In patients with castration-resistant prostate cancer (CRPC), a variant of the HSD3B1 gene predicts sensitivity to the CYP17A1 inhibitor ketoconazole, according to results of a single-center, observational study including 90 men treated between June 1998 and December 2012.

Median progression-free survival (PFS) increased along with the number of variant HSD3B1(1245C) alleles, wrote Nima Almassi, MD, of the Cleveland Clinic, and coauthors (JAMA Oncol. 2017 Oct 12. doi: 10.1001/jamaoncol.2017.3159).

Specifically, median PFS was just 5.0 months for patients with no variant HSD3B1(1245C) alleles, 7.5 months for patients with one allele, and 12.3 months for those with two alleles (P = .03).

“These findings suggest that the variant allele … may be a predictive biomarker of tumor vulnerability to pharmacologic CYP17A1 inhibition with a nonsteroidal drug,” Dr. Almassi and colleagues wrote.

The HSD3B1(1245C) germline variant was already known in the prostate cancer research community as a marker of tumor resistance to androgen deprivation therapy (ADT) and more rapid disease onset. In a separate study published in the same issue (JAMA Oncol. 2017 Oct 12. doi: 10.1001/jamaoncol.2017.3164) investigators provided additional evidence, showing that the genotype was associated with more rapid metastasis development in men with localized prostate cancer who received ADT for biochemical recurrence after radiation treatment.

In that observational study of 218 men treated between 1996 and 2003, median time to metastasis (TTM) decreased according to the number of inherited variant alleles, wrote Jason W. D. Hearn, MD, University of Michigan, Ann Arbor, and coauthors. Those with no variant HSD3B1(1245C) alleles had a TTM of 7.4 months, while those with one allele had a TTM of 5.8 months, and for those with two, TTM was only 4.4 months (P = .03).

However, investigators could not detect any such relationship between variant HSD3B1(1245C) alleles and time to progression (TTP) or overall survival (OS): “It is possible that the high rates of prior ADT exposure and frequent use of androgen receptor (AR) antagonists during salvage ADT modified the impact of genotype with respect to composite TTP and OS,” Dr. Hearn and colleagues wrote. “Nonetheless, the large impact on TTM is statistically and clinically significant.”

While the findings of Dr. Hearn and colleagues bolster existing knowledge that variant HSD3B1(1245C) alleles are associated with poorer outcomes in prostate cancer, the findings from Dr. Almassi and colleagues add new insights regarding the potential role of CYP17A1 inhibitors in patients with this genotype.

“As only a proportion of patients treated with potent CYP17A1 inhibitors or AR antagonists respond clinically, a predictive biomarker for the identification of patients who benefit would undoubtedly have clinical value,” Dr. Almassi and colleagues said.

The findings are somewhat limited, however, because they were focused on ketoconazole, a nonsteroidal CYP17A1 inhibitor that is no longer routinely used in clinic for prostate cancer.

Similar studies of the steroidal CYP17A1 inhibitor abiraterone acetate would be possible, however, “steroidal metabolites of [steroidal CYP17A1 inhibitors] make evaluation more complex,” Dr. Almassi and colleagues wrote.

In patients with castration-resistant prostate cancer (CRPC), a variant of the HSD3B1 gene predicts sensitivity to the CYP17A1 inhibitor ketoconazole, according to results of a single-center, observational study including 90 men treated between June 1998 and December 2012.

Median progression-free survival (PFS) increased along with the number of variant HSD3B1(1245C) alleles, wrote Nima Almassi, MD, of the Cleveland Clinic, and coauthors (JAMA Oncol. 2017 Oct 12. doi: 10.1001/jamaoncol.2017.3159).

Specifically, median PFS was just 5.0 months for patients with no variant HSD3B1(1245C) alleles, 7.5 months for patients with one allele, and 12.3 months for those with two alleles (P = .03).

“These findings suggest that the variant allele … may be a predictive biomarker of tumor vulnerability to pharmacologic CYP17A1 inhibition with a nonsteroidal drug,” Dr. Almassi and colleagues wrote.

The HSD3B1(1245C) germline variant was already known in the prostate cancer research community as a marker of tumor resistance to androgen deprivation therapy (ADT) and more rapid disease onset. In a separate study published in the same issue (JAMA Oncol. 2017 Oct 12. doi: 10.1001/jamaoncol.2017.3164) investigators provided additional evidence, showing that the genotype was associated with more rapid metastasis development in men with localized prostate cancer who received ADT for biochemical recurrence after radiation treatment.

In that observational study of 218 men treated between 1996 and 2003, median time to metastasis (TTM) decreased according to the number of inherited variant alleles, wrote Jason W. D. Hearn, MD, University of Michigan, Ann Arbor, and coauthors. Those with no variant HSD3B1(1245C) alleles had a TTM of 7.4 months, while those with one allele had a TTM of 5.8 months, and for those with two, TTM was only 4.4 months (P = .03).

However, investigators could not detect any such relationship between variant HSD3B1(1245C) alleles and time to progression (TTP) or overall survival (OS): “It is possible that the high rates of prior ADT exposure and frequent use of androgen receptor (AR) antagonists during salvage ADT modified the impact of genotype with respect to composite TTP and OS,” Dr. Hearn and colleagues wrote. “Nonetheless, the large impact on TTM is statistically and clinically significant.”

While the findings of Dr. Hearn and colleagues bolster existing knowledge that variant HSD3B1(1245C) alleles are associated with poorer outcomes in prostate cancer, the findings from Dr. Almassi and colleagues add new insights regarding the potential role of CYP17A1 inhibitors in patients with this genotype.

“As only a proportion of patients treated with potent CYP17A1 inhibitors or AR antagonists respond clinically, a predictive biomarker for the identification of patients who benefit would undoubtedly have clinical value,” Dr. Almassi and colleagues said.

The findings are somewhat limited, however, because they were focused on ketoconazole, a nonsteroidal CYP17A1 inhibitor that is no longer routinely used in clinic for prostate cancer.

Similar studies of the steroidal CYP17A1 inhibitor abiraterone acetate would be possible, however, “steroidal metabolites of [steroidal CYP17A1 inhibitors] make evaluation more complex,” Dr. Almassi and colleagues wrote.

In patients with castration-resistant prostate cancer (CRPC), a variant of the HSD3B1 gene predicts sensitivity to the CYP17A1 inhibitor ketoconazole, according to results of a single-center, observational study including 90 men treated between June 1998 and December 2012.

Median progression-free survival (PFS) increased along with the number of variant HSD3B1(1245C) alleles, wrote Nima Almassi, MD, of the Cleveland Clinic, and coauthors (JAMA Oncol. 2017 Oct 12. doi: 10.1001/jamaoncol.2017.3159).

Specifically, median PFS was just 5.0 months for patients with no variant HSD3B1(1245C) alleles, 7.5 months for patients with one allele, and 12.3 months for those with two alleles (P = .03).

“These findings suggest that the variant allele … may be a predictive biomarker of tumor vulnerability to pharmacologic CYP17A1 inhibition with a nonsteroidal drug,” Dr. Almassi and colleagues wrote.

The HSD3B1(1245C) germline variant was already known in the prostate cancer research community as a marker of tumor resistance to androgen deprivation therapy (ADT) and more rapid disease onset. In a separate study published in the same issue (JAMA Oncol. 2017 Oct 12. doi: 10.1001/jamaoncol.2017.3164) investigators provided additional evidence, showing that the genotype was associated with more rapid metastasis development in men with localized prostate cancer who received ADT for biochemical recurrence after radiation treatment.

In that observational study of 218 men treated between 1996 and 2003, median time to metastasis (TTM) decreased according to the number of inherited variant alleles, wrote Jason W. D. Hearn, MD, University of Michigan, Ann Arbor, and coauthors. Those with no variant HSD3B1(1245C) alleles had a TTM of 7.4 months, while those with one allele had a TTM of 5.8 months, and for those with two, TTM was only 4.4 months (P = .03).

However, investigators could not detect any such relationship between variant HSD3B1(1245C) alleles and time to progression (TTP) or overall survival (OS): “It is possible that the high rates of prior ADT exposure and frequent use of androgen receptor (AR) antagonists during salvage ADT modified the impact of genotype with respect to composite TTP and OS,” Dr. Hearn and colleagues wrote. “Nonetheless, the large impact on TTM is statistically and clinically significant.”

While the findings of Dr. Hearn and colleagues bolster existing knowledge that variant HSD3B1(1245C) alleles are associated with poorer outcomes in prostate cancer, the findings from Dr. Almassi and colleagues add new insights regarding the potential role of CYP17A1 inhibitors in patients with this genotype.

“As only a proportion of patients treated with potent CYP17A1 inhibitors or AR antagonists respond clinically, a predictive biomarker for the identification of patients who benefit would undoubtedly have clinical value,” Dr. Almassi and colleagues said.

The findings are somewhat limited, however, because they were focused on ketoconazole, a nonsteroidal CYP17A1 inhibitor that is no longer routinely used in clinic for prostate cancer.

Similar studies of the steroidal CYP17A1 inhibitor abiraterone acetate would be possible, however, “steroidal metabolites of [steroidal CYP17A1 inhibitors] make evaluation more complex,” Dr. Almassi and colleagues wrote.

The VA has boiled down its experience in dealing with the opioid epidemic to 8 best practices, which it is now sharing with others in government and the health care industry who work to balance pain management and opioid prescribing. 

The best practices are summed up by the acronym STOP PAIN, which stands for:

• S—Stepped Care Model, which encourages a continuum of care from onset through treatment. It also incorporates self-management through participation in groups such as Narcotics or Alcoholics Anonymous, counseling, treatment programs, primary care, and other medical specialists;
• T—Treatment alternatives/complementary care, expanding provider options beyond standard care in treating chronic pain. “Complementary health” includes evidence-based treatments, such as acupuncture, yoga, and progressive relaxation;

Related:  Implementation and Evaluation of an APRN-Led Opioid Monitoring Clinic

• O—Ongoing monitoring of usage;
• P—Practice guidelines, which provide evidence-based recommendations for minimizing harm and increasing patient safety. (https://www.healthquality.va.gov/guidelines/MH/sud/ and https://www.healthquality.va.gov/guidelines/Pain/cot/);
• P—Prescription monitoring. The VA has a number of data sources to allow it to monitor opioid use to target specific education in real time. The practice patterns of providers differ, along with the case mixes: a provider with relatively high opioid prescribing may have an appropriate practice, or be someone who could benefit from education. These tools allow the VA to drill down to the patient level to evaluate use. Other tools can evaluate the treatment of patient panels and the veterans’ risk of potential abuse. Together, these allow identification of potential problems, educational targeting, and tracking of progress;

Related: Prescribing Patterns Shift After Detailing-Policy Change

• A—Academic detailing. The Academic Detailing program, a one-on-one peer education program for frontline providers, gives specific information on practice alternatives and resources, opioid safety, and can compare the practice of the provider to that of peers; (https://www.pbm.va.gov/PBM/academicdetailingservicehome.asp and

https://www.pbm.va.gov/PBM/academicdetailingservice/Pain_and_Opioid_Safety.asp)

• I—Informed consent for patients prior to long-term opioid therapy. This process includes education on the risks of opioid therapy, opioid interactions, and safe prescribing practices such as urine drug screens; and
• N—Naloxone distribution. The Opioid Overdose Education & Naloxone Distribution program focuses on educating providers (https://www.pbm.va.gov/PBM/academicdetailingservice/Opioid_Overdose_Education_and_Naloxone_Distribution.asp).

For more information, visit https://www.va.gov/painmanagement.

The VA has boiled down its experience in dealing with the opioid epidemic to 8 best practices, which it is now sharing with others in government and the health care industry who work to balance pain management and opioid prescribing. 

The best practices are summed up by the acronym STOP PAIN, which stands for:

• S—Stepped Care Model, which encourages a continuum of care from onset through treatment. It also incorporates self-management through participation in groups such as Narcotics or Alcoholics Anonymous, counseling, treatment programs, primary care, and other medical specialists;
• T—Treatment alternatives/complementary care, expanding provider options beyond standard care in treating chronic pain. “Complementary health” includes evidence-based treatments, such as acupuncture, yoga, and progressive relaxation;

Related:  Implementation and Evaluation of an APRN-Led Opioid Monitoring Clinic

• O—Ongoing monitoring of usage;
• P—Practice guidelines, which provide evidence-based recommendations for minimizing harm and increasing patient safety. (https://www.healthquality.va.gov/guidelines/MH/sud/ and https://www.healthquality.va.gov/guidelines/Pain/cot/);
• P—Prescription monitoring. The VA has a number of data sources to allow it to monitor opioid use to target specific education in real time. The practice patterns of providers differ, along with the case mixes: a provider with relatively high opioid prescribing may have an appropriate practice, or be someone who could benefit from education. These tools allow the VA to drill down to the patient level to evaluate use. Other tools can evaluate the treatment of patient panels and the veterans’ risk of potential abuse. Together, these allow identification of potential problems, educational targeting, and tracking of progress;

Related: Prescribing Patterns Shift After Detailing-Policy Change

• A—Academic detailing. The Academic Detailing program, a one-on-one peer education program for frontline providers, gives specific information on practice alternatives and resources, opioid safety, and can compare the practice of the provider to that of peers; (https://www.pbm.va.gov/PBM/academicdetailingservicehome.asp and

https://www.pbm.va.gov/PBM/academicdetailingservice/Pain_and_Opioid_Safety.asp)

• I—Informed consent for patients prior to long-term opioid therapy. This process includes education on the risks of opioid therapy, opioid interactions, and safe prescribing practices such as urine drug screens; and
• N—Naloxone distribution. The Opioid Overdose Education & Naloxone Distribution program focuses on educating providers (https://www.pbm.va.gov/PBM/academicdetailingservice/Opioid_Overdose_Education_and_Naloxone_Distribution.asp).

For more information, visit https://www.va.gov/painmanagement.

The VA has boiled down its experience in dealing with the opioid epidemic to 8 best practices, which it is now sharing with others in government and the health care industry who work to balance pain management and opioid prescribing. 

The best practices are summed up by the acronym STOP PAIN, which stands for:

• S—Stepped Care Model, which encourages a continuum of care from onset through treatment. It also incorporates self-management through participation in groups such as Narcotics or Alcoholics Anonymous, counseling, treatment programs, primary care, and other medical specialists;
• T—Treatment alternatives/complementary care, expanding provider options beyond standard care in treating chronic pain. “Complementary health” includes evidence-based treatments, such as acupuncture, yoga, and progressive relaxation;

Related:  Implementation and Evaluation of an APRN-Led Opioid Monitoring Clinic

• O—Ongoing monitoring of usage;
• P—Practice guidelines, which provide evidence-based recommendations for minimizing harm and increasing patient safety. (https://www.healthquality.va.gov/guidelines/MH/sud/ and https://www.healthquality.va.gov/guidelines/Pain/cot/);
• P—Prescription monitoring. The VA has a number of data sources to allow it to monitor opioid use to target specific education in real time. The practice patterns of providers differ, along with the case mixes: a provider with relatively high opioid prescribing may have an appropriate practice, or be someone who could benefit from education. These tools allow the VA to drill down to the patient level to evaluate use. Other tools can evaluate the treatment of patient panels and the veterans’ risk of potential abuse. Together, these allow identification of potential problems, educational targeting, and tracking of progress;

Related: Prescribing Patterns Shift After Detailing-Policy Change

• A—Academic detailing. The Academic Detailing program, a one-on-one peer education program for frontline providers, gives specific information on practice alternatives and resources, opioid safety, and can compare the practice of the provider to that of peers; (https://www.pbm.va.gov/PBM/academicdetailingservicehome.asp and

https://www.pbm.va.gov/PBM/academicdetailingservice/Pain_and_Opioid_Safety.asp)

• I—Informed consent for patients prior to long-term opioid therapy. This process includes education on the risks of opioid therapy, opioid interactions, and safe prescribing practices such as urine drug screens; and
• N—Naloxone distribution. The Opioid Overdose Education & Naloxone Distribution program focuses on educating providers (https://www.pbm.va.gov/PBM/academicdetailingservice/Opioid_Overdose_Education_and_Naloxone_Distribution.asp).

For more information, visit https://www.va.gov/painmanagement.

A 40-year-old man suddenly began to lose vision in his left eye. The retinal exam was normal for the right eye. But the left showed isolated subinternal limited membrane hemorrhage at the fovea along with a white-centered hemorrhage above the fovea.

The patient had no history of trauma or Valsalva retinopathy. His blood pressure was normal as was his blood glucose. However, when bloodwork showed a high total count, increased platelet count, and the peripheral smear indicated myeloid hyperplasia, clinicians at LV Prasad Eye Institute in Hyderabad, India, diagnosed the patient with underlying chronic myeloid leukemia (CML).  

A physical examination revealed a palpable spleenomegaly—underscoring the fact, the clinicians note, that when an ophthalmologic finding suggests a systemic disease, a general physical examination will reveal more clinical clues. The patient was referred to an oncologist and started on imatinib for CML.

White-centered or pale-centered hemorrhages are believed to represent an accumulation of leukemic cells or platelet fibrin aggregates, the clinicians say. Blood dyscrasias, such as anemias, leukemia, multiple myeloma, and other platelet disorders may present with similar features. Such hemorrhages are known to resolve spontaneously when the patient is treated for the underlying condition, and the hematologic status improves, the clinicians say. This patient’s hemorrhage gradually resolved over the next month, and his visual acuity improved to 20/20.

Ocular manifestations as a presenting sign of leukemia, especially chronic, are rare, the clinicians say. They note that retinal hemorrhages are one of the “most striking findings” in leukemia, and because they can be directly observed, they provide a “subtle but important clue toward an otherwise asymptomatic disease.” If diagnosed early and treated promptly, patients with CML have a good survival rate.

Source:

Tyagi M, Agarwal K, Paulose RM, Rani PK. BMJ Case Rep. 2017;2017: pii: bcr-2017-21974.

doi: 10.1136/bcr-2017-219741.

A 40-year-old man suddenly began to lose vision in his left eye. The retinal exam was normal for the right eye. But the left showed isolated subinternal limited membrane hemorrhage at the fovea along with a white-centered hemorrhage above the fovea.

The patient had no history of trauma or Valsalva retinopathy. His blood pressure was normal as was his blood glucose. However, when bloodwork showed a high total count, increased platelet count, and the peripheral smear indicated myeloid hyperplasia, clinicians at LV Prasad Eye Institute in Hyderabad, India, diagnosed the patient with underlying chronic myeloid leukemia (CML).  

A physical examination revealed a palpable spleenomegaly—underscoring the fact, the clinicians note, that when an ophthalmologic finding suggests a systemic disease, a general physical examination will reveal more clinical clues. The patient was referred to an oncologist and started on imatinib for CML.

White-centered or pale-centered hemorrhages are believed to represent an accumulation of leukemic cells or platelet fibrin aggregates, the clinicians say. Blood dyscrasias, such as anemias, leukemia, multiple myeloma, and other platelet disorders may present with similar features. Such hemorrhages are known to resolve spontaneously when the patient is treated for the underlying condition, and the hematologic status improves, the clinicians say. This patient’s hemorrhage gradually resolved over the next month, and his visual acuity improved to 20/20.

Ocular manifestations as a presenting sign of leukemia, especially chronic, are rare, the clinicians say. They note that retinal hemorrhages are one of the “most striking findings” in leukemia, and because they can be directly observed, they provide a “subtle but important clue toward an otherwise asymptomatic disease.” If diagnosed early and treated promptly, patients with CML have a good survival rate.

Source:

Tyagi M, Agarwal K, Paulose RM, Rani PK. BMJ Case Rep. 2017;2017: pii: bcr-2017-21974.

doi: 10.1136/bcr-2017-219741.

A 40-year-old man suddenly began to lose vision in his left eye. The retinal exam was normal for the right eye. But the left showed isolated subinternal limited membrane hemorrhage at the fovea along with a white-centered hemorrhage above the fovea.

The patient had no history of trauma or Valsalva retinopathy. His blood pressure was normal as was his blood glucose. However, when bloodwork showed a high total count, increased platelet count, and the peripheral smear indicated myeloid hyperplasia, clinicians at LV Prasad Eye Institute in Hyderabad, India, diagnosed the patient with underlying chronic myeloid leukemia (CML).  

A physical examination revealed a palpable spleenomegaly—underscoring the fact, the clinicians note, that when an ophthalmologic finding suggests a systemic disease, a general physical examination will reveal more clinical clues. The patient was referred to an oncologist and started on imatinib for CML.

White-centered or pale-centered hemorrhages are believed to represent an accumulation of leukemic cells or platelet fibrin aggregates, the clinicians say. Blood dyscrasias, such as anemias, leukemia, multiple myeloma, and other platelet disorders may present with similar features. Such hemorrhages are known to resolve spontaneously when the patient is treated for the underlying condition, and the hematologic status improves, the clinicians say. This patient’s hemorrhage gradually resolved over the next month, and his visual acuity improved to 20/20.

Ocular manifestations as a presenting sign of leukemia, especially chronic, are rare, the clinicians say. They note that retinal hemorrhages are one of the “most striking findings” in leukemia, and because they can be directly observed, they provide a “subtle but important clue toward an otherwise asymptomatic disease.” If diagnosed early and treated promptly, patients with CML have a good survival rate.

Source:

Tyagi M, Agarwal K, Paulose RM, Rani PK. BMJ Case Rep. 2017;2017: pii: bcr-2017-21974.

doi: 10.1136/bcr-2017-219741.

Photo by Bill Branson

Vaccination may fail to protect young leukemia patients from developing influenza during cancer treatment, according to research published in the Journal of Pediatrics.

Researchers found that young patients with acute leukemia who received flu shots were just as likely as their unvaccinated peers to develop the flu.

The team said these results are preliminary, but they suggest a need for more research and additional efforts to prevent flu in young patients with leukemia.

“The annual flu shot, whose side effects are generally mild and short-lived, is still recommended for patients with acute leukemia who are being treated for their disease,” said study author Elisabeth Adderson, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“However, the results do highlight the need for additional research in this area and for us to redouble our efforts to protect our patients through other means.”

In this retrospective study, Dr Adderson and her colleagues looked at rates of flu infection during 3 successive flu seasons (2010-2013) in 498 patients treated for acute leukemia at St. Jude.

The patients’ median age was 6 years (range, 1-21). Most patients had acute lymphoblastic leukemia (ALL, 94%), though some had acute myeloid leukemia (4.8%) or mixed-lineage leukemia (1.2%).

Most patients (n=354) received flu shots, including 98 patients who received booster doses. The remaining 144 patients were not vaccinated.

The vaccinated patients received the trivalent vaccine, which is designed to protect against 3 flu strains predicted to be in wide circulation during a particular flu season. The vaccine was a fairly good match for circulating flu viruses during the flu seasons included in this analysis.

Demographic characteristic were largely similar between vaccinated and unvaccinated patients. The exceptions were that more vaccinated patients had ALL (95.5% vs 90.3%; P=0.034) and vaccinated patients were more likely to be in a low-intensity phase of cancer therapy (90.7% vs 73.6%, P<0.0001).

Results

There were no significant differences between vaccinated and unvaccinated patients when it came to flu rates or rates of flu-like illnesses.

There were 37 episodes of flu in vaccinated patients and 16 episodes in unvaccinated patients. The rates (per 1000 patient days) were 0.73 and 0.70, respectively (P=0.874).

There were 123 cases of flu-like illnesses in vaccinated patients and 55 cases in unvaccinated patients. The rates were 2.44 and 2.41, respectively (P=0.932).

Likewise, there was no significant difference in the rates of flu or flu-like illnesses between patients who received 1 dose of flu vaccine and those who received 2 doses.

The flu rates were 0.60 and 1.02, respectively (P=0.107). And the rates of flu-like illnesses were 2.42 and 2.73, respectively (P=0.529).

Dr Adderson said additional research is needed to determine if a subset of young leukemia patients may benefit from vaccination.

She added that patients at risk of flu should practice good hand hygiene and avoid crowds during the flu season. Patients may also benefit from “cocooning,” a process that focuses on getting family members, healthcare providers, and others in close contact with at-risk patients vaccinated.

Photo by Bill Branson

Vaccination may fail to protect young leukemia patients from developing influenza during cancer treatment, according to research published in the Journal of Pediatrics.

Researchers found that young patients with acute leukemia who received flu shots were just as likely as their unvaccinated peers to develop the flu.

The team said these results are preliminary, but they suggest a need for more research and additional efforts to prevent flu in young patients with leukemia.

“The annual flu shot, whose side effects are generally mild and short-lived, is still recommended for patients with acute leukemia who are being treated for their disease,” said study author Elisabeth Adderson, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“However, the results do highlight the need for additional research in this area and for us to redouble our efforts to protect our patients through other means.”

In this retrospective study, Dr Adderson and her colleagues looked at rates of flu infection during 3 successive flu seasons (2010-2013) in 498 patients treated for acute leukemia at St. Jude.

The patients’ median age was 6 years (range, 1-21). Most patients had acute lymphoblastic leukemia (ALL, 94%), though some had acute myeloid leukemia (4.8%) or mixed-lineage leukemia (1.2%).

Most patients (n=354) received flu shots, including 98 patients who received booster doses. The remaining 144 patients were not vaccinated.

The vaccinated patients received the trivalent vaccine, which is designed to protect against 3 flu strains predicted to be in wide circulation during a particular flu season. The vaccine was a fairly good match for circulating flu viruses during the flu seasons included in this analysis.

Demographic characteristic were largely similar between vaccinated and unvaccinated patients. The exceptions were that more vaccinated patients had ALL (95.5% vs 90.3%; P=0.034) and vaccinated patients were more likely to be in a low-intensity phase of cancer therapy (90.7% vs 73.6%, P<0.0001).

Results

There were no significant differences between vaccinated and unvaccinated patients when it came to flu rates or rates of flu-like illnesses.

There were 37 episodes of flu in vaccinated patients and 16 episodes in unvaccinated patients. The rates (per 1000 patient days) were 0.73 and 0.70, respectively (P=0.874).

There were 123 cases of flu-like illnesses in vaccinated patients and 55 cases in unvaccinated patients. The rates were 2.44 and 2.41, respectively (P=0.932).

Likewise, there was no significant difference in the rates of flu or flu-like illnesses between patients who received 1 dose of flu vaccine and those who received 2 doses.

The flu rates were 0.60 and 1.02, respectively (P=0.107). And the rates of flu-like illnesses were 2.42 and 2.73, respectively (P=0.529).

Dr Adderson said additional research is needed to determine if a subset of young leukemia patients may benefit from vaccination.

She added that patients at risk of flu should practice good hand hygiene and avoid crowds during the flu season. Patients may also benefit from “cocooning,” a process that focuses on getting family members, healthcare providers, and others in close contact with at-risk patients vaccinated.

Photo by Bill Branson

Vaccination may fail to protect young leukemia patients from developing influenza during cancer treatment, according to research published in the Journal of Pediatrics.

Researchers found that young patients with acute leukemia who received flu shots were just as likely as their unvaccinated peers to develop the flu.

The team said these results are preliminary, but they suggest a need for more research and additional efforts to prevent flu in young patients with leukemia.

“The annual flu shot, whose side effects are generally mild and short-lived, is still recommended for patients with acute leukemia who are being treated for their disease,” said study author Elisabeth Adderson, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“However, the results do highlight the need for additional research in this area and for us to redouble our efforts to protect our patients through other means.”

In this retrospective study, Dr Adderson and her colleagues looked at rates of flu infection during 3 successive flu seasons (2010-2013) in 498 patients treated for acute leukemia at St. Jude.

The patients’ median age was 6 years (range, 1-21). Most patients had acute lymphoblastic leukemia (ALL, 94%), though some had acute myeloid leukemia (4.8%) or mixed-lineage leukemia (1.2%).

Most patients (n=354) received flu shots, including 98 patients who received booster doses. The remaining 144 patients were not vaccinated.

The vaccinated patients received the trivalent vaccine, which is designed to protect against 3 flu strains predicted to be in wide circulation during a particular flu season. The vaccine was a fairly good match for circulating flu viruses during the flu seasons included in this analysis.

Demographic characteristic were largely similar between vaccinated and unvaccinated patients. The exceptions were that more vaccinated patients had ALL (95.5% vs 90.3%; P=0.034) and vaccinated patients were more likely to be in a low-intensity phase of cancer therapy (90.7% vs 73.6%, P<0.0001).

Results

There were no significant differences between vaccinated and unvaccinated patients when it came to flu rates or rates of flu-like illnesses.

There were 37 episodes of flu in vaccinated patients and 16 episodes in unvaccinated patients. The rates (per 1000 patient days) were 0.73 and 0.70, respectively (P=0.874).

There were 123 cases of flu-like illnesses in vaccinated patients and 55 cases in unvaccinated patients. The rates were 2.44 and 2.41, respectively (P=0.932).

Likewise, there was no significant difference in the rates of flu or flu-like illnesses between patients who received 1 dose of flu vaccine and those who received 2 doses.

The flu rates were 0.60 and 1.02, respectively (P=0.107). And the rates of flu-like illnesses were 2.42 and 2.73, respectively (P=0.529).

Dr Adderson said additional research is needed to determine if a subset of young leukemia patients may benefit from vaccination.

She added that patients at risk of flu should practice good hand hygiene and avoid crowds during the flu season. Patients may also benefit from “cocooning,” a process that focuses on getting family members, healthcare providers, and others in close contact with at-risk patients vaccinated.

mycosis fungoides

LONDON—Results of a phase 2 trial suggest the topical histone deacetylase (HDAC) inhibitor remetinostat can elicit responses in patients with early stage mycosis fungoides (MF).

At the highest dose level tested, remetinostat gel reduced the severity of skin lesions in 40% of patients and reduced the severity of pruritus in 80% of patients.

In addition, the HDAC inhibitor was considered well tolerated and did not produce systemic adverse effects.

These results were presented at the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Task Force meeting, which took place October 13-15.

The study was sponsored by Medivir AB, which purchased remetinostat from TetraLogic Pharmaceuticals last year.

The trial of remetinostat enrolled 60 patients with stage IA-IIA MF across 5 clinical sites in the US. Patients were randomized to receive remetinostat gel 0.5% twice daily, remetinostat gel 1% once daily, or remetinostat gel 1% twice daily for up to 12 months.

The study’s primary endpoint was the proportion of patients with a confirmed response to therapy, assessed using the Composite Assessment of Index Lesion Severity.

The researchers observed a dose response, with patients in the 1% twice-daily arm having the highest proportion of confirmed responses.

Based on an intent-to-treat analysis, confirmed response rates were as follows:

The researchers also assessed the effect of remetinostat gel on the severity of pruritus. This was assessed monthly for the duration of the study using the visual analogue scale.

Among patients with clinically significant pruritus at baseline, those who received remetinostat gel 1% twice daily were most likely to have a clinically significant reduction in pruritus. This was defined as at least a 30 mm reduction in the visual analogue scale score sustained for more than 4 weeks.

The proportion of patients who had confirmed, clinically significant reductions in pruritus from baseline was 80% in the 1% twice-daily arm, 50% in the 0.5% twice-daily arm, and 37.5% in the 1% once-daily arm.

The researchers said remetinostat was generally well tolerated, with adverse events evenly distributed across the treatment arms. The most common adverse events were skin-related and mostly grade 1-2.

There were no signs of systemic adverse effects related to remetinostat, including those associated with systemic HDAC inhibitors.

Most patients remained on study for the maximum possible duration, and the median treatment time was 350 days.

Based on the outcomes of this study, Medivir expects to meet with regulatory authorities to discuss the design of a pivotal clinical program for remetinostat in MF.

mycosis fungoides

LONDON—Results of a phase 2 trial suggest the topical histone deacetylase (HDAC) inhibitor remetinostat can elicit responses in patients with early stage mycosis fungoides (MF).

At the highest dose level tested, remetinostat gel reduced the severity of skin lesions in 40% of patients and reduced the severity of pruritus in 80% of patients.

In addition, the HDAC inhibitor was considered well tolerated and did not produce systemic adverse effects.

These results were presented at the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Task Force meeting, which took place October 13-15.

The study was sponsored by Medivir AB, which purchased remetinostat from TetraLogic Pharmaceuticals last year.

The trial of remetinostat enrolled 60 patients with stage IA-IIA MF across 5 clinical sites in the US. Patients were randomized to receive remetinostat gel 0.5% twice daily, remetinostat gel 1% once daily, or remetinostat gel 1% twice daily for up to 12 months.

The study’s primary endpoint was the proportion of patients with a confirmed response to therapy, assessed using the Composite Assessment of Index Lesion Severity.

The researchers observed a dose response, with patients in the 1% twice-daily arm having the highest proportion of confirmed responses.

Based on an intent-to-treat analysis, confirmed response rates were as follows:

The researchers also assessed the effect of remetinostat gel on the severity of pruritus. This was assessed monthly for the duration of the study using the visual analogue scale.

Among patients with clinically significant pruritus at baseline, those who received remetinostat gel 1% twice daily were most likely to have a clinically significant reduction in pruritus. This was defined as at least a 30 mm reduction in the visual analogue scale score sustained for more than 4 weeks.

The proportion of patients who had confirmed, clinically significant reductions in pruritus from baseline was 80% in the 1% twice-daily arm, 50% in the 0.5% twice-daily arm, and 37.5% in the 1% once-daily arm.

The researchers said remetinostat was generally well tolerated, with adverse events evenly distributed across the treatment arms. The most common adverse events were skin-related and mostly grade 1-2.

There were no signs of systemic adverse effects related to remetinostat, including those associated with systemic HDAC inhibitors.

Most patients remained on study for the maximum possible duration, and the median treatment time was 350 days.

Based on the outcomes of this study, Medivir expects to meet with regulatory authorities to discuss the design of a pivotal clinical program for remetinostat in MF.

mycosis fungoides

LONDON—Results of a phase 2 trial suggest the topical histone deacetylase (HDAC) inhibitor remetinostat can elicit responses in patients with early stage mycosis fungoides (MF).

At the highest dose level tested, remetinostat gel reduced the severity of skin lesions in 40% of patients and reduced the severity of pruritus in 80% of patients.

In addition, the HDAC inhibitor was considered well tolerated and did not produce systemic adverse effects.

These results were presented at the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Task Force meeting, which took place October 13-15.

The study was sponsored by Medivir AB, which purchased remetinostat from TetraLogic Pharmaceuticals last year.

The trial of remetinostat enrolled 60 patients with stage IA-IIA MF across 5 clinical sites in the US. Patients were randomized to receive remetinostat gel 0.5% twice daily, remetinostat gel 1% once daily, or remetinostat gel 1% twice daily for up to 12 months.

The study’s primary endpoint was the proportion of patients with a confirmed response to therapy, assessed using the Composite Assessment of Index Lesion Severity.

The researchers observed a dose response, with patients in the 1% twice-daily arm having the highest proportion of confirmed responses.

Based on an intent-to-treat analysis, confirmed response rates were as follows:

The researchers also assessed the effect of remetinostat gel on the severity of pruritus. This was assessed monthly for the duration of the study using the visual analogue scale.

Among patients with clinically significant pruritus at baseline, those who received remetinostat gel 1% twice daily were most likely to have a clinically significant reduction in pruritus. This was defined as at least a 30 mm reduction in the visual analogue scale score sustained for more than 4 weeks.

The proportion of patients who had confirmed, clinically significant reductions in pruritus from baseline was 80% in the 1% twice-daily arm, 50% in the 0.5% twice-daily arm, and 37.5% in the 1% once-daily arm.

The researchers said remetinostat was generally well tolerated, with adverse events evenly distributed across the treatment arms. The most common adverse events were skin-related and mostly grade 1-2.

There were no signs of systemic adverse effects related to remetinostat, including those associated with systemic HDAC inhibitors.

Most patients remained on study for the maximum possible duration, and the median treatment time was 350 days.

Based on the outcomes of this study, Medivir expects to meet with regulatory authorities to discuss the design of a pivotal clinical program for remetinostat in MF.

Angelyn Nguyen/UCLA

Biophysicists have developed a new method to determine a cell’s mechanical properties, and they believe this method could provide insights regarding cancers, sickle cell anemia, and other diseases.

The method allows researchers to make standardized measurements of single cells, determine each cell’s stiffness, and assign it a number, generally between 10 and 20,000, in pascals.

“Measuring cells with our calibrated instrument is like measuring time with a standardized clock,” said Amy Rowat, PhD, of the University of California Los Angeles.

“Our method can be used to obtain stiffness measurements of hundreds of cells per second.”

Dr Rowat and her colleagues described their method in Biophysical Journal.

The method is called quantitative deformability cytometry (q-DC). It involves a small device (about 1 inch by 2 inches) made of a soft, flexible rubber that has integrated circuit chips like those in computers.

The researchers use gel particles containing molecules derived from seaweed to force cells through tiny pores in the device. As the cells flow through the device, the researchers take videos at thousands of frames per second—more than 100 times faster than standard video.

Dr Rowat and her colleagues used the device to analyze promyelocytic leukemia cells (HL-60) and breast cancer cells.

The researchers believe this work will provide scientists with a more precise, standardized method to distinguish cancer cells from normal cells.

The team thinks that, in the future, their method could be used to track a cancer patient over time to see how a drug is affecting the patient’s cancer cells.

“By using q-DC, we can very rapidly assess how specific drug treatments affect physical properties of single cells—such as shape, size, and stiffness—and achieve calibrated, quantitative measurements,” Dr Rowat said.

She and her colleagues believe q-DC might also help predict how invasive a cancer cell could be and which drugs might be most effective in fighting the cancer, as well as revealing which proteins are important in regulating the invasion of a cancer cell.

The researchers are now applying q-DC to other types of cancer cells. The team would like to better understand the relationship between a cancer cell’s physical properties and how easily cancer cells can spread through the body.

Dr Rowat’s hypothesis is that properties such as stiffness, size, and a cell’s ability to change shape are important in enabling cancer cells to maneuver.

The researchers said they can also use q-DC to measure other types of cells, such as normal and sickled red blood cells.

Angelyn Nguyen/UCLA

Biophysicists have developed a new method to determine a cell’s mechanical properties, and they believe this method could provide insights regarding cancers, sickle cell anemia, and other diseases.

The method allows researchers to make standardized measurements of single cells, determine each cell’s stiffness, and assign it a number, generally between 10 and 20,000, in pascals.

“Measuring cells with our calibrated instrument is like measuring time with a standardized clock,” said Amy Rowat, PhD, of the University of California Los Angeles.

“Our method can be used to obtain stiffness measurements of hundreds of cells per second.”

Dr Rowat and her colleagues described their method in Biophysical Journal.

The method is called quantitative deformability cytometry (q-DC). It involves a small device (about 1 inch by 2 inches) made of a soft, flexible rubber that has integrated circuit chips like those in computers.

The researchers use gel particles containing molecules derived from seaweed to force cells through tiny pores in the device. As the cells flow through the device, the researchers take videos at thousands of frames per second—more than 100 times faster than standard video.

Dr Rowat and her colleagues used the device to analyze promyelocytic leukemia cells (HL-60) and breast cancer cells.

The researchers believe this work will provide scientists with a more precise, standardized method to distinguish cancer cells from normal cells.

The team thinks that, in the future, their method could be used to track a cancer patient over time to see how a drug is affecting the patient’s cancer cells.

“By using q-DC, we can very rapidly assess how specific drug treatments affect physical properties of single cells—such as shape, size, and stiffness—and achieve calibrated, quantitative measurements,” Dr Rowat said.

She and her colleagues believe q-DC might also help predict how invasive a cancer cell could be and which drugs might be most effective in fighting the cancer, as well as revealing which proteins are important in regulating the invasion of a cancer cell.

The researchers are now applying q-DC to other types of cancer cells. The team would like to better understand the relationship between a cancer cell’s physical properties and how easily cancer cells can spread through the body.

Dr Rowat’s hypothesis is that properties such as stiffness, size, and a cell’s ability to change shape are important in enabling cancer cells to maneuver.

The researchers said they can also use q-DC to measure other types of cells, such as normal and sickled red blood cells.

Angelyn Nguyen/UCLA

Biophysicists have developed a new method to determine a cell’s mechanical properties, and they believe this method could provide insights regarding cancers, sickle cell anemia, and other diseases.

The method allows researchers to make standardized measurements of single cells, determine each cell’s stiffness, and assign it a number, generally between 10 and 20,000, in pascals.

“Measuring cells with our calibrated instrument is like measuring time with a standardized clock,” said Amy Rowat, PhD, of the University of California Los Angeles.

“Our method can be used to obtain stiffness measurements of hundreds of cells per second.”

Dr Rowat and her colleagues described their method in Biophysical Journal.

The method is called quantitative deformability cytometry (q-DC). It involves a small device (about 1 inch by 2 inches) made of a soft, flexible rubber that has integrated circuit chips like those in computers.

The researchers use gel particles containing molecules derived from seaweed to force cells through tiny pores in the device. As the cells flow through the device, the researchers take videos at thousands of frames per second—more than 100 times faster than standard video.

Dr Rowat and her colleagues used the device to analyze promyelocytic leukemia cells (HL-60) and breast cancer cells.

The researchers believe this work will provide scientists with a more precise, standardized method to distinguish cancer cells from normal cells.

The team thinks that, in the future, their method could be used to track a cancer patient over time to see how a drug is affecting the patient’s cancer cells.

“By using q-DC, we can very rapidly assess how specific drug treatments affect physical properties of single cells—such as shape, size, and stiffness—and achieve calibrated, quantitative measurements,” Dr Rowat said.

She and her colleagues believe q-DC might also help predict how invasive a cancer cell could be and which drugs might be most effective in fighting the cancer, as well as revealing which proteins are important in regulating the invasion of a cancer cell.

The researchers are now applying q-DC to other types of cancer cells. The team would like to better understand the relationship between a cancer cell’s physical properties and how easily cancer cells can spread through the body.

Dr Rowat’s hypothesis is that properties such as stiffness, size, and a cell’s ability to change shape are important in enabling cancer cells to maneuver.

The researchers said they can also use q-DC to measure other types of cells, such as normal and sickled red blood cells.

Case 1 Lola, 28, has a history of muscular aches and joint pain throughout her body, fatigue, and mental fogginess. A rheumatologist diagnosed fibromyalgia, but Lola just moved to your town and is establishing care. She is feeling desperate because her pain has worsened and the medication previously prescribed (gabapentin 300 mg tid) is no longer working. She asks to try oxycodone.

Case 2 Matt is a 59-year-old truck driver with severe hip osteoarthritis (OA). His orthopedist recommended against hip replacement at this time because of his young age and a heart condition that makes him high risk. His pain makes sitting for long periods very difficult. He presents to you for help because he is worried he will be unable to continue working.

Case 3 Keith is a 56-year-old construction worker who has been experiencing back pain for many years. The pain has become more debilitating over time; it is now constant, and Keith can hardly make it through his work day. He has been getting hydrocodone/acetaminophen from urgent care centers and emergency departments, but he isn’t sure it is helping and is coming to you to assume his pain management.

Chronic pain (defined as > 3 mo in duration) is a complex, heterogeneous condition affecting an estimated 116 million US adults.¹ Much of the management of chronic pain occurs in primary care settings, placing family practice providers (FPPs) on the frontlines of two epidemics: that of chronic pain and that of the abuse and misuse of opioid pain medications.

To improve communication about the risks and benefits of opioid therapy and the safety and effectiveness of pain treatments in general, many professional organizations, health care institutions, and recently the CDC, have published guidelines on the use of opioids for nonmalignant chronic pain.² With these guidelines in mind—and in light of the latest evidence—we propose the following paradigm for the treatment of chronic pain. A critical aspect is determining the underlying pathophysiology of a patient’s pain in order to develop a well-rounded, multimodal, evidence-based treatment plan. Detailed here is the application of this approach to the treatment of three common diagnoses: fibromyalgia, osteoarthritis, and low back pain.

LOOK TO THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM

Acute pain begins with activation of peripheral nociceptors at the site of injury. This causes depolarization up the spinal cord and through the brain stem to higher cortical centers where the pain is perceived and localized. Descending neural pathways transport both excitatory and inhibitory information from the brain to the periphery via the spinal cord, which either increases or decreases the perception of pain.³

When damage/injury doesn’t correlate with the perception of pain

Until recently, it was assumed that chronic pain worked much the same way as acute pain and was caused by ongoing nociceptive input in the periphery, but research has shown us that the central nervous system (CNS) can play a large role in the modulation of nociception. This new understanding comes from the lack of evidence pointing to any pain state in which the degree of nociceptive input correlates with the degree of pain experienced.

For most patients with chronic pain, regardless of their diagnosis, there is some degree of alteration in the processing of nociceptive signals by the CNS contributing to the experience of pain.⁴ This alteration is thought to result from peripheral nociceptive signaling persisting past the point of tissue healing, leading to a hypersensitivity of nerve fibers, which then continue to respond to low, or absent, sensory stimuli.

Central sensitization is when this hypersensitivity develops in the superficial, deep, and ventral cord nerves. When this happens, pain is often accompanied by systemic symptoms such as fatigue and slowed cognitive processing, often with little to no actual stimulation of the peripheral nociceptors.³

Table 1 lists the possible mechanisms of pain, which can be broken down into four categories: peripheral nociceptive (inflammatory or mechanical), peripheral neuropathic (underlying damage to a peripheral nerve), central (when the CNS is the primary entity involved in maintaining the pain), or any combination of the three.⁴

As pain becomes chronic, multiple mechanisms overlap

It is important to remember that for any single pain diagnosis, there is likely to be—at least initially—a principle underlying mechanism generating the pain. But as the pain becomes chronic, an overlap of multiple mechanisms develops, with central sensitization often playing a more dominant role than peripheral stimulation (regardless of the diagnosis).

For example, in a patient with rheumatoid arthritis (RA), peripheral nociceptive input (in the form of inflammation) is likely the initial mechanism at work, but as time goes on, central processing becomes more involved. The patient may then begin to experience pain that is disproportionate to what is generally expected with RA and may develop other somatic symptoms. The diagnosis then becomes pain primarily related to RA with central sensitization, and both need to be addressed in a treatment plan. In rheumatic conditions, comorbid fibromyalgia (indicative of central sensitization) is thought to occur in 15% to 30% of patients.⁵

FPPs can utilize the underlying mechanisms to cut across diagnostic labels and tailor treatments to those that are most likely to be effective. For a patient with more prominent peripheral involvement, a procedural intervention such as injections or surgery alone may suffice, whereas a broader approach including psychotherapy, medications, exercise, and other lifestyle interventions may be necessary for a patient with pain caused predominantly by central sensitization.

Addressing both peripheral and central components is essential. One prospective, observational cohort study of more than 600 patients scheduled for unilateral total knee or total hip arthroplasty found that patients with a higher degree of centralization of pain (measured by widespread pain index and modified fibromyalgia screening scales) were less likely to report improvement in the affected body part and in overall body pain following surgery.^6,7

There is a high degree of overlap among many of the chronic pain syndromes (fibromyalgia, irritable bowel syndrome, interstitial cystitis, chronic headaches) that have been found to have a central sensitization component.⁸ Providers of primary care are aptly positioned to recognize central sensitization as the underlying pathology and target treatment effectively.

TAILOR TREATMENT TO THE UNDERLYING MECHANISMS OF PAIN

As with any chronic condition, a thorough workup (complete with history, physical exam, and diagnostic testing, as appropriate) is indicated. In the setting of chronic pain, it’s important to identify the primary mechanism, as well as secondary factors that may contribute to the patient’s pain, before developing your treatment plan. These secondary factors may include co-occurring affect disorders, a history of trauma, poor sleep, and tobacco use.^9-12 A history of trauma, for example, co-exists with many pain syndromes. For these patients, central sensitization is responsible for much of their pain. As a result, traditional cognitive behavioral therapy (CBT) may not be the best option because of its focus on accepting pain as a chronic diagnosis; more trauma-focused treatments, such as those dealing in emotional awareness and understanding of the CNS’s role in chronic pain, need to be considered.¹³

Three common conditions. Below we present evidence-based treatment approaches for conditions typically associated with each of the major mechanisms of chronic pain: fibromyalgia (central sensitization), OA (peripheral nociceptive), and low back pain (mixed pain state).

Fibromyalgia: a case of central sensitization

Fibromyalgia is a hallmark diagnosis for patients in whom central sensitization is the dominant cause of pain. They usually present with widespread, diffuse pain and somatic symptoms such as fatigue, memory difficulties, and poor sleep quality.⁸ When explaining the pain mechanism to patients, it may be useful to use the analogy of a volume control dial that is stuck in the “high” position and can’t be turned down.

Genes, the environment, and neurotransmitters play a role. The origin of the pain amplification process is believed to be multifactorial.

Genetic factors are thought to contribute to a predisposition for amplification. To date, five sets of genes have been implicated in increased sensitivity to pain leading to increased risk of the development of chronic pain during a patient’s lifetime.^14-19

Environmental factors (eg, early life trauma, physical trauma especially to the trunk, certain infections such as Lyme disease and Epstein-Barr virus, and emotional stress) may trigger or exacerbate symptoms.⁸ Of note: Only about 5% to 10% of people who experience these triggers actually develop a chronic pain state, while the rest regain their baseline health.⁴ This raises the question of whether there is a point during an acute pain episode in which one can intervene and prevent the acute pain from becoming chronic in those at higher risk.⁴

Imbalances of neurotransmitters (high glutamate; low norepinephrine, serotonin, and gamma-aminobutyric acid [GABA]) play a role in central amplification.^20-22 These substances not only affect sensory transmission, but also control levels of alertness, sleep, mood, and memory.

The diagnostic criteria for fibromyalgia were modified in 2011 to remove the tender point examination and to add somatic symptoms.⁶ These criteria can be useful in the clinical setting in identifying not only fibromyalgia itself but also the degree of “fibromyalgianess” a patient has, which is an indicator of how large a role the centralization process plays in the maintenance of chronic pain.^23,24

Treatment: multimodal and patient empowering. Evidence-based treatment options for fibromyalgia, as well as other conditions for which there is a high degree of centralized pain, can be found in Table 2.^25-36 Multimodal treatment, with an emphasis on patient knowledge and empowerment, is generally thought to be the most beneficial.^25,37 Treatment should almost always include CBT and exercise/activity therapies, which have high degrees of efficacy with few adverse effects.^26,29

In terms of medication, centrally-acting agents (tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors [SNRIs], and alpha 2 delta ligands) are the most effective. There is little to no data showing benefit from anti-inflammatories or opioids in the setting of fibromyalgia. There is some data to suggest that combination therapy, for example with an SNRI (milnacipran) and an alpha 2 delta ligand (pregabalin), may provide more benefit than treating with pregabalin alone.³⁸

Complementary and alternative therapies (eg, yoga, chiropractic care, acupuncture, massage) are being studied more, and while evidence is only preliminary in terms of efficacy, there is increasing emphasis being placed on the need for patients with chronic pain to shift their treatment expectations to greater acceptance of pain and the need for ongoing self-care.²⁸

OA: an example of peripheral nociceptive pain

OA is a condition long thought to be characterized by damage to the cartilage and bone; however, as with many other pain diagnoses, there is frequently little correlation between damage seen on radiographs and the amount of pain that patients experience.

One study analyzed data on almost 7,000 patients from the National Health and Nutrition Examination Survey (NHANES I) and found that between 30% and 50% of OA patients with moderate to severe radiographic changes were asymptomatic, and 10% of those with moderate to severe pain had normal radiographs or only mild changes.³⁹ Research is showing that many factors may contribute to this discrepancy, including the typical “wear and tear” of the disease, subacute levels of inflammation that can lead to peripheral sensitization, and, in some patients, a centralized pain component.⁴⁰ The patients with more centralized pain often have pain that is disproportionate to radiographic evidence, as well as more somatic symptoms, such as fatigue, sleep disturbance, and memory issues.⁴¹

Treatment should be multimodal and include interventions targeted at halting the progression of damage as well as palliation of pain. All treatment plans for OA should also include exercise, weight reduction, and self-management, in addition to pharmacologic interventions, to reduce both the micro-inflammation and the centralized pain component (when present). Intra-articular injections of various types have been studied with some having more efficacy in pain reduction and functional improvement than others.^42-45 See Table 3 for a summary of evidence-based treatment options.^42-61

Low back pain: a mixed pain state

Low back pain (LBP) has been recognized as a mixed pain state for quite some time. While some patients may experience purely nociceptive and/or neuropathic pain, most cases are nonspecific, with patients experiencing varying degrees of nociceptive (myofascial LBP), neuropathic (lumbar radiculopathy), and central sensitization pain.^62,63 Evidence for centralized pain is demonstrated in studies showing hyperalgesia, augmented central pain processing, involvement of the emotional brain, and delayed recovery influenced by poor coping strategies.^64-67

When developing a treatment plan for a patient with chronic LBP, remember that the pain derives from a complex combination of pathophysiologic contributors. Identifying where a patient lies on the pain centralization spectrum can help you tailor treatment.

In one study of 548 patients presenting to a tertiary pain clinic with primary spine pain diagnoses, 42% met diagnostic criteria for fibromyalgia.⁶⁸ Compared to criteria-negative patients, these patients tended to be younger, unemployed, and receiving compensation; they had greater pain intensity, pain interference, and used stronger words to describe their neuropathic pain, as well as having higher levels of depression/anxiety and a lower level of physical function.

Because LBP is a condition with high prevalence and associated disability, many clinical boards have created guidelines for management. These guidelines tend to vary in the strength of evidence used, and the extent to which they are followed in clinical practice remains largely unknown. Recommendations frequently discourage the use of ultrasound/electrotherapy, but many encourage short-term use of medications, supervised exercise therapy, CBT, and multidisciplinary treatment.

Guidelines tend to differ most widely with regard to recommendations for spinal manipulation and specific drug therapies.⁶⁹ The classes of drugs that may be most useful when centralized pain is present include the SNRIs and the alpha 2 delta calcium channel ligands.⁴ See Table 4 for a summary of evidence-based treatment options.^70-89

Case 1 Lola is started on amitriptyline 25 mg at bedtime, which improves her fatigue and cognitive symptoms. During monthly office visits, her FPP educates her about the pathophysiology of fibromyalgia and uses motivational interviewing to get her slowly moving and increasing her activity level. She is weaned off the gabapentin previously prescribed, as her symptoms stabilize and improve.

Case 2 Matt is sent for a steroid injection, which decreases his pain temporarily. During this time, he begins physical therapy; slowly, with increased movement, his function improves. A trial of duloxetine provides pain relief; that combined with intermittent NSAIDs has allowed Matt to maintain his function and his job.

Case 3 Because Keith was only taking the narcotics intermittently and wasn’t certain they were helping, CBT was sufficient to wean him off the medication without any worsening of his pain in the process. By participating in physical therapy, he has learned how to perform certain tasks at his job without pain or injury. He uses NSAIDs as needed for pain.

The authors thank Drs. Daniel Clauw (University of Michigan, Ann Arbor) and Martha Rumschlag (Providence Family Medicine Residency Program, Southfield, Michigan), for their valuable contributions to this article.

Case 1 Lola, 28, has a history of muscular aches and joint pain throughout her body, fatigue, and mental fogginess. A rheumatologist diagnosed fibromyalgia, but Lola just moved to your town and is establishing care. She is feeling desperate because her pain has worsened and the medication previously prescribed (gabapentin 300 mg tid) is no longer working. She asks to try oxycodone.

Case 2 Matt is a 59-year-old truck driver with severe hip osteoarthritis (OA). His orthopedist recommended against hip replacement at this time because of his young age and a heart condition that makes him high risk. His pain makes sitting for long periods very difficult. He presents to you for help because he is worried he will be unable to continue working.

Case 3 Keith is a 56-year-old construction worker who has been experiencing back pain for many years. The pain has become more debilitating over time; it is now constant, and Keith can hardly make it through his work day. He has been getting hydrocodone/acetaminophen from urgent care centers and emergency departments, but he isn’t sure it is helping and is coming to you to assume his pain management.

Chronic pain (defined as > 3 mo in duration) is a complex, heterogeneous condition affecting an estimated 116 million US adults.¹ Much of the management of chronic pain occurs in primary care settings, placing family practice providers (FPPs) on the frontlines of two epidemics: that of chronic pain and that of the abuse and misuse of opioid pain medications.

To improve communication about the risks and benefits of opioid therapy and the safety and effectiveness of pain treatments in general, many professional organizations, health care institutions, and recently the CDC, have published guidelines on the use of opioids for nonmalignant chronic pain.² With these guidelines in mind—and in light of the latest evidence—we propose the following paradigm for the treatment of chronic pain. A critical aspect is determining the underlying pathophysiology of a patient’s pain in order to develop a well-rounded, multimodal, evidence-based treatment plan. Detailed here is the application of this approach to the treatment of three common diagnoses: fibromyalgia, osteoarthritis, and low back pain.

LOOK TO THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM

Acute pain begins with activation of peripheral nociceptors at the site of injury. This causes depolarization up the spinal cord and through the brain stem to higher cortical centers where the pain is perceived and localized. Descending neural pathways transport both excitatory and inhibitory information from the brain to the periphery via the spinal cord, which either increases or decreases the perception of pain.³

When damage/injury doesn’t correlate with the perception of pain

Until recently, it was assumed that chronic pain worked much the same way as acute pain and was caused by ongoing nociceptive input in the periphery, but research has shown us that the central nervous system (CNS) can play a large role in the modulation of nociception. This new understanding comes from the lack of evidence pointing to any pain state in which the degree of nociceptive input correlates with the degree of pain experienced.

For most patients with chronic pain, regardless of their diagnosis, there is some degree of alteration in the processing of nociceptive signals by the CNS contributing to the experience of pain.⁴ This alteration is thought to result from peripheral nociceptive signaling persisting past the point of tissue healing, leading to a hypersensitivity of nerve fibers, which then continue to respond to low, or absent, sensory stimuli.

Central sensitization is when this hypersensitivity develops in the superficial, deep, and ventral cord nerves. When this happens, pain is often accompanied by systemic symptoms such as fatigue and slowed cognitive processing, often with little to no actual stimulation of the peripheral nociceptors.³

Table 1 lists the possible mechanisms of pain, which can be broken down into four categories: peripheral nociceptive (inflammatory or mechanical), peripheral neuropathic (underlying damage to a peripheral nerve), central (when the CNS is the primary entity involved in maintaining the pain), or any combination of the three.⁴

As pain becomes chronic, multiple mechanisms overlap

It is important to remember that for any single pain diagnosis, there is likely to be—at least initially—a principle underlying mechanism generating the pain. But as the pain becomes chronic, an overlap of multiple mechanisms develops, with central sensitization often playing a more dominant role than peripheral stimulation (regardless of the diagnosis).

For example, in a patient with rheumatoid arthritis (RA), peripheral nociceptive input (in the form of inflammation) is likely the initial mechanism at work, but as time goes on, central processing becomes more involved. The patient may then begin to experience pain that is disproportionate to what is generally expected with RA and may develop other somatic symptoms. The diagnosis then becomes pain primarily related to RA with central sensitization, and both need to be addressed in a treatment plan. In rheumatic conditions, comorbid fibromyalgia (indicative of central sensitization) is thought to occur in 15% to 30% of patients.⁵

FPPs can utilize the underlying mechanisms to cut across diagnostic labels and tailor treatments to those that are most likely to be effective. For a patient with more prominent peripheral involvement, a procedural intervention such as injections or surgery alone may suffice, whereas a broader approach including psychotherapy, medications, exercise, and other lifestyle interventions may be necessary for a patient with pain caused predominantly by central sensitization.

Addressing both peripheral and central components is essential. One prospective, observational cohort study of more than 600 patients scheduled for unilateral total knee or total hip arthroplasty found that patients with a higher degree of centralization of pain (measured by widespread pain index and modified fibromyalgia screening scales) were less likely to report improvement in the affected body part and in overall body pain following surgery.^6,7

There is a high degree of overlap among many of the chronic pain syndromes (fibromyalgia, irritable bowel syndrome, interstitial cystitis, chronic headaches) that have been found to have a central sensitization component.⁸ Providers of primary care are aptly positioned to recognize central sensitization as the underlying pathology and target treatment effectively.

TAILOR TREATMENT TO THE UNDERLYING MECHANISMS OF PAIN

As with any chronic condition, a thorough workup (complete with history, physical exam, and diagnostic testing, as appropriate) is indicated. In the setting of chronic pain, it’s important to identify the primary mechanism, as well as secondary factors that may contribute to the patient’s pain, before developing your treatment plan. These secondary factors may include co-occurring affect disorders, a history of trauma, poor sleep, and tobacco use.^9-12 A history of trauma, for example, co-exists with many pain syndromes. For these patients, central sensitization is responsible for much of their pain. As a result, traditional cognitive behavioral therapy (CBT) may not be the best option because of its focus on accepting pain as a chronic diagnosis; more trauma-focused treatments, such as those dealing in emotional awareness and understanding of the CNS’s role in chronic pain, need to be considered.¹³

Three common conditions. Below we present evidence-based treatment approaches for conditions typically associated with each of the major mechanisms of chronic pain: fibromyalgia (central sensitization), OA (peripheral nociceptive), and low back pain (mixed pain state).

Fibromyalgia: a case of central sensitization

Fibromyalgia is a hallmark diagnosis for patients in whom central sensitization is the dominant cause of pain. They usually present with widespread, diffuse pain and somatic symptoms such as fatigue, memory difficulties, and poor sleep quality.⁸ When explaining the pain mechanism to patients, it may be useful to use the analogy of a volume control dial that is stuck in the “high” position and can’t be turned down.

Genes, the environment, and neurotransmitters play a role. The origin of the pain amplification process is believed to be multifactorial.

Genetic factors are thought to contribute to a predisposition for amplification. To date, five sets of genes have been implicated in increased sensitivity to pain leading to increased risk of the development of chronic pain during a patient’s lifetime.^14-19

Environmental factors (eg, early life trauma, physical trauma especially to the trunk, certain infections such as Lyme disease and Epstein-Barr virus, and emotional stress) may trigger or exacerbate symptoms.⁸ Of note: Only about 5% to 10% of people who experience these triggers actually develop a chronic pain state, while the rest regain their baseline health.⁴ This raises the question of whether there is a point during an acute pain episode in which one can intervene and prevent the acute pain from becoming chronic in those at higher risk.⁴

Imbalances of neurotransmitters (high glutamate; low norepinephrine, serotonin, and gamma-aminobutyric acid [GABA]) play a role in central amplification.^20-22 These substances not only affect sensory transmission, but also control levels of alertness, sleep, mood, and memory.

The diagnostic criteria for fibromyalgia were modified in 2011 to remove the tender point examination and to add somatic symptoms.⁶ These criteria can be useful in the clinical setting in identifying not only fibromyalgia itself but also the degree of “fibromyalgianess” a patient has, which is an indicator of how large a role the centralization process plays in the maintenance of chronic pain.^23,24

Treatment: multimodal and patient empowering. Evidence-based treatment options for fibromyalgia, as well as other conditions for which there is a high degree of centralized pain, can be found in Table 2.^25-36 Multimodal treatment, with an emphasis on patient knowledge and empowerment, is generally thought to be the most beneficial.^25,37 Treatment should almost always include CBT and exercise/activity therapies, which have high degrees of efficacy with few adverse effects.^26,29

In terms of medication, centrally-acting agents (tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors [SNRIs], and alpha 2 delta ligands) are the most effective. There is little to no data showing benefit from anti-inflammatories or opioids in the setting of fibromyalgia. There is some data to suggest that combination therapy, for example with an SNRI (milnacipran) and an alpha 2 delta ligand (pregabalin), may provide more benefit than treating with pregabalin alone.³⁸

Complementary and alternative therapies (eg, yoga, chiropractic care, acupuncture, massage) are being studied more, and while evidence is only preliminary in terms of efficacy, there is increasing emphasis being placed on the need for patients with chronic pain to shift their treatment expectations to greater acceptance of pain and the need for ongoing self-care.²⁸

OA: an example of peripheral nociceptive pain

OA is a condition long thought to be characterized by damage to the cartilage and bone; however, as with many other pain diagnoses, there is frequently little correlation between damage seen on radiographs and the amount of pain that patients experience.

One study analyzed data on almost 7,000 patients from the National Health and Nutrition Examination Survey (NHANES I) and found that between 30% and 50% of OA patients with moderate to severe radiographic changes were asymptomatic, and 10% of those with moderate to severe pain had normal radiographs or only mild changes.³⁹ Research is showing that many factors may contribute to this discrepancy, including the typical “wear and tear” of the disease, subacute levels of inflammation that can lead to peripheral sensitization, and, in some patients, a centralized pain component.⁴⁰ The patients with more centralized pain often have pain that is disproportionate to radiographic evidence, as well as more somatic symptoms, such as fatigue, sleep disturbance, and memory issues.⁴¹

Treatment should be multimodal and include interventions targeted at halting the progression of damage as well as palliation of pain. All treatment plans for OA should also include exercise, weight reduction, and self-management, in addition to pharmacologic interventions, to reduce both the micro-inflammation and the centralized pain component (when present). Intra-articular injections of various types have been studied with some having more efficacy in pain reduction and functional improvement than others.^42-45 See Table 3 for a summary of evidence-based treatment options.^42-61

Low back pain: a mixed pain state

Low back pain (LBP) has been recognized as a mixed pain state for quite some time. While some patients may experience purely nociceptive and/or neuropathic pain, most cases are nonspecific, with patients experiencing varying degrees of nociceptive (myofascial LBP), neuropathic (lumbar radiculopathy), and central sensitization pain.^62,63 Evidence for centralized pain is demonstrated in studies showing hyperalgesia, augmented central pain processing, involvement of the emotional brain, and delayed recovery influenced by poor coping strategies.^64-67

When developing a treatment plan for a patient with chronic LBP, remember that the pain derives from a complex combination of pathophysiologic contributors. Identifying where a patient lies on the pain centralization spectrum can help you tailor treatment.

In one study of 548 patients presenting to a tertiary pain clinic with primary spine pain diagnoses, 42% met diagnostic criteria for fibromyalgia.⁶⁸ Compared to criteria-negative patients, these patients tended to be younger, unemployed, and receiving compensation; they had greater pain intensity, pain interference, and used stronger words to describe their neuropathic pain, as well as having higher levels of depression/anxiety and a lower level of physical function.

Because LBP is a condition with high prevalence and associated disability, many clinical boards have created guidelines for management. These guidelines tend to vary in the strength of evidence used, and the extent to which they are followed in clinical practice remains largely unknown. Recommendations frequently discourage the use of ultrasound/electrotherapy, but many encourage short-term use of medications, supervised exercise therapy, CBT, and multidisciplinary treatment.

Guidelines tend to differ most widely with regard to recommendations for spinal manipulation and specific drug therapies.⁶⁹ The classes of drugs that may be most useful when centralized pain is present include the SNRIs and the alpha 2 delta calcium channel ligands.⁴ See Table 4 for a summary of evidence-based treatment options.^70-89

Case 1 Lola is started on amitriptyline 25 mg at bedtime, which improves her fatigue and cognitive symptoms. During monthly office visits, her FPP educates her about the pathophysiology of fibromyalgia and uses motivational interviewing to get her slowly moving and increasing her activity level. She is weaned off the gabapentin previously prescribed, as her symptoms stabilize and improve.

Case 2 Matt is sent for a steroid injection, which decreases his pain temporarily. During this time, he begins physical therapy; slowly, with increased movement, his function improves. A trial of duloxetine provides pain relief; that combined with intermittent NSAIDs has allowed Matt to maintain his function and his job.

Case 3 Because Keith was only taking the narcotics intermittently and wasn’t certain they were helping, CBT was sufficient to wean him off the medication without any worsening of his pain in the process. By participating in physical therapy, he has learned how to perform certain tasks at his job without pain or injury. He uses NSAIDs as needed for pain.

The authors thank Drs. Daniel Clauw (University of Michigan, Ann Arbor) and Martha Rumschlag (Providence Family Medicine Residency Program, Southfield, Michigan), for their valuable contributions to this article.

Case 1 Lola, 28, has a history of muscular aches and joint pain throughout her body, fatigue, and mental fogginess. A rheumatologist diagnosed fibromyalgia, but Lola just moved to your town and is establishing care. She is feeling desperate because her pain has worsened and the medication previously prescribed (gabapentin 300 mg tid) is no longer working. She asks to try oxycodone.

Case 2 Matt is a 59-year-old truck driver with severe hip osteoarthritis (OA). His orthopedist recommended against hip replacement at this time because of his young age and a heart condition that makes him high risk. His pain makes sitting for long periods very difficult. He presents to you for help because he is worried he will be unable to continue working.

Case 3 Keith is a 56-year-old construction worker who has been experiencing back pain for many years. The pain has become more debilitating over time; it is now constant, and Keith can hardly make it through his work day. He has been getting hydrocodone/acetaminophen from urgent care centers and emergency departments, but he isn’t sure it is helping and is coming to you to assume his pain management.

Chronic pain (defined as > 3 mo in duration) is a complex, heterogeneous condition affecting an estimated 116 million US adults.¹ Much of the management of chronic pain occurs in primary care settings, placing family practice providers (FPPs) on the frontlines of two epidemics: that of chronic pain and that of the abuse and misuse of opioid pain medications.

To improve communication about the risks and benefits of opioid therapy and the safety and effectiveness of pain treatments in general, many professional organizations, health care institutions, and recently the CDC, have published guidelines on the use of opioids for nonmalignant chronic pain.² With these guidelines in mind—and in light of the latest evidence—we propose the following paradigm for the treatment of chronic pain. A critical aspect is determining the underlying pathophysiology of a patient’s pain in order to develop a well-rounded, multimodal, evidence-based treatment plan. Detailed here is the application of this approach to the treatment of three common diagnoses: fibromyalgia, osteoarthritis, and low back pain.

LOOK TO THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM

Acute pain begins with activation of peripheral nociceptors at the site of injury. This causes depolarization up the spinal cord and through the brain stem to higher cortical centers where the pain is perceived and localized. Descending neural pathways transport both excitatory and inhibitory information from the brain to the periphery via the spinal cord, which either increases or decreases the perception of pain.³

When damage/injury doesn’t correlate with the perception of pain

Until recently, it was assumed that chronic pain worked much the same way as acute pain and was caused by ongoing nociceptive input in the periphery, but research has shown us that the central nervous system (CNS) can play a large role in the modulation of nociception. This new understanding comes from the lack of evidence pointing to any pain state in which the degree of nociceptive input correlates with the degree of pain experienced.

For most patients with chronic pain, regardless of their diagnosis, there is some degree of alteration in the processing of nociceptive signals by the CNS contributing to the experience of pain.⁴ This alteration is thought to result from peripheral nociceptive signaling persisting past the point of tissue healing, leading to a hypersensitivity of nerve fibers, which then continue to respond to low, or absent, sensory stimuli.

Central sensitization is when this hypersensitivity develops in the superficial, deep, and ventral cord nerves. When this happens, pain is often accompanied by systemic symptoms such as fatigue and slowed cognitive processing, often with little to no actual stimulation of the peripheral nociceptors.³

Table 1 lists the possible mechanisms of pain, which can be broken down into four categories: peripheral nociceptive (inflammatory or mechanical), peripheral neuropathic (underlying damage to a peripheral nerve), central (when the CNS is the primary entity involved in maintaining the pain), or any combination of the three.⁴

As pain becomes chronic, multiple mechanisms overlap

It is important to remember that for any single pain diagnosis, there is likely to be—at least initially—a principle underlying mechanism generating the pain. But as the pain becomes chronic, an overlap of multiple mechanisms develops, with central sensitization often playing a more dominant role than peripheral stimulation (regardless of the diagnosis).

For example, in a patient with rheumatoid arthritis (RA), peripheral nociceptive input (in the form of inflammation) is likely the initial mechanism at work, but as time goes on, central processing becomes more involved. The patient may then begin to experience pain that is disproportionate to what is generally expected with RA and may develop other somatic symptoms. The diagnosis then becomes pain primarily related to RA with central sensitization, and both need to be addressed in a treatment plan. In rheumatic conditions, comorbid fibromyalgia (indicative of central sensitization) is thought to occur in 15% to 30% of patients.⁵

FPPs can utilize the underlying mechanisms to cut across diagnostic labels and tailor treatments to those that are most likely to be effective. For a patient with more prominent peripheral involvement, a procedural intervention such as injections or surgery alone may suffice, whereas a broader approach including psychotherapy, medications, exercise, and other lifestyle interventions may be necessary for a patient with pain caused predominantly by central sensitization.

Addressing both peripheral and central components is essential. One prospective, observational cohort study of more than 600 patients scheduled for unilateral total knee or total hip arthroplasty found that patients with a higher degree of centralization of pain (measured by widespread pain index and modified fibromyalgia screening scales) were less likely to report improvement in the affected body part and in overall body pain following surgery.^6,7

There is a high degree of overlap among many of the chronic pain syndromes (fibromyalgia, irritable bowel syndrome, interstitial cystitis, chronic headaches) that have been found to have a central sensitization component.⁸ Providers of primary care are aptly positioned to recognize central sensitization as the underlying pathology and target treatment effectively.

TAILOR TREATMENT TO THE UNDERLYING MECHANISMS OF PAIN

As with any chronic condition, a thorough workup (complete with history, physical exam, and diagnostic testing, as appropriate) is indicated. In the setting of chronic pain, it’s important to identify the primary mechanism, as well as secondary factors that may contribute to the patient’s pain, before developing your treatment plan. These secondary factors may include co-occurring affect disorders, a history of trauma, poor sleep, and tobacco use.^9-12 A history of trauma, for example, co-exists with many pain syndromes. For these patients, central sensitization is responsible for much of their pain. As a result, traditional cognitive behavioral therapy (CBT) may not be the best option because of its focus on accepting pain as a chronic diagnosis; more trauma-focused treatments, such as those dealing in emotional awareness and understanding of the CNS’s role in chronic pain, need to be considered.¹³

Three common conditions. Below we present evidence-based treatment approaches for conditions typically associated with each of the major mechanisms of chronic pain: fibromyalgia (central sensitization), OA (peripheral nociceptive), and low back pain (mixed pain state).

Fibromyalgia: a case of central sensitization

Fibromyalgia is a hallmark diagnosis for patients in whom central sensitization is the dominant cause of pain. They usually present with widespread, diffuse pain and somatic symptoms such as fatigue, memory difficulties, and poor sleep quality.⁸ When explaining the pain mechanism to patients, it may be useful to use the analogy of a volume control dial that is stuck in the “high” position and can’t be turned down.

Genes, the environment, and neurotransmitters play a role. The origin of the pain amplification process is believed to be multifactorial.

Genetic factors are thought to contribute to a predisposition for amplification. To date, five sets of genes have been implicated in increased sensitivity to pain leading to increased risk of the development of chronic pain during a patient’s lifetime.^14-19

Environmental factors (eg, early life trauma, physical trauma especially to the trunk, certain infections such as Lyme disease and Epstein-Barr virus, and emotional stress) may trigger or exacerbate symptoms.⁸ Of note: Only about 5% to 10% of people who experience these triggers actually develop a chronic pain state, while the rest regain their baseline health.⁴ This raises the question of whether there is a point during an acute pain episode in which one can intervene and prevent the acute pain from becoming chronic in those at higher risk.⁴

Imbalances of neurotransmitters (high glutamate; low norepinephrine, serotonin, and gamma-aminobutyric acid [GABA]) play a role in central amplification.^20-22 These substances not only affect sensory transmission, but also control levels of alertness, sleep, mood, and memory.

The diagnostic criteria for fibromyalgia were modified in 2011 to remove the tender point examination and to add somatic symptoms.⁶ These criteria can be useful in the clinical setting in identifying not only fibromyalgia itself but also the degree of “fibromyalgianess” a patient has, which is an indicator of how large a role the centralization process plays in the maintenance of chronic pain.^23,24

Treatment: multimodal and patient empowering. Evidence-based treatment options for fibromyalgia, as well as other conditions for which there is a high degree of centralized pain, can be found in Table 2.^25-36 Multimodal treatment, with an emphasis on patient knowledge and empowerment, is generally thought to be the most beneficial.^25,37 Treatment should almost always include CBT and exercise/activity therapies, which have high degrees of efficacy with few adverse effects.^26,29

In terms of medication, centrally-acting agents (tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors [SNRIs], and alpha 2 delta ligands) are the most effective. There is little to no data showing benefit from anti-inflammatories or opioids in the setting of fibromyalgia. There is some data to suggest that combination therapy, for example with an SNRI (milnacipran) and an alpha 2 delta ligand (pregabalin), may provide more benefit than treating with pregabalin alone.³⁸

Complementary and alternative therapies (eg, yoga, chiropractic care, acupuncture, massage) are being studied more, and while evidence is only preliminary in terms of efficacy, there is increasing emphasis being placed on the need for patients with chronic pain to shift their treatment expectations to greater acceptance of pain and the need for ongoing self-care.²⁸

OA: an example of peripheral nociceptive pain

OA is a condition long thought to be characterized by damage to the cartilage and bone; however, as with many other pain diagnoses, there is frequently little correlation between damage seen on radiographs and the amount of pain that patients experience.

One study analyzed data on almost 7,000 patients from the National Health and Nutrition Examination Survey (NHANES I) and found that between 30% and 50% of OA patients with moderate to severe radiographic changes were asymptomatic, and 10% of those with moderate to severe pain had normal radiographs or only mild changes.³⁹ Research is showing that many factors may contribute to this discrepancy, including the typical “wear and tear” of the disease, subacute levels of inflammation that can lead to peripheral sensitization, and, in some patients, a centralized pain component.⁴⁰ The patients with more centralized pain often have pain that is disproportionate to radiographic evidence, as well as more somatic symptoms, such as fatigue, sleep disturbance, and memory issues.⁴¹

Treatment should be multimodal and include interventions targeted at halting the progression of damage as well as palliation of pain. All treatment plans for OA should also include exercise, weight reduction, and self-management, in addition to pharmacologic interventions, to reduce both the micro-inflammation and the centralized pain component (when present). Intra-articular injections of various types have been studied with some having more efficacy in pain reduction and functional improvement than others.^42-45 See Table 3 for a summary of evidence-based treatment options.^42-61

Low back pain: a mixed pain state

Low back pain (LBP) has been recognized as a mixed pain state for quite some time. While some patients may experience purely nociceptive and/or neuropathic pain, most cases are nonspecific, with patients experiencing varying degrees of nociceptive (myofascial LBP), neuropathic (lumbar radiculopathy), and central sensitization pain.^62,63 Evidence for centralized pain is demonstrated in studies showing hyperalgesia, augmented central pain processing, involvement of the emotional brain, and delayed recovery influenced by poor coping strategies.^64-67

When developing a treatment plan for a patient with chronic LBP, remember that the pain derives from a complex combination of pathophysiologic contributors. Identifying where a patient lies on the pain centralization spectrum can help you tailor treatment.

In one study of 548 patients presenting to a tertiary pain clinic with primary spine pain diagnoses, 42% met diagnostic criteria for fibromyalgia.⁶⁸ Compared to criteria-negative patients, these patients tended to be younger, unemployed, and receiving compensation; they had greater pain intensity, pain interference, and used stronger words to describe their neuropathic pain, as well as having higher levels of depression/anxiety and a lower level of physical function.

Because LBP is a condition with high prevalence and associated disability, many clinical boards have created guidelines for management. These guidelines tend to vary in the strength of evidence used, and the extent to which they are followed in clinical practice remains largely unknown. Recommendations frequently discourage the use of ultrasound/electrotherapy, but many encourage short-term use of medications, supervised exercise therapy, CBT, and multidisciplinary treatment.

Guidelines tend to differ most widely with regard to recommendations for spinal manipulation and specific drug therapies.⁶⁹ The classes of drugs that may be most useful when centralized pain is present include the SNRIs and the alpha 2 delta calcium channel ligands.⁴ See Table 4 for a summary of evidence-based treatment options.^70-89

Case 1 Lola is started on amitriptyline 25 mg at bedtime, which improves her fatigue and cognitive symptoms. During monthly office visits, her FPP educates her about the pathophysiology of fibromyalgia and uses motivational interviewing to get her slowly moving and increasing her activity level. She is weaned off the gabapentin previously prescribed, as her symptoms stabilize and improve.

Case 2 Matt is sent for a steroid injection, which decreases his pain temporarily. During this time, he begins physical therapy; slowly, with increased movement, his function improves. A trial of duloxetine provides pain relief; that combined with intermittent NSAIDs has allowed Matt to maintain his function and his job.

Case 3 Because Keith was only taking the narcotics intermittently and wasn’t certain they were helping, CBT was sufficient to wean him off the medication without any worsening of his pain in the process. By participating in physical therapy, he has learned how to perform certain tasks at his job without pain or injury. He uses NSAIDs as needed for pain.

The authors thank Drs. Daniel Clauw (University of Michigan, Ann Arbor) and Martha Rumschlag (Providence Family Medicine Residency Program, Southfield, Michigan), for their valuable contributions to this article.

The rate of breast reconstruction surgery for mastectomy increased 62% from 2009 to 2014, while the mastectomy rate itself “remained relatively stable,” according to the Agency for Healthcare Research and Quality.

The rate of breast reconstructions in hospitals and ambulatory surgery settings rose steadily over the 6-year period, going from 21.7 per 100,000 women in 2009 to 35.1 per 100,000 in 2014. Meanwhile, the mastectomy rate dipped from 90.1 in 2009 to 83.2 in 2010 but varied less than 10% over the 2009-2014 time period, reaching 88.4 per 100,000 women in 2014. To put those numbers in a different context, the ratio of reconstructions to mastectomies went from 24-to-100 in 2009 to 40-to-100 in 2014, the AHRQ reported in a Statistical Brief.

[email protected]

The rate of breast reconstruction surgery for mastectomy increased 62% from 2009 to 2014, while the mastectomy rate itself “remained relatively stable,” according to the Agency for Healthcare Research and Quality.

The rate of breast reconstructions in hospitals and ambulatory surgery settings rose steadily over the 6-year period, going from 21.7 per 100,000 women in 2009 to 35.1 per 100,000 in 2014. Meanwhile, the mastectomy rate dipped from 90.1 in 2009 to 83.2 in 2010 but varied less than 10% over the 2009-2014 time period, reaching 88.4 per 100,000 women in 2014. To put those numbers in a different context, the ratio of reconstructions to mastectomies went from 24-to-100 in 2009 to 40-to-100 in 2014, the AHRQ reported in a Statistical Brief.

[email protected]

The rate of breast reconstruction surgery for mastectomy increased 62% from 2009 to 2014, while the mastectomy rate itself “remained relatively stable,” according to the Agency for Healthcare Research and Quality.

The rate of breast reconstructions in hospitals and ambulatory surgery settings rose steadily over the 6-year period, going from 21.7 per 100,000 women in 2009 to 35.1 per 100,000 in 2014. Meanwhile, the mastectomy rate dipped from 90.1 in 2009 to 83.2 in 2010 but varied less than 10% over the 2009-2014 time period, reaching 88.4 per 100,000 women in 2014. To put those numbers in a different context, the ratio of reconstructions to mastectomies went from 24-to-100 in 2009 to 40-to-100 in 2014, the AHRQ reported in a Statistical Brief.

[email protected]

MADRID – The drug sequence matters when it comes to the treatment of advanced or metastatic renal cell carcinoma (mRCC) investigators have found.

The median progression-free survival (PFS) for patients treated with first-line pazopanib (Votrient) followed by sorafenib (Nexavar) as a second-line therapy at the time of first progression was 12.9 months, compared with 8.6 months for patients started on sorafenib and then crossed over to pazopanib at progression, reported Margitta Retz, MD, of the Technical University of Munich.

Neil Osterweil/Frontline Medical News

Neil Osterweil/Frontline Medical News

[email protected]

MADRID – The drug sequence matters when it comes to the treatment of advanced or metastatic renal cell carcinoma (mRCC) investigators have found.

The median progression-free survival (PFS) for patients treated with first-line pazopanib (Votrient) followed by sorafenib (Nexavar) as a second-line therapy at the time of first progression was 12.9 months, compared with 8.6 months for patients started on sorafenib and then crossed over to pazopanib at progression, reported Margitta Retz, MD, of the Technical University of Munich.

Neil Osterweil/Frontline Medical News

Neil Osterweil/Frontline Medical News

[email protected]

MADRID – The drug sequence matters when it comes to the treatment of advanced or metastatic renal cell carcinoma (mRCC) investigators have found.

The median progression-free survival (PFS) for patients treated with first-line pazopanib (Votrient) followed by sorafenib (Nexavar) as a second-line therapy at the time of first progression was 12.9 months, compared with 8.6 months for patients started on sorafenib and then crossed over to pazopanib at progression, reported Margitta Retz, MD, of the Technical University of Munich.

Neil Osterweil/Frontline Medical News

Neil Osterweil/Frontline Medical News

[email protected]

The Diagnosis: Merkel Cell Carcinoma

A partial biopsy was performed during the dermatology examination. Histopathology demonstrated a dense dermal infiltrate of small, dark blue, pleomorphic cells (Figure 1). On high power, the individual cells were noted to have vesicular nuclei with finely granular and dusty chromatin (Figure 2). Numerous mitotic figures were present. Immunohistochemical stains were performed and revealed positive staining for cytokeratin 20 (with a perinuclear dot pattern), synaptophysin, and chromogranin.

Merkel cell carcinoma (MCC) is an uncommon carcinoma of the epidermal neuroendocrine cells with approximately 1500 cases a year in the United States.¹ Merkel cell carcinoma has a poor prognosis with approximately one-third of cases resulting in death within 5 years and with a survival rate strongly dependent on the stage of disease at presentation.² A complete surgical excision with histologically verified clear margins is the main form of treatment of the primary cancer.³ Although the effectiveness of adjuvant therapy for MCC has been debated,⁴ retrospective analysis has shown that the high local recurrence rate of the primary tumor can be reduced by combining surgical excision with a form of radiation therapy.⁵

A systematic cohort study of 195 patients diagnosed with MCC summarized its most clinical factors with the acronym AEIOU: asymptomatic, expanding rapidly, immunosuppression, older than 50 years of age, and UV-exposed site on a fair-skinned individual.⁶ The role of immune function in MCC was highlighted by a 16-fold overrepresentation of immunosuppressed patients in the studied cohort as compared to the general US population. The immunosuppressed patients included individuals with human immunodeficiency virus, chronic lymphocytic leukemia, and iatrogenic suppression secondary to solid organ transplantation.⁶

In 2008, Merkel cell polyomavirus (MCPyV) was found in 80% (8/10) of MCC tumors tested.⁷ Since then, many different studies have suggested that MCPyV is an etiologic agent of MCC.^8-10 A natural component of skin flora, MCPyV only becomes tumorigenic after integration into the host DNA and with mutations to the viral genome.¹¹ Although there currently is no difference in treatment of MCPyV-positive and MCPyV-negative MCC,¹² research is being done to determine how the discovery of the MCPyV could impact the treatment of MCC.

The Diagnosis: Merkel Cell Carcinoma

A partial biopsy was performed during the dermatology examination. Histopathology demonstrated a dense dermal infiltrate of small, dark blue, pleomorphic cells (Figure 1). On high power, the individual cells were noted to have vesicular nuclei with finely granular and dusty chromatin (Figure 2). Numerous mitotic figures were present. Immunohistochemical stains were performed and revealed positive staining for cytokeratin 20 (with a perinuclear dot pattern), synaptophysin, and chromogranin.

Merkel cell carcinoma (MCC) is an uncommon carcinoma of the epidermal neuroendocrine cells with approximately 1500 cases a year in the United States.¹ Merkel cell carcinoma has a poor prognosis with approximately one-third of cases resulting in death within 5 years and with a survival rate strongly dependent on the stage of disease at presentation.² A complete surgical excision with histologically verified clear margins is the main form of treatment of the primary cancer.³ Although the effectiveness of adjuvant therapy for MCC has been debated,⁴ retrospective analysis has shown that the high local recurrence rate of the primary tumor can be reduced by combining surgical excision with a form of radiation therapy.⁵

A systematic cohort study of 195 patients diagnosed with MCC summarized its most clinical factors with the acronym AEIOU: asymptomatic, expanding rapidly, immunosuppression, older than 50 years of age, and UV-exposed site on a fair-skinned individual.⁶ The role of immune function in MCC was highlighted by a 16-fold overrepresentation of immunosuppressed patients in the studied cohort as compared to the general US population. The immunosuppressed patients included individuals with human immunodeficiency virus, chronic lymphocytic leukemia, and iatrogenic suppression secondary to solid organ transplantation.⁶

In 2008, Merkel cell polyomavirus (MCPyV) was found in 80% (8/10) of MCC tumors tested.⁷ Since then, many different studies have suggested that MCPyV is an etiologic agent of MCC.^8-10 A natural component of skin flora, MCPyV only becomes tumorigenic after integration into the host DNA and with mutations to the viral genome.¹¹ Although there currently is no difference in treatment of MCPyV-positive and MCPyV-negative MCC,¹² research is being done to determine how the discovery of the MCPyV could impact the treatment of MCC.

The Diagnosis: Merkel Cell Carcinoma

A partial biopsy was performed during the dermatology examination. Histopathology demonstrated a dense dermal infiltrate of small, dark blue, pleomorphic cells (Figure 1). On high power, the individual cells were noted to have vesicular nuclei with finely granular and dusty chromatin (Figure 2). Numerous mitotic figures were present. Immunohistochemical stains were performed and revealed positive staining for cytokeratin 20 (with a perinuclear dot pattern), synaptophysin, and chromogranin.

Merkel cell carcinoma (MCC) is an uncommon carcinoma of the epidermal neuroendocrine cells with approximately 1500 cases a year in the United States.¹ Merkel cell carcinoma has a poor prognosis with approximately one-third of cases resulting in death within 5 years and with a survival rate strongly dependent on the stage of disease at presentation.² A complete surgical excision with histologically verified clear margins is the main form of treatment of the primary cancer.³ Although the effectiveness of adjuvant therapy for MCC has been debated,⁴ retrospective analysis has shown that the high local recurrence rate of the primary tumor can be reduced by combining surgical excision with a form of radiation therapy.⁵

A systematic cohort study of 195 patients diagnosed with MCC summarized its most clinical factors with the acronym AEIOU: asymptomatic, expanding rapidly, immunosuppression, older than 50 years of age, and UV-exposed site on a fair-skinned individual.⁶ The role of immune function in MCC was highlighted by a 16-fold overrepresentation of immunosuppressed patients in the studied cohort as compared to the general US population. The immunosuppressed patients included individuals with human immunodeficiency virus, chronic lymphocytic leukemia, and iatrogenic suppression secondary to solid organ transplantation.⁶

In 2008, Merkel cell polyomavirus (MCPyV) was found in 80% (8/10) of MCC tumors tested.⁷ Since then, many different studies have suggested that MCPyV is an etiologic agent of MCC.^8-10 A natural component of skin flora, MCPyV only becomes tumorigenic after integration into the host DNA and with mutations to the viral genome.¹¹ Although there currently is no difference in treatment of MCPyV-positive and MCPyV-negative MCC,¹² research is being done to determine how the discovery of the MCPyV could impact the treatment of MCC.