placebo for participant-reported pain relief of ≥30% and sleep disturbances. There was no benefit in terms of participant-reported improvement of quality of life, fatigue, or negative mood.⁶³ The evidence was considered to be of low quality overall.

Headache

Amitriptyline has been employed off-label to address headache prophylaxis since 1964.⁶⁴ Compared with placebo, it is efficacious in ameliorating migraine frequency and intensity as well as the frequency of tension headache.^65,66 However, SSRIs and SNRIs (venlafaxine) failed to produce significant reductions in migraine frequency or severity or the frequencies of tension headache when compared with placebo.^67,68

Continue to: Irritable bowel syndrome

Early studies addressing antidepressant efficacy in IBS reveal inconsistencies. For example, whereas some suggest that TCAs are effective in mitigating chronic, severe abdominal pain,^39,40 others concluded that TCAs failed to demonstrate a significant analgesic benefit.⁶⁹ A recent meta-analysis that restricted analysis of efficacy to randomized controlled trials (RCTs) with more rigorous methodological adherence found that pain relief in IBS is possible with both TCAs as well as SSRIs. However, adverse effects were more commonly encountered with TCAs than with SSRIs. Some of the inconsistencies in treatment efficacy reported in early studies may be due to variations in responsiveness of subsets of IBS patients. Specifically, the utility of TCAs appears to be best among patients with diarrheal-type (as opposed to constipation-type) IBS, presumably due to TCAs’ anticholinergic effects, whereas SSRIs may provide more of a benefit for patients with predominantly constipation-type IBS.^40,70

Other chronic pain conditions

Antidepressants have been used to assist in the management of several other pain conditions, including oral-facial pain, interstitial cystitis, non-cardiac chest pain, and others. The role of antidepressants for such conditions remains unclear due to limitations in the prevailing empirical work, such as few trials, small sample sizes, variations in outcome measures, and insufficient randomization and blinding.^71-76 The interpretation of results from systematic reviews and meta-analyses is limited because of these shortcomings.⁷⁷ Hence, it has not always been possible to determine whether, and to what extent, patients with such conditions may benefit from antidepressants.

Neuromodulatory effects and efficacy for pain

The interplay of norepinephrine (NE) and serotonin (5-HT) neurotransmitter systems and cellular mechanisms involved in the descending modulation of pain pathways is complex. Experimental animal models of pain modulation suggest that 5-HT can both inhibit as well as promote pain perception by different physiological mechanisms, in contrast to NE, which is predominately inhibitory. While 5-HT in the descending modulating system can inhibit pain transmission ascending to the brain from the periphery, it appears that an intact noradrenergic system is necessary for the inhibitory influences of the serotonergic system to be appreciated.^16,78,79 Deficiencies in one or both of these neurotransmitter systems may contribute to hyperactive pain processing, and thereby precipitate or maintain chronic pain.

Pain mitigation may be achieved best by enhancing both neurotransmitters simultaneously, less so by enhancing NE alone, and least by enhancing 5-HT alone.⁶ The ability to impact pain modulation would, therefore, depend on the degree to which an antidepressant capitalizes on both noradrenergic and serotonergic neurotransmission. Antidepressants commonly employed to manage pain are presented in Table 1^{47,60,68,80-88} according to their primary neurotransmitter effects. Thus, the literature summarized above suggests that antidepressants that influence both NE and 5-HT transmission have greater analgesic effects than antidepressants with more specific effects, such as influencing 5-HT reuptake alone.^80-85 It is unsurprising, therefore, that the SSRIs have not been demonstrated to be as consistently analgesic.^{47,60,68,80,86-88}

Similarly, pharmacodynamic and pharmacokinetic differences within antidepressant classes may influence analgesic effectiveness. Simultaneous effects on NE and 5-HT are achieved at low doses with duloxetine and milnacipran. By contrast, 5-HT effects predominate at low doses for venlafaxine. To achieve pain-mitigating effects, higher doses of venlafaxine generally are required.⁸⁹ Therefore, inconsistencies across studies regarding the analgesic benefits of venlafaxine may be attributable to variability in dosing; patients treated with lower doses may not have experienced sufficient NE effects to garner positive results.

Continue to: The differences in analgesic efficacy...

The differences in analgesic efficacy among specific TCAs may be understood in a similar fashion. Specifically, tertiary TCAs (imipramine and amitriptyline) inhibit both 5-HT and NE reuptake.^6,90 Secondary amines (desipramine and nortriptyline) predominantly impact NE reuptake, possibly accounting for the lesser pain-mitigating benefit achieved with these agents, such as for treating neuro­pathic pain. Further, in vivo imipramine and amitriptyline are rapidly metabolized to secondary amines that are potent and selective NE reuptake inhibitors. In this way, the secondary amines may substantially lose the ability to modulate pain transmission because of the loss of concurrent 5-HT influences.⁹⁰

Clinical pearls

The following practical points can help guide clinicians regarding the usefulness of antidepressants for pain management:

• Antidepressants can alleviate symptoms of depression and pain. The pain-mitigating effects of antidepressants are possible even among chronic pain patients who are not depressed. Antidepressants may confer benefits for chronic pain patients with depression and other comorbid conditions, such as somatic symptom and related disorders.
• Antidepressants are useful for select chronic pain states. Although the noradrenergic and serotonergic antidepressants (SNRIs and, to some extent, amitriptyline) appear to have efficacy for neuropathic pain and FM, the benefits of SSRIs appear to be less robust. On the other hand, SSRIs and TCAs may have potential benefit for patients with IBS. However, the results of meta-analyses are limited in the ability to provide information about which patients will best respond to which specific antidepressant or how well. Future research directed at identifying characteristics that can predict which patients are likely to benefit from one antidepressant vs another would help inform how best to tailor treatment to individual needs.
• The pain-mitigating effects of antidepressants often emerge early in the course of treatment (often before mood-elevating effects are observed). For example, in the case of amitriptyline, pain relief may be possible for some patients at doses generally lower than those required for mood-elevating effects. To date, there is limited information in the literature to determine what constitutes a sufficient duration of treatment, or when treatment should be modified.
• Failure to reduce pain should raise questions about whether the dose should be increased, an alternative agent should be tried, or combinations with other analgesic agents should be considered. Failure to achieve pain-mitigating effects with one antidepressant does not mean failure with others. Hence, failure to achieve desired effects with one agent might warrant an empirical trial with another agent. Presently, too few double-blind RCTs have been conducted to assess the pain-mitigating effects of other antidepressants (eg, bupropion and newer SNRIs such as desvenlafaxine and levomilnacipran). Meta-analysis of the analgesic effectiveness of these agents or comparisons to the efficacy of other antidepressant classes is, therefore, impossible at this time.

Because many chronic pain states are complex, patients will seldom experience clinically relevant benefit from any one intervention.⁵³ The bigger implication for clinical research is to determine whether there is a sequence or combination of medication use that will provide overall better clinical effectiveness.⁵³ Only limited data are available exploring the utility of combining pharmacologic approaches to address pain.⁹¹ For example, preliminary evidence suggests that combinations of complementary strategies, such as duloxetine combined with pregabalin, may result in significantly greater numbers of FM patients achieving ≥30% pain reduction compared with monotherapy with either agent alone or placebo.⁹²

• Antidepressant selection may need to be based on medication-related adverse effect profiles and the potential for drug interactions. These factors are useful to consider in delineating multimodal treatment regimens for chronic pain in light of patients’ comorbidities and co-medication regimen. For example, the adverse effects of TCAs (anticholinergic and alpha-adrenergic influences) limit their utility for treating pain. Some of these effects can be more problematic in select populations, such as older adults or those with orthostatic difficulties, among others. TCAs are contraindicated in patients with closed-angle glaucoma, recent myocardial infarction, cardiac arrhythmias, poorly controlled seizures, or severe benign prostatic hypertrophy. Although the pain-mitigating effects of SNRIs have not been demonstrated to significantly exceed those of TCAs,^68,93,94 SNRIs would offer an advantage of greater tolerability of adverse effects and relative safety in patients with comorbid medical conditions that would otherwise preclude TCA use. The adverse effects and common drug interactions associated with antidepressants are summarized in Table 2⁹⁵.

Conclusion

Chronic, nonmalignant pain conditions afflict many patients and significantly impair their ability to function. Because of heightened concerns related to the appropriateness of, and restricting inordinate access to, long-term opioid analgesics, clinicians need to explore the usefulness of co-analgesic agents, such as antidepressants. Significant comorbidities exist between psychiatric disorders and chronic pain, and psychiatrists are uniquely positioned to diagnose and treat psychiatric comorbidities, as well as pain, among their patients, especially since they understand the kinetics and dynamics of antidepressants.

Bottom Line

Antidepressants can alleviate symptoms of depression and pain. Noradrenergic and serotonergic antidepressants appear to have efficacy for pain associated with neuropathy and fibromyalgia, while selective serotonin reuptake inhibitors and tricyclic antidepressants may have benefit for patients with irritable bowel syndrome. However, evidence regarding which patients will best respond to which specific antidepressant is limited.

Continue to: Related Resources

• Williams AM, Knox ED. When to prescribe antidepressants to treat comorbid depression and pain disorders. Current Psychiatry. 2017;16(1):55-58.
• Maletic V, Demuri B. Chronic pain and depression: treatment of 2 culprits in common. Current Psychiatry. 2016;15(3):41,47-50,52.

Drug Brand Names

Amitriptyline • Elavil, Endep
Bupropion • Wellbutrin, Zyban
Carisoprodol • Rela, Soma
Cyclobenzaprine • Amrix, Flexeril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Fluoxetine • Prozac
Gabapentin • Horizant, Neurontin
Imipramine • Tofranil
Levomilnacipran • Fetzima
Methadone • Dolophine, Methadose
Milnacipran • Savella
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Pregabalin • Lyrica, Lyrica CR
Tapentadol • Nucynta
Tramadol • Ultram
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Warfarin • Coumadin, Jantoven

Approximately 55 years ago, tricyclic antidepressants (TCAs) began to be used to treat neuropathic pain.¹ Eventually, clinical trials emerged suggesting the utility of TCAs for other chronic pain conditions, such as fibromyalgia (FM) and migraine prophylaxis. However, despite TCAs’ effectiveness in mitigating painful conditions, their adverse effects limited their use.

Pharmacologic advancements have led to the development of other antidepressant classes, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), and the use of these agents has come to eclipse that of TCAs. In the realm of pain management, such developments have raised the hope of possible alternative co-analgesic agents that could avoid the adverse effects associated with TCAs. Some of these agents have demonstrated efficacy for managing chronic pain states, while others have demonstrated only limited utility.

This article provides a synopsis of systematic reviews and meta-analyses examining the role of antidepressant therapy for managing several chronic pain conditions, including pain associated with neuropathy, FM, headache, and irritable bowel syndrome (IBS). Because the literature base is rapidly evolving, it is necessary to revisit the information gleaned from clinical data with respect to treatment effectiveness, and to clarify how antidepressants might be positioned in the management of chronic pain.

The effectiveness of antidepressants for pain

The pathophysiologic processes that precipitate and maintain chronic pain conditions are complex (Box 1^2-10). The pain-mitigating effects of antidepressants can be thought of in terms of direct analgesic effects and indirect effects (Box 2^{2,3,8,10,11-33}).

Box 1

During the last several decades, anti­depressants have been used to address—and have demonstrated clinical utility for—a variety of chronic pain states. However, antidepressants are not a panacea; some chronic pain conditions are more responsive to antidepressants than are others. The chronic painful states most amenable to antidepressants are those that result primarily from a process of neural sensitization, as opposed to acute somatic or visceral nociception. Hence, several meta-analyses and evidence-based reviews have long suggested the usefulness of antidepressants for mitigating pain associated with neuropathy,^34,35 FM,^36,37 headache,³⁸ and IBS.^39,40

Box 2

Continue to: Neuropathic pain

Several treatment guidelines advocate for the use of antidepressants for neuropathic pain.^41-44 For decades, TCAs have been employed off-label to successfully treat many patients with neuropathic pain states. Early investigations suggested that TCAs were robustly efficacious in managing patients with neuropathy.^45-48 Calculated number-needed-to-treat (NNT) values for TCAs were quite low (ie, reflecting that few patients would need to be treated to yield a positive response in one patient compared with placebo), and were comparable to, if not slightly better than, the NNTs generated for anticonvulsants and α2-δ ligands, such as gabapentin or pregabalin.^45-48

Unfortunately, early studies involving TCAs conducted many years ago do not meet contemporary standards of methodological rigor; they featured relatively small samples of patients assessed for brief post-treatment intervals with variable outcome measures. Thus, the NNT values obtained in meta-analyses based on these studies may overestimate treatment benefits.⁴⁹ Further, NNT values derived from meta-analyses tended to combine all drugs within a particular antidepressant class (eg, amitriptyline, nortriptyline, desipramine, and imipramine among the TCAs) employed at diverse doses. Taken together, these limitations raise questions about the results of those meta-analyses.

Subsequent meta-analyses, which employed strict criteria to eliminate data from studies with potential sources of bias and used a primary outcome of frequencies of patients reporting at least 30% pain reduction compared with a placebo-controlled sample, suggest that the effectiveness of TCAs as a class for treating neuropathic pain is not as compelling as once was thought. Meta-analyses of studies employing specific TCAs revealed that there was little evidence to support the use of desipramine,⁵⁰ imipramine,⁵¹ or nortriptyline⁵² in managing diabetic neuropathy or postherpetic neuralgia. Studies evaluating amitriptyline (dose range 12.5 to 150 mg/d), found low-level evidence of effectiveness; the benefit was expected to be present for a small subset (approximately 25%) of patients with neuropathic pain.⁵³

There is moderate-quality evidence that duloxetine (60 to 120 mg/d) can produce a ≥50% improvement in pain severity ratings among patients with diabetic peripheral neuropathy.⁵⁴ Although head-to-head studies with other antidepressants are limited, it appears that duloxetine and amitriptyline have comparable efficacy, even though the NNTs for amitriptyline were derived from lower-quality studies than those for duloxetine. Duloxetine is the only antidepressant to receive FDA approval for managing diabetic neuropathy. By contrast, studies assessing the utility of venlafaxine in neuropathic pain comprised small samples for brief durations, which limits the ability to draw clear (unbiased) support for its usefulness.⁵⁵

Given the diversity of pathophysiologic processes underlying the disturbances that cause neuropathic pain disorders, it is unsurprising that the effectiveness of amitriptyline and duloxetine were not generalizable to all neuropathic pain states. Although amitriptyline produced pain-mitigating effects in patients with diabetic neuropathy and post-herpetic neuralgia, and duloxetine mitigated pain among patients with diabetic neuropathy, there was no evidence to suggest their effectiveness in phantom limb pain or human immunodeficiency virus-related and spinal cord-related neuropathies.^{35,53,54,56-58}

Continue to: Fibromyalgia

As with the issues encountered in interpreting the effectiveness of antidepressants in neuropathic pain, interpreting results gleaned from clinical trials of antidepressants for treating FM are fraught with similar difficulties. Although amitriptyline has been a first-line treatment for FM for many years, the evidence upon which such recommendations were based consisted of low-level studies that had a significant potential for bias.⁵⁹ Large randomized trials would offer more compelling data regarding the efficacy of amitriptyline, but the prohibitive costs of such studies makes it unlikely they will be conducted. Amitriptyline (25 to 50 mg/d) was effective in mitigating FM-related pain in a small percentage of patients studied, with an estimated NNT of 4.⁵⁹ Adverse effects, often contributing to treatment discontinuation, were encountered more frequently among patients who received amitriptyline compared with placebo.

Selective serotonin reuptake inhibitors failed to demonstrate significant pain relief (estimated NNT of 10), or improvement in fatigue or sleep problems, even though the studies upon which such conclusions were based were low-level studies with a high potential for bias.⁶⁰ Although SSRIs have limited utility for mitigating pain, they are still quite useful for reducing depression among patients with FM.⁶⁰

By contrast, the SNRIs duloxetine and milnacipran provided clinically relevant benefit over placebo in the frequency of patients reporting pain relief of ≥30%, as well as patients’ global impression of change.⁶¹ These agents, however, failed to provide clinically relevant benefit over placebo in improving health-related quality of life, reducing sleep problems, or improving fatigue. Nonetheless, duloxetine and milnacipran are FDA-approved for managing pain in FM. Studies assessing the efficacy of venlafaxine in the treatment of FM to date have been limited by small sample sizes, inconsistent dosing, lack of a placebo control, and lack of blinding, which limits the ability to clearly delineate the role of venlafaxine in managing FM.⁶²

Mirtazapine (15 to 45 mg/d) showed a clinically relevant benefit compared with placebo for participant-reported pain relief of ≥30% and sleep disturbances. There was no benefit in terms of participant-reported improvement of quality of life, fatigue, or negative mood.⁶³ The evidence was considered to be of low quality overall.

Headache

Amitriptyline has been employed off-label to address headache prophylaxis since 1964.⁶⁴ Compared with placebo, it is efficacious in ameliorating migraine frequency and intensity as well as the frequency of tension headache.^65,66 However, SSRIs and SNRIs (venlafaxine) failed to produce significant reductions in migraine frequency or severity or the frequencies of tension headache when compared with placebo.^67,68

Continue to: Irritable bowel syndrome

Early studies addressing antidepressant efficacy in IBS reveal inconsistencies. For example, whereas some suggest that TCAs are effective in mitigating chronic, severe abdominal pain,^39,40 others concluded that TCAs failed to demonstrate a significant analgesic benefit.⁶⁹ A recent meta-analysis that restricted analysis of efficacy to randomized controlled trials (RCTs) with more rigorous methodological adherence found that pain relief in IBS is possible with both TCAs as well as SSRIs. However, adverse effects were more commonly encountered with TCAs than with SSRIs. Some of the inconsistencies in treatment efficacy reported in early studies may be due to variations in responsiveness of subsets of IBS patients. Specifically, the utility of TCAs appears to be best among patients with diarrheal-type (as opposed to constipation-type) IBS, presumably due to TCAs’ anticholinergic effects, whereas SSRIs may provide more of a benefit for patients with predominantly constipation-type IBS.^40,70

Other chronic pain conditions

Antidepressants have been used to assist in the management of several other pain conditions, including oral-facial pain, interstitial cystitis, non-cardiac chest pain, and others. The role of antidepressants for such conditions remains unclear due to limitations in the prevailing empirical work, such as few trials, small sample sizes, variations in outcome measures, and insufficient randomization and blinding.^71-76 The interpretation of results from systematic reviews and meta-analyses is limited because of these shortcomings.⁷⁷ Hence, it has not always been possible to determine whether, and to what extent, patients with such conditions may benefit from antidepressants.

Neuromodulatory effects and efficacy for pain

The interplay of norepinephrine (NE) and serotonin (5-HT) neurotransmitter systems and cellular mechanisms involved in the descending modulation of pain pathways is complex. Experimental animal models of pain modulation suggest that 5-HT can both inhibit as well as promote pain perception by different physiological mechanisms, in contrast to NE, which is predominately inhibitory. While 5-HT in the descending modulating system can inhibit pain transmission ascending to the brain from the periphery, it appears that an intact noradrenergic system is necessary for the inhibitory influences of the serotonergic system to be appreciated.^16,78,79 Deficiencies in one or both of these neurotransmitter systems may contribute to hyperactive pain processing, and thereby precipitate or maintain chronic pain.

Pain mitigation may be achieved best by enhancing both neurotransmitters simultaneously, less so by enhancing NE alone, and least by enhancing 5-HT alone.⁶ The ability to impact pain modulation would, therefore, depend on the degree to which an antidepressant capitalizes on both noradrenergic and serotonergic neurotransmission. Antidepressants commonly employed to manage pain are presented in Table 1^{47,60,68,80-88} according to their primary neurotransmitter effects. Thus, the literature summarized above suggests that antidepressants that influence both NE and 5-HT transmission have greater analgesic effects than antidepressants with more specific effects, such as influencing 5-HT reuptake alone.^80-85 It is unsurprising, therefore, that the SSRIs have not been demonstrated to be as consistently analgesic.^{47,60,68,80,86-88}

Similarly, pharmacodynamic and pharmacokinetic differences within antidepressant classes may influence analgesic effectiveness. Simultaneous effects on NE and 5-HT are achieved at low doses with duloxetine and milnacipran. By contrast, 5-HT effects predominate at low doses for venlafaxine. To achieve pain-mitigating effects, higher doses of venlafaxine generally are required.⁸⁹ Therefore, inconsistencies across studies regarding the analgesic benefits of venlafaxine may be attributable to variability in dosing; patients treated with lower doses may not have experienced sufficient NE effects to garner positive results.

Continue to: The differences in analgesic efficacy...

The differences in analgesic efficacy among specific TCAs may be understood in a similar fashion. Specifically, tertiary TCAs (imipramine and amitriptyline) inhibit both 5-HT and NE reuptake.^6,90 Secondary amines (desipramine and nortriptyline) predominantly impact NE reuptake, possibly accounting for the lesser pain-mitigating benefit achieved with these agents, such as for treating neuro­pathic pain. Further, in vivo imipramine and amitriptyline are rapidly metabolized to secondary amines that are potent and selective NE reuptake inhibitors. In this way, the secondary amines may substantially lose the ability to modulate pain transmission because of the loss of concurrent 5-HT influences.⁹⁰

Clinical pearls

The following practical points can help guide clinicians regarding the usefulness of antidepressants for pain management:

• Antidepressants can alleviate symptoms of depression and pain. The pain-mitigating effects of antidepressants are possible even among chronic pain patients who are not depressed. Antidepressants may confer benefits for chronic pain patients with depression and other comorbid conditions, such as somatic symptom and related disorders.
• Antidepressants are useful for select chronic pain states. Although the noradrenergic and serotonergic antidepressants (SNRIs and, to some extent, amitriptyline) appear to have efficacy for neuropathic pain and FM, the benefits of SSRIs appear to be less robust. On the other hand, SSRIs and TCAs may have potential benefit for patients with IBS. However, the results of meta-analyses are limited in the ability to provide information about which patients will best respond to which specific antidepressant or how well. Future research directed at identifying characteristics that can predict which patients are likely to benefit from one antidepressant vs another would help inform how best to tailor treatment to individual needs.
• The pain-mitigating effects of antidepressants often emerge early in the course of treatment (often before mood-elevating effects are observed). For example, in the case of amitriptyline, pain relief may be possible for some patients at doses generally lower than those required for mood-elevating effects. To date, there is limited information in the literature to determine what constitutes a sufficient duration of treatment, or when treatment should be modified.
• Failure to reduce pain should raise questions about whether the dose should be increased, an alternative agent should be tried, or combinations with other analgesic agents should be considered. Failure to achieve pain-mitigating effects with one antidepressant does not mean failure with others. Hence, failure to achieve desired effects with one agent might warrant an empirical trial with another agent. Presently, too few double-blind RCTs have been conducted to assess the pain-mitigating effects of other antidepressants (eg, bupropion and newer SNRIs such as desvenlafaxine and levomilnacipran). Meta-analysis of the analgesic effectiveness of these agents or comparisons to the efficacy of other antidepressant classes is, therefore, impossible at this time.

Because many chronic pain states are complex, patients will seldom experience clinically relevant benefit from any one intervention.⁵³ The bigger implication for clinical research is to determine whether there is a sequence or combination of medication use that will provide overall better clinical effectiveness.⁵³ Only limited data are available exploring the utility of combining pharmacologic approaches to address pain.⁹¹ For example, preliminary evidence suggests that combinations of complementary strategies, such as duloxetine combined with pregabalin, may result in significantly greater numbers of FM patients achieving ≥30% pain reduction compared with monotherapy with either agent alone or placebo.⁹²

• Antidepressant selection may need to be based on medication-related adverse effect profiles and the potential for drug interactions. These factors are useful to consider in delineating multimodal treatment regimens for chronic pain in light of patients’ comorbidities and co-medication regimen. For example, the adverse effects of TCAs (anticholinergic and alpha-adrenergic influences) limit their utility for treating pain. Some of these effects can be more problematic in select populations, such as older adults or those with orthostatic difficulties, among others. TCAs are contraindicated in patients with closed-angle glaucoma, recent myocardial infarction, cardiac arrhythmias, poorly controlled seizures, or severe benign prostatic hypertrophy. Although the pain-mitigating effects of SNRIs have not been demonstrated to significantly exceed those of TCAs,^68,93,94 SNRIs would offer an advantage of greater tolerability of adverse effects and relative safety in patients with comorbid medical conditions that would otherwise preclude TCA use. The adverse effects and common drug interactions associated with antidepressants are summarized in Table 2⁹⁵.

Conclusion

Chronic, nonmalignant pain conditions afflict many patients and significantly impair their ability to function. Because of heightened concerns related to the appropriateness of, and restricting inordinate access to, long-term opioid analgesics, clinicians need to explore the usefulness of co-analgesic agents, such as antidepressants. Significant comorbidities exist between psychiatric disorders and chronic pain, and psychiatrists are uniquely positioned to diagnose and treat psychiatric comorbidities, as well as pain, among their patients, especially since they understand the kinetics and dynamics of antidepressants.

Bottom Line

Antidepressants can alleviate symptoms of depression and pain. Noradrenergic and serotonergic antidepressants appear to have efficacy for pain associated with neuropathy and fibromyalgia, while selective serotonin reuptake inhibitors and tricyclic antidepressants may have benefit for patients with irritable bowel syndrome. However, evidence regarding which patients will best respond to which specific antidepressant is limited.

Continue to: Related Resources

• Williams AM, Knox ED. When to prescribe antidepressants to treat comorbid depression and pain disorders. Current Psychiatry. 2017;16(1):55-58.
• Maletic V, Demuri B. Chronic pain and depression: treatment of 2 culprits in common. Current Psychiatry. 2016;15(3):41,47-50,52.

Drug Brand Names

Amitriptyline • Elavil, Endep
Bupropion • Wellbutrin, Zyban
Carisoprodol • Rela, Soma
Cyclobenzaprine • Amrix, Flexeril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Fluoxetine • Prozac
Gabapentin • Horizant, Neurontin
Imipramine • Tofranil
Levomilnacipran • Fetzima
Methadone • Dolophine, Methadose
Milnacipran • Savella
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Pregabalin • Lyrica, Lyrica CR
Tapentadol • Nucynta
Tramadol • Ultram
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Warfarin • Coumadin, Jantoven

In elderly patients with osteoarthritis, long-term opioid use is highly prevalent and varies substantially by state, suggest the results of a large, observational cohort study.

sdominick/iStock/Getty Images

Long term opioid use prior to total joint replacement (TJR) varied somewhat by access to primary care providers, but not by access to rheumatologists, according to authors of the study, led by Rishi J Desai, MS, PhD, of the department of medicine at Brigham and Women’s Hospital and Harvard Medical School, both in Boston.

“These findings suggest that geographically targeted dissemination strategies for safe opioid prescribing guidelines may be required to address the high use observed in certain states,” said Dr. Desai and his colleagues in a report on the study published in Arthritis & Rheumatology.

This study by Dr. Desai and his colleagues looked at long-term use of opioids, which was defined as at least 90 days of use in the year prior to TJR. They analyzed a total of 358,121 Medicare enrollees with advanced osteoarthritis, with a mean age of 74 years.

Geographic areas in the South tended to have higher proportions of long-term opioid users, while the Northeast and Midwest had lower proportions, according to investigators.

Long-term use of opioids ranged from a low of 8.9% in Minnesota to 26.4% in Alabama, they reported. Beyond Alabama, the top 10 states included West Virginia, Georgia, Kentucky, Louisiana, Oklahoma, North Carolina, Virginia, Indiana, and Mississippi, with proportions of long-term opioid users ranging from 17% to 25%, the report shows.

Only modest associations were seen between provider density and opioid use, investigators said. There was a 1.4% mean difference (95% confidence interval, 0.8%-2.0%) in long-term opioid users between primary care service areas (PCSAs) with the highest concentrations of primary care providers versus those with the lowest, and there was just a 0.6% mean difference (95% CI, –0.1% to 1.3%) between PCSAs with the highest concentrations of rheumatologists and those with the lowest.

Among long-term opioid users, almost 20% were using an average daily dose of 50 or more morphine milligram equivalents, a range that potentially imparts a high risk of opioid-related harms, according to investigators.

Funding for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Desai reported disclosures related to Merck and Vertex. Co-authors provided disclosures related to a number of pharmaceutical companies.

SOURCE: Desai RJ et al. Arthritis Rheumatol. 2019. doi: 10.1002/art.40834.

In elderly patients with osteoarthritis, long-term opioid use is highly prevalent and varies substantially by state, suggest the results of a large, observational cohort study.

sdominick/iStock/Getty Images

Long term opioid use prior to total joint replacement (TJR) varied somewhat by access to primary care providers, but not by access to rheumatologists, according to authors of the study, led by Rishi J Desai, MS, PhD, of the department of medicine at Brigham and Women’s Hospital and Harvard Medical School, both in Boston.

“These findings suggest that geographically targeted dissemination strategies for safe opioid prescribing guidelines may be required to address the high use observed in certain states,” said Dr. Desai and his colleagues in a report on the study published in Arthritis & Rheumatology.

This study by Dr. Desai and his colleagues looked at long-term use of opioids, which was defined as at least 90 days of use in the year prior to TJR. They analyzed a total of 358,121 Medicare enrollees with advanced osteoarthritis, with a mean age of 74 years.

Geographic areas in the South tended to have higher proportions of long-term opioid users, while the Northeast and Midwest had lower proportions, according to investigators.

Long-term use of opioids ranged from a low of 8.9% in Minnesota to 26.4% in Alabama, they reported. Beyond Alabama, the top 10 states included West Virginia, Georgia, Kentucky, Louisiana, Oklahoma, North Carolina, Virginia, Indiana, and Mississippi, with proportions of long-term opioid users ranging from 17% to 25%, the report shows.

Only modest associations were seen between provider density and opioid use, investigators said. There was a 1.4% mean difference (95% confidence interval, 0.8%-2.0%) in long-term opioid users between primary care service areas (PCSAs) with the highest concentrations of primary care providers versus those with the lowest, and there was just a 0.6% mean difference (95% CI, –0.1% to 1.3%) between PCSAs with the highest concentrations of rheumatologists and those with the lowest.

Among long-term opioid users, almost 20% were using an average daily dose of 50 or more morphine milligram equivalents, a range that potentially imparts a high risk of opioid-related harms, according to investigators.

Funding for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Desai reported disclosures related to Merck and Vertex. Co-authors provided disclosures related to a number of pharmaceutical companies.

SOURCE: Desai RJ et al. Arthritis Rheumatol. 2019. doi: 10.1002/art.40834.

In elderly patients with osteoarthritis, long-term opioid use is highly prevalent and varies substantially by state, suggest the results of a large, observational cohort study.

sdominick/iStock/Getty Images

Long term opioid use prior to total joint replacement (TJR) varied somewhat by access to primary care providers, but not by access to rheumatologists, according to authors of the study, led by Rishi J Desai, MS, PhD, of the department of medicine at Brigham and Women’s Hospital and Harvard Medical School, both in Boston.

“These findings suggest that geographically targeted dissemination strategies for safe opioid prescribing guidelines may be required to address the high use observed in certain states,” said Dr. Desai and his colleagues in a report on the study published in Arthritis & Rheumatology.

This study by Dr. Desai and his colleagues looked at long-term use of opioids, which was defined as at least 90 days of use in the year prior to TJR. They analyzed a total of 358,121 Medicare enrollees with advanced osteoarthritis, with a mean age of 74 years.

Geographic areas in the South tended to have higher proportions of long-term opioid users, while the Northeast and Midwest had lower proportions, according to investigators.

Long-term use of opioids ranged from a low of 8.9% in Minnesota to 26.4% in Alabama, they reported. Beyond Alabama, the top 10 states included West Virginia, Georgia, Kentucky, Louisiana, Oklahoma, North Carolina, Virginia, Indiana, and Mississippi, with proportions of long-term opioid users ranging from 17% to 25%, the report shows.

Only modest associations were seen between provider density and opioid use, investigators said. There was a 1.4% mean difference (95% confidence interval, 0.8%-2.0%) in long-term opioid users between primary care service areas (PCSAs) with the highest concentrations of primary care providers versus those with the lowest, and there was just a 0.6% mean difference (95% CI, –0.1% to 1.3%) between PCSAs with the highest concentrations of rheumatologists and those with the lowest.

Among long-term opioid users, almost 20% were using an average daily dose of 50 or more morphine milligram equivalents, a range that potentially imparts a high risk of opioid-related harms, according to investigators.

Funding for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Desai reported disclosures related to Merck and Vertex. Co-authors provided disclosures related to a number of pharmaceutical companies.

SOURCE: Desai RJ et al. Arthritis Rheumatol. 2019. doi: 10.1002/art.40834.

EVIDENCE SUMMARY

A 2015 meta-analysis of 8 RCTs compared pain reduction in adults >50 years with osteoporotic compression fractures who received either vertebral augmentation (vertebroplasty or balloon kyphoplasty; 495 patients) or conservative or sham treatment (492 patients).¹ Pain was measured by the visual analog scale (VAS) periodically between 1 week and 1 year.

The study included patients of both sexes who had an acute or chronic osteoporotic vertebral compression fracture that caused pain and functional limitations in daily activities. It excluded patients with neoplasm, pre-existing chronic pain or functional disability unrelated to vertebral fractures, and vertebral fractures unaccompanied by signal changes on magnetic resonance imaging.

Vertebral augmentation resulted in small to moderate reductions in pain scores compared with placebo at 1 to 4 weeks (7 trials, 938 patients; standardized mean difference [SMD]=0.3; 95% confidence interval [CI], 0.1-0.5), 2 to 3 months (7 trials, 953 patients; SMD=0.3; 95% CI, 0.1-0.4), and 1 year (5 trials, 744 patients; SMD=0.3; 95% CI, 0.1-0.4). The study is considered low-quality because of increased heterogeneity.

Calcitonin reduces pain but with some adverse effects

A 2011 meta-analysis of 10 RCTs (467 patients) examined the analgesic effectiveness of calcitonin in adults >60 years, of either sex, with osteoporotic compression fractures who received calcitonin in the acute phase (<10 days after fracture) and chronic phase (>3 months after fracture).² For acute fractures, pain was measured at 1, 2, 3, and 4 weeks following treatment. For chronic fractures, pain was measured at 1, 3, and 6 months post-treatment.

Continue to: Calcitonin was administered...

Calcitonin was administered in varying doses by various routes (200 IU intranasal, 50-200 IU intramuscular or subcutaneous injection, or 200 IU rectal suppository) and compared with placebo, usual treatment, or other analgesia. The VAS was varied (10 cm, 100 mm, or 5-point) and assessed pain and length of time to mobilization with patients at rest, sitting, standing, and walking by using mean deviation (MD) and SMD.

In the acute phase, calcitonin resulted in greater pain relief 1 week after fracture at rest (4 trials; 260 patients; 10-cm VAS; MD=−3.4; 95% CI, −4 to −2.8) and with walking (4 trials, 228 patients; SMD=2.6; 95% CI, −4.1 to −1.1) compared with the control group. At 6 months, calcitonin had reduced pain in mobile patients more than in the control group (7 trials, 207 patients; SMD=−0.5; 95% CI, −0.9 to −0.1).

Statistically significant adverse effects of calcitonin included gastrointestinal disturbances and flushing compared with placebo. Adverse effects were more predominant in the studies that used injectable calcitonin and in the chronic pain group. The study is considered low-quality because of increased heterogeneity in the acute pain studies.

EVIDENCE SUMMARY

A 2015 meta-analysis of 8 RCTs compared pain reduction in adults >50 years with osteoporotic compression fractures who received either vertebral augmentation (vertebroplasty or balloon kyphoplasty; 495 patients) or conservative or sham treatment (492 patients).¹ Pain was measured by the visual analog scale (VAS) periodically between 1 week and 1 year.

The study included patients of both sexes who had an acute or chronic osteoporotic vertebral compression fracture that caused pain and functional limitations in daily activities. It excluded patients with neoplasm, pre-existing chronic pain or functional disability unrelated to vertebral fractures, and vertebral fractures unaccompanied by signal changes on magnetic resonance imaging.

Vertebral augmentation resulted in small to moderate reductions in pain scores compared with placebo at 1 to 4 weeks (7 trials, 938 patients; standardized mean difference [SMD]=0.3; 95% confidence interval [CI], 0.1-0.5), 2 to 3 months (7 trials, 953 patients; SMD=0.3; 95% CI, 0.1-0.4), and 1 year (5 trials, 744 patients; SMD=0.3; 95% CI, 0.1-0.4). The study is considered low-quality because of increased heterogeneity.

Calcitonin reduces pain but with some adverse effects

A 2011 meta-analysis of 10 RCTs (467 patients) examined the analgesic effectiveness of calcitonin in adults >60 years, of either sex, with osteoporotic compression fractures who received calcitonin in the acute phase (<10 days after fracture) and chronic phase (>3 months after fracture).² For acute fractures, pain was measured at 1, 2, 3, and 4 weeks following treatment. For chronic fractures, pain was measured at 1, 3, and 6 months post-treatment.

Continue to: Calcitonin was administered...

Calcitonin was administered in varying doses by various routes (200 IU intranasal, 50-200 IU intramuscular or subcutaneous injection, or 200 IU rectal suppository) and compared with placebo, usual treatment, or other analgesia. The VAS was varied (10 cm, 100 mm, or 5-point) and assessed pain and length of time to mobilization with patients at rest, sitting, standing, and walking by using mean deviation (MD) and SMD.

In the acute phase, calcitonin resulted in greater pain relief 1 week after fracture at rest (4 trials; 260 patients; 10-cm VAS; MD=−3.4; 95% CI, −4 to −2.8) and with walking (4 trials, 228 patients; SMD=2.6; 95% CI, −4.1 to −1.1) compared with the control group. At 6 months, calcitonin had reduced pain in mobile patients more than in the control group (7 trials, 207 patients; SMD=−0.5; 95% CI, −0.9 to −0.1).

Statistically significant adverse effects of calcitonin included gastrointestinal disturbances and flushing compared with placebo. Adverse effects were more predominant in the studies that used injectable calcitonin and in the chronic pain group. The study is considered low-quality because of increased heterogeneity in the acute pain studies.

EVIDENCE SUMMARY

A 2015 meta-analysis of 8 RCTs compared pain reduction in adults >50 years with osteoporotic compression fractures who received either vertebral augmentation (vertebroplasty or balloon kyphoplasty; 495 patients) or conservative or sham treatment (492 patients).¹ Pain was measured by the visual analog scale (VAS) periodically between 1 week and 1 year.

The study included patients of both sexes who had an acute or chronic osteoporotic vertebral compression fracture that caused pain and functional limitations in daily activities. It excluded patients with neoplasm, pre-existing chronic pain or functional disability unrelated to vertebral fractures, and vertebral fractures unaccompanied by signal changes on magnetic resonance imaging.

Vertebral augmentation resulted in small to moderate reductions in pain scores compared with placebo at 1 to 4 weeks (7 trials, 938 patients; standardized mean difference [SMD]=0.3; 95% confidence interval [CI], 0.1-0.5), 2 to 3 months (7 trials, 953 patients; SMD=0.3; 95% CI, 0.1-0.4), and 1 year (5 trials, 744 patients; SMD=0.3; 95% CI, 0.1-0.4). The study is considered low-quality because of increased heterogeneity.

Calcitonin reduces pain but with some adverse effects

A 2011 meta-analysis of 10 RCTs (467 patients) examined the analgesic effectiveness of calcitonin in adults >60 years, of either sex, with osteoporotic compression fractures who received calcitonin in the acute phase (<10 days after fracture) and chronic phase (>3 months after fracture).² For acute fractures, pain was measured at 1, 2, 3, and 4 weeks following treatment. For chronic fractures, pain was measured at 1, 3, and 6 months post-treatment.

Continue to: Calcitonin was administered...

Calcitonin was administered in varying doses by various routes (200 IU intranasal, 50-200 IU intramuscular or subcutaneous injection, or 200 IU rectal suppository) and compared with placebo, usual treatment, or other analgesia. The VAS was varied (10 cm, 100 mm, or 5-point) and assessed pain and length of time to mobilization with patients at rest, sitting, standing, and walking by using mean deviation (MD) and SMD.

In the acute phase, calcitonin resulted in greater pain relief 1 week after fracture at rest (4 trials; 260 patients; 10-cm VAS; MD=−3.4; 95% CI, −4 to −2.8) and with walking (4 trials, 228 patients; SMD=2.6; 95% CI, −4.1 to −1.1) compared with the control group. At 6 months, calcitonin had reduced pain in mobile patients more than in the control group (7 trials, 207 patients; SMD=−0.5; 95% CI, −0.9 to −0.1).

Statistically significant adverse effects of calcitonin included gastrointestinal disturbances and flushing compared with placebo. Adverse effects were more predominant in the studies that used injectable calcitonin and in the chronic pain group. The study is considered low-quality because of increased heterogeneity in the acute pain studies.

A 3-year-old girl presented with a rapidly progressing rash. The rash began the previous day with redness around her lips and nose (FIGURE 1). Twelve hours later, the rash had progressed to involve her neck, trunk, and inguinal area (FIGURE 2). The child’s parents reported that she had no recent illnesses or treatment with antibiotics.

On physical examination, she was febrile (101.8° F) and irritable throughout the encounter. She had perioral and nasolabial erythema and dryness. Her lips were dry with no intraoral mucosal lesions, and her conjunctiva was clear. She had a tender erythrodermal rash that was most prominent on her neck folds, back, and inguinal folds. Superficial layers of skin sloughed off when pressure was applied to areas along her back.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Based on the patient’s classic presentation and exam findings, the physician suspected staphylococcal scalded skin syndrome. SSSS is a rare but serious condition that progresses quickly with high fevers and diffuse painful erythema. The exact epidemiology of SSSS is unclear; some articles report incidences between 0.09 and 0.13 cases per 1 million people.¹ The mortality rate is about 5% due to complications of sepsis, superinfection, and electrolyte disturbances.²

SSSS is caused by Staphylococcus aureus from a localized source that produces exfoliative toxins A and B that spread hematogenously, causing extensive epidermal damage. Exotoxins bind to desmosomes, causing skin cells to lose adherence.³ Histopathology shows intraepidermal cleavage through the stratum granulosum.

Infants and younger children appear more likely to be affected by SSSS, although it may occur in older children or adults who are immunocompromised. It may be that younger children are most susceptible due to a lack of antibodies to the toxin produced or because of a delayed clearance of the toxin-antibody complex from an immature renal system.

Staphylococcal scalded skin syndrome progresses quickly, with high fevers and diffuse, painful erythema.

What you’ll see. Patients with SSSS may have a prodrome of irritability, malaise, and fever. The rash is first noticeable as erythema in the flexural areas.⁴ The erythematous tender patches spread and coalesce into a scarlatiniform erythema. Fragile bullae become large sheets of epidermis that slough (a positive Nikolsky’s sign).⁵ The desquamated areas can exhibit a scalded appearance.³

Differential diagnosis includes TEN and SJS

There is a broad differential for vesiculobullous rashes, ranging from self-limiting conditions to those that are life threatening.

Toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome (SJS), and erythema multiforme major (EMM) are immunological reactions to certain drugs or infections varying in the severity of their presentation. EMM, SJS, and TEN involve the mucosal surfaces, while SSSS does not. The histopathology of these conditions also differs from SSSS as they have keratinocyte necrosis of varying levels of the skin, whereas SSSS only involves the epidermis.

SSSS also may be confused with drug reactions, such as DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome. DRESS typically is associated with anticonvulsants and sulfonamides and may have peripheral eosinophilia and a transaminitis.⁴

Continue to: Other more self-limited vesiculobullous rashes...

Other more self-limited vesiculobullous rashes include human enteroviruses such as coxsackie virus (hand-foot-mouth disease), echovirus, and enterovirus. However, unlike SSSS, which only affects the epidermis, these disorders may produce epidermal necrosis resulting in epidermal-dermal separation and mucocutaneous blistering.⁴

Making the diagnosis

When a patient has classic SSSS, the diagnosis can be made based on exam findings and the patient’s history. Families will usually report a generalized rash in neonates with desquamation of the entire skin. Fever is often present. Recent exposures to other family members with skin and soft-tissue infections is a possibility. If there is doubt, a skin biopsy can be obtained for histology. Lab work may reveal an elevated white blood cell count; blood culture is often negative.

The primary site of S aureus infection is usually the nasopharynx, causing a mild upper respiratory tract infection; therefore, nasopharyngeal cultures may be positive.⁴ Cultures can also be drawn from blood, wounds, nares, and ocular exudates if there is suspicion. Cultures from the actual blisters are typically negative, as the toxin—not the actual bacteria—is responsible for the blistering. Unlike adults who experience SSSS, children typically have negative blood cultures.⁴

Prompt treatment is essential

Swift diagnosis and management of SSSS is important due to the risk of severe disease. It is important to start antibiotics early because methicillin-sensitive S aureus is a predominant cause of SSSS.² The epidemiology of methicillin-sensitive and methicillin-resistant S aureus (MRSA) continues to shift. A recent study suggests that empiric therapy with penicillinase-resistant penicillins, along with clindamycin, be employed until culture sensitivities are available to guide therapy.² Local resistance patterns to S aureus should help guide initial empiric antibiotic treatment. Patients should receive intravenous (IV) fluids to compensate for insensible fluid losses similar to an extensive burn wound. Wound dressings placed over sloughed skin can help prevent secondary infection.² Lastly, the use of anti-inflammatory drugs and opiates often depends upon the extent of pain the patient experiences.

Our patient was immediately started on IV clindamycin 10 mg/kg tid and IV fluids. She was given morphine 0.01 mg/kg for pain control. As expected, cultures of her nasopharynx, blood, and vulva did not grow S aureus. Although no organism was isolated, her rash rapidly improved, and she was discharged home to complete a 10-day oral course of clindamycin 10 mg/kg tid.

CORRESPONDENCE
Nicholas M. Potisek, MD, Wake Forest School of Medicine, Department of Pediatrics, Medical Center Blvd, Winston-Salem, NC 27157; [email protected]

A 3-year-old girl presented with a rapidly progressing rash. The rash began the previous day with redness around her lips and nose (FIGURE 1). Twelve hours later, the rash had progressed to involve her neck, trunk, and inguinal area (FIGURE 2). The child’s parents reported that she had no recent illnesses or treatment with antibiotics.

On physical examination, she was febrile (101.8° F) and irritable throughout the encounter. She had perioral and nasolabial erythema and dryness. Her lips were dry with no intraoral mucosal lesions, and her conjunctiva was clear. She had a tender erythrodermal rash that was most prominent on her neck folds, back, and inguinal folds. Superficial layers of skin sloughed off when pressure was applied to areas along her back.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Based on the patient’s classic presentation and exam findings, the physician suspected staphylococcal scalded skin syndrome. SSSS is a rare but serious condition that progresses quickly with high fevers and diffuse painful erythema. The exact epidemiology of SSSS is unclear; some articles report incidences between 0.09 and 0.13 cases per 1 million people.¹ The mortality rate is about 5% due to complications of sepsis, superinfection, and electrolyte disturbances.²

SSSS is caused by Staphylococcus aureus from a localized source that produces exfoliative toxins A and B that spread hematogenously, causing extensive epidermal damage. Exotoxins bind to desmosomes, causing skin cells to lose adherence.³ Histopathology shows intraepidermal cleavage through the stratum granulosum.

Infants and younger children appear more likely to be affected by SSSS, although it may occur in older children or adults who are immunocompromised. It may be that younger children are most susceptible due to a lack of antibodies to the toxin produced or because of a delayed clearance of the toxin-antibody complex from an immature renal system.

Staphylococcal scalded skin syndrome progresses quickly, with high fevers and diffuse, painful erythema.

What you’ll see. Patients with SSSS may have a prodrome of irritability, malaise, and fever. The rash is first noticeable as erythema in the flexural areas.⁴ The erythematous tender patches spread and coalesce into a scarlatiniform erythema. Fragile bullae become large sheets of epidermis that slough (a positive Nikolsky’s sign).⁵ The desquamated areas can exhibit a scalded appearance.³

Differential diagnosis includes TEN and SJS

There is a broad differential for vesiculobullous rashes, ranging from self-limiting conditions to those that are life threatening.

Toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome (SJS), and erythema multiforme major (EMM) are immunological reactions to certain drugs or infections varying in the severity of their presentation. EMM, SJS, and TEN involve the mucosal surfaces, while SSSS does not. The histopathology of these conditions also differs from SSSS as they have keratinocyte necrosis of varying levels of the skin, whereas SSSS only involves the epidermis.

SSSS also may be confused with drug reactions, such as DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome. DRESS typically is associated with anticonvulsants and sulfonamides and may have peripheral eosinophilia and a transaminitis.⁴

Continue to: Other more self-limited vesiculobullous rashes...

Other more self-limited vesiculobullous rashes include human enteroviruses such as coxsackie virus (hand-foot-mouth disease), echovirus, and enterovirus. However, unlike SSSS, which only affects the epidermis, these disorders may produce epidermal necrosis resulting in epidermal-dermal separation and mucocutaneous blistering.⁴

Making the diagnosis

When a patient has classic SSSS, the diagnosis can be made based on exam findings and the patient’s history. Families will usually report a generalized rash in neonates with desquamation of the entire skin. Fever is often present. Recent exposures to other family members with skin and soft-tissue infections is a possibility. If there is doubt, a skin biopsy can be obtained for histology. Lab work may reveal an elevated white blood cell count; blood culture is often negative.

The primary site of S aureus infection is usually the nasopharynx, causing a mild upper respiratory tract infection; therefore, nasopharyngeal cultures may be positive.⁴ Cultures can also be drawn from blood, wounds, nares, and ocular exudates if there is suspicion. Cultures from the actual blisters are typically negative, as the toxin—not the actual bacteria—is responsible for the blistering. Unlike adults who experience SSSS, children typically have negative blood cultures.⁴

Prompt treatment is essential

Swift diagnosis and management of SSSS is important due to the risk of severe disease. It is important to start antibiotics early because methicillin-sensitive S aureus is a predominant cause of SSSS.² The epidemiology of methicillin-sensitive and methicillin-resistant S aureus (MRSA) continues to shift. A recent study suggests that empiric therapy with penicillinase-resistant penicillins, along with clindamycin, be employed until culture sensitivities are available to guide therapy.² Local resistance patterns to S aureus should help guide initial empiric antibiotic treatment. Patients should receive intravenous (IV) fluids to compensate for insensible fluid losses similar to an extensive burn wound. Wound dressings placed over sloughed skin can help prevent secondary infection.² Lastly, the use of anti-inflammatory drugs and opiates often depends upon the extent of pain the patient experiences.

Our patient was immediately started on IV clindamycin 10 mg/kg tid and IV fluids. She was given morphine 0.01 mg/kg for pain control. As expected, cultures of her nasopharynx, blood, and vulva did not grow S aureus. Although no organism was isolated, her rash rapidly improved, and she was discharged home to complete a 10-day oral course of clindamycin 10 mg/kg tid.

CORRESPONDENCE
Nicholas M. Potisek, MD, Wake Forest School of Medicine, Department of Pediatrics, Medical Center Blvd, Winston-Salem, NC 27157; [email protected]

A 3-year-old girl presented with a rapidly progressing rash. The rash began the previous day with redness around her lips and nose (FIGURE 1). Twelve hours later, the rash had progressed to involve her neck, trunk, and inguinal area (FIGURE 2). The child’s parents reported that she had no recent illnesses or treatment with antibiotics.

On physical examination, she was febrile (101.8° F) and irritable throughout the encounter. She had perioral and nasolabial erythema and dryness. Her lips were dry with no intraoral mucosal lesions, and her conjunctiva was clear. She had a tender erythrodermal rash that was most prominent on her neck folds, back, and inguinal folds. Superficial layers of skin sloughed off when pressure was applied to areas along her back.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Based on the patient’s classic presentation and exam findings, the physician suspected staphylococcal scalded skin syndrome. SSSS is a rare but serious condition that progresses quickly with high fevers and diffuse painful erythema. The exact epidemiology of SSSS is unclear; some articles report incidences between 0.09 and 0.13 cases per 1 million people.¹ The mortality rate is about 5% due to complications of sepsis, superinfection, and electrolyte disturbances.²

SSSS is caused by Staphylococcus aureus from a localized source that produces exfoliative toxins A and B that spread hematogenously, causing extensive epidermal damage. Exotoxins bind to desmosomes, causing skin cells to lose adherence.³ Histopathology shows intraepidermal cleavage through the stratum granulosum.

Infants and younger children appear more likely to be affected by SSSS, although it may occur in older children or adults who are immunocompromised. It may be that younger children are most susceptible due to a lack of antibodies to the toxin produced or because of a delayed clearance of the toxin-antibody complex from an immature renal system.

Staphylococcal scalded skin syndrome progresses quickly, with high fevers and diffuse, painful erythema.

What you’ll see. Patients with SSSS may have a prodrome of irritability, malaise, and fever. The rash is first noticeable as erythema in the flexural areas.⁴ The erythematous tender patches spread and coalesce into a scarlatiniform erythema. Fragile bullae become large sheets of epidermis that slough (a positive Nikolsky’s sign).⁵ The desquamated areas can exhibit a scalded appearance.³

Differential diagnosis includes TEN and SJS

There is a broad differential for vesiculobullous rashes, ranging from self-limiting conditions to those that are life threatening.

Toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome (SJS), and erythema multiforme major (EMM) are immunological reactions to certain drugs or infections varying in the severity of their presentation. EMM, SJS, and TEN involve the mucosal surfaces, while SSSS does not. The histopathology of these conditions also differs from SSSS as they have keratinocyte necrosis of varying levels of the skin, whereas SSSS only involves the epidermis.

SSSS also may be confused with drug reactions, such as DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome. DRESS typically is associated with anticonvulsants and sulfonamides and may have peripheral eosinophilia and a transaminitis.⁴

Continue to: Other more self-limited vesiculobullous rashes...

Other more self-limited vesiculobullous rashes include human enteroviruses such as coxsackie virus (hand-foot-mouth disease), echovirus, and enterovirus. However, unlike SSSS, which only affects the epidermis, these disorders may produce epidermal necrosis resulting in epidermal-dermal separation and mucocutaneous blistering.⁴

Making the diagnosis

When a patient has classic SSSS, the diagnosis can be made based on exam findings and the patient’s history. Families will usually report a generalized rash in neonates with desquamation of the entire skin. Fever is often present. Recent exposures to other family members with skin and soft-tissue infections is a possibility. If there is doubt, a skin biopsy can be obtained for histology. Lab work may reveal an elevated white blood cell count; blood culture is often negative.

The primary site of S aureus infection is usually the nasopharynx, causing a mild upper respiratory tract infection; therefore, nasopharyngeal cultures may be positive.⁴ Cultures can also be drawn from blood, wounds, nares, and ocular exudates if there is suspicion. Cultures from the actual blisters are typically negative, as the toxin—not the actual bacteria—is responsible for the blistering. Unlike adults who experience SSSS, children typically have negative blood cultures.⁴

Prompt treatment is essential

Swift diagnosis and management of SSSS is important due to the risk of severe disease. It is important to start antibiotics early because methicillin-sensitive S aureus is a predominant cause of SSSS.² The epidemiology of methicillin-sensitive and methicillin-resistant S aureus (MRSA) continues to shift. A recent study suggests that empiric therapy with penicillinase-resistant penicillins, along with clindamycin, be employed until culture sensitivities are available to guide therapy.² Local resistance patterns to S aureus should help guide initial empiric antibiotic treatment. Patients should receive intravenous (IV) fluids to compensate for insensible fluid losses similar to an extensive burn wound. Wound dressings placed over sloughed skin can help prevent secondary infection.² Lastly, the use of anti-inflammatory drugs and opiates often depends upon the extent of pain the patient experiences.

Our patient was immediately started on IV clindamycin 10 mg/kg tid and IV fluids. She was given morphine 0.01 mg/kg for pain control. As expected, cultures of her nasopharynx, blood, and vulva did not grow S aureus. Although no organism was isolated, her rash rapidly improved, and she was discharged home to complete a 10-day oral course of clindamycin 10 mg/kg tid.

CORRESPONDENCE
Nicholas M. Potisek, MD, Wake Forest School of Medicine, Department of Pediatrics, Medical Center Blvd, Winston-Salem, NC 27157; [email protected]