THE CASE

A 76-year-old Caucasian woman presented to the emergency department with a 7-day history of weakness and pain in her arms and legs. She had a history of Candida albicans vertebral osteomyelitis that had been treated for 3 months with fluconazole; non-Hodgkin lymphoma that had been in remission for 6 months; diabetes mellitus; hyperlipidemia; and hypothyroidism. The woman had dark urine, but denied chills, fever, respiratory symptoms, bowel or bladder leakage, falls/trauma, or grapefruit juice intake.

Her current medications included oral fluconazole 400 mg/d, simvastatin 20 mg/d, levothyroxine 88 mcg/d, pregabalin 75 mg/d, metformin 1000 mg twice daily, 6 units of subcutaneous insulin glargine at bedtime, and 2 units of insulin lispro with each meal. During the examination, we noted marked proximal muscle weakness, significant tenderness in all extremities, and diminished deep tendon reflexes. The patient had no saddle anesthesia, impaired rectal tone, or sensory abnormalities.

THE DIAGNOSIS

Magnetic resonance imaging of the patient’s spine confirmed multilevel discitis and osteomyelitis (T7-T9, L5-S1) with no cord compression. Laboratory data included a creatinine level of 1.42 mg/dL (the patient’s baseline was 0.8 mg/dL); a creatine kinase (CK) level of 8876 U/L (normal range, 0-220 U/L); a thyroid-stimulating hormone (TSH) level of 9.35 mIU/L (normal range, 0.4-5.5 mIU/L); and an erythrocyte sedimentation rate of 27 mm/hr (normal range, 0-31 mm/hr).

The patient received aggressive fluid hydration, orally and intravenously. On Day 2, the patient’s serum myoglobin level was 14,301 ng/mL (normal range, 30-90 ng/mL) and her aldolase level was 87.6 U/L (normal range, 1.5-8.5 U/L).

Zeroing in on the cause. There were no signs of drug abuse or use of other non-statin culprit medications that could have caused the patient’s rhabdomyolysis. She also did not describe any triggers of rhabdomyolysis, such as trauma, viral infection, metabolic disturbances, or temperature dysregulation. We believed the most likely cause of our patient’s signs and symptoms was statin-induced rhabdomyolysis, likely due to an interaction between simvastatin and fluconazole. We considered hypothyroidism-induced rhabdomyolysis, but thought it was unlikely because the patient had a mildly increased TSH level on admission, and one would expect to see levels higher than 100 mIU/L.^1-3

We also considered viral myositis in the differential, but it was an unlikely culprit because the patient lacked any history of fever or respiratory or gastrointestinal symptoms. And while paraneoplastic polymyositis could have caused the patient’s weakness, the marked muscle pain and acute kidney injury were far more suggestive of rhabdomyolysis.

DISCUSSION

Rhabdomyolysis is a serious complication of statin treatment. Both higher statin doses and pharmacokinetic factors can raise statin levels, leading to this serious muscle-related syndrome.^4,5 Co-administration of statins with drugs that are strong inhibitors of cytochrome P450 (CYP) 3A4 (the main cytochrome P450 isoform that metabolizes most statins) can increase statin levels several fold.^6,7 The trigger for our patient’s statin-induced rhabdomyolysis was fluconazole, a known moderate inhibitor of CYP3A4, which is comparatively weaker than certain potent azoles like itraconazole or ketoconazole.^7-10 Doses of fluconazole generally ≥200 mg/d are needed to produce clinical interactions with CYP3A4 substrates.⁷ There are only 3 reported cases of fluconazole-simvastatin–induced rhabdomyolysis (TABLE 1).^11-13

The Food and Drug Administration advises against simvastatin co-prescription with itraconazole and ketoconazole, but doesn’t mention fluconazole in its Drug Safety communication on simvastatin.¹⁴

Lexicomp places the simvastatin-fluconazole drug interaction into category C, which means that the agents can interact in a clinically significant manner (and a monitoring plan should be implemented), but that the benefits of concomitant use usually outweigh the risks.¹⁵

How our patient’s case differs from previous cases

Several features distinguish our patient’s scenario from previous cases. First, unlike other cases in which both drugs were stopped, only simvastatin was discontinued in our patient. Simvastatin and fluconazole have a half-life of 3 hours⁶ and 32 hours,⁷ respectively, suggesting that when simvastatin has fully cleared, fluconazole’s concentration will not even have halved. Thus, fluconazole was safely continued to treat the patient’s osteomyelitis.

Second, compared to previous case reports, our patient was taking a lower dose of simvastatin (20 mg). A 20-mg dose can make the drug interaction easier to miss; pharmacists are more likely to inform the physician of a potential drug interaction when the dose of a statin is ≥40 mg compared to when it is <40 mg (odds ratio=1.89; 95% confidence interval, 0.98-3.63).¹⁶

Researchers involved in the British randomized trial SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) sought to evaluate any added benefit to a higher dose of simvastatin in post-myocardial infarction patients. Among approximately 12,000 patients in the trial, there were 7 cases of rhabdomyolysis for the 80-mg simvastatin group and none for the 20-mg group.⁵ Another large case-control study showed that a 40-mg simvastatin dose was 5 times more likely to cause rhabdomyolysis than a 20-mg dose.¹⁷ Yet, based on our patient’s case, even 20 mg/d simvastatin should not decrease physician suspicion for rhabdomyolysis if patients are also taking a CYP3A4 inhibitor.

Third, the simvastatin-fluconazole co-administration time in our patient was 12 weeks, which is longer than previously reported (TABLE 1^11-13). Azole inhibition of CYP450 occurs relatively rapidly, but that does not mean that rhabdomyolysis will always occur immediately. For example, in cases of statin monotherapy, rhabdomyolysis secondary to statin biochemical toxicity can occur up to 1050 (mean=348) days after the drug’s initiation.¹⁸

Avoiding a drug-drug interaction in your patient

Physicians can use pharmacokinetic profiles to choose among different statins and azoles to help avoid a drug interaction (TABLE 2^6,7,10,19). Pravastatin’s serum concentration, for example, is not influenced by CYP3A4 inhibitors such as itraconazole¹¹ because pravastatin is metabolized by sulfation⁶ and not by the CYP450 system. Rosuvastatin and pitavastatin are minimally metabolized by the CYP450 system.^19,20

Even 20 mg/d simvastatin should not diminish your suspicion for rhabdomyolysis if a patient is taking a CYP3A4 inhibitor.

Among approximately 2700 statin-treated outpatients,⁴ the prevalence of potentially harmful statin interactions with other drugs (including CYP3A4 inhibitors), was significantly higher among patients treated with simvastatin or atorvastatin (CYP3A4-metabolized statins), than among patients treated with fluvastatin (CYP2C9-metabolized statin) or pravastatin (metabolized by sulfation). Apart from drug-drug interactions, other risk factors for statin-induced rhabdomyolysis include use of lipophilic statins, advanced age, and female gender.²¹

We discontinued our patient’s simvastatin on the day she was admitted to the hospital, but continued with the fluconazole throughout her hospitalization. Her CK level continued to rise, peaked on hospital Day 3 at 32,886 U/L, and then progressively decreased. The patient’s weakness and pain improved and her acute kidney injury resolved with hydration. She was discharged on hospital Day 7 on oral fluconazole, but no statin, and her muscle symptoms have since resolved.

THE TAKEAWAY

When hyperlipidemic patients have to take an azole for an extended period (eg, cancer prophylaxis or chronic osteomyelitis) and the azole is a strong CYP450 inhibitor (eg, itraconazole), switching to a statin that is not primarily metabolized by the CYP450 system (eg, pravastatin, pitavastatin) is wise. If the azole is a moderate CYP450 inhibitor (eg, fluconazole), we suggest that therapy should be closely monitored. In the case of short-term azole treatment (eg, such as for oral candidiasis), the statin should be stopped or the dose reduced by at least 50% (eg, from 40 or 20 mg to 10 mg).⁶

Prescriber knowledge is sometimes a limiting factor in identifying clinically significant interactions.²² This is especially pertinent in a case like this one, where a lower statin dose may result in a lower chance of the pharmacist alerting the prescribing physician¹⁶ and when an azole is used that is a comparatively weaker CYP450 inhibitor than other azoles such as itraconazole. Even in the era of electronic medical records, approximately 90% of drug interaction alerts are overridden by physicians, and alert fatigue is pronounced.²³

The intricacies and pharmacokinetic principles of this case should contribute to greater provider familiarity with even low-dose simvastatin-fluconazole interactions and help prevent iatrogenic complications such as rhabdomyolysis.

THE CASE

A 76-year-old Caucasian woman presented to the emergency department with a 7-day history of weakness and pain in her arms and legs. She had a history of Candida albicans vertebral osteomyelitis that had been treated for 3 months with fluconazole; non-Hodgkin lymphoma that had been in remission for 6 months; diabetes mellitus; hyperlipidemia; and hypothyroidism. The woman had dark urine, but denied chills, fever, respiratory symptoms, bowel or bladder leakage, falls/trauma, or grapefruit juice intake.

Her current medications included oral fluconazole 400 mg/d, simvastatin 20 mg/d, levothyroxine 88 mcg/d, pregabalin 75 mg/d, metformin 1000 mg twice daily, 6 units of subcutaneous insulin glargine at bedtime, and 2 units of insulin lispro with each meal. During the examination, we noted marked proximal muscle weakness, significant tenderness in all extremities, and diminished deep tendon reflexes. The patient had no saddle anesthesia, impaired rectal tone, or sensory abnormalities.

THE DIAGNOSIS

Magnetic resonance imaging of the patient’s spine confirmed multilevel discitis and osteomyelitis (T7-T9, L5-S1) with no cord compression. Laboratory data included a creatinine level of 1.42 mg/dL (the patient’s baseline was 0.8 mg/dL); a creatine kinase (CK) level of 8876 U/L (normal range, 0-220 U/L); a thyroid-stimulating hormone (TSH) level of 9.35 mIU/L (normal range, 0.4-5.5 mIU/L); and an erythrocyte sedimentation rate of 27 mm/hr (normal range, 0-31 mm/hr).

The patient received aggressive fluid hydration, orally and intravenously. On Day 2, the patient’s serum myoglobin level was 14,301 ng/mL (normal range, 30-90 ng/mL) and her aldolase level was 87.6 U/L (normal range, 1.5-8.5 U/L).

Zeroing in on the cause. There were no signs of drug abuse or use of other non-statin culprit medications that could have caused the patient’s rhabdomyolysis. She also did not describe any triggers of rhabdomyolysis, such as trauma, viral infection, metabolic disturbances, or temperature dysregulation. We believed the most likely cause of our patient’s signs and symptoms was statin-induced rhabdomyolysis, likely due to an interaction between simvastatin and fluconazole. We considered hypothyroidism-induced rhabdomyolysis, but thought it was unlikely because the patient had a mildly increased TSH level on admission, and one would expect to see levels higher than 100 mIU/L.^1-3

We also considered viral myositis in the differential, but it was an unlikely culprit because the patient lacked any history of fever or respiratory or gastrointestinal symptoms. And while paraneoplastic polymyositis could have caused the patient’s weakness, the marked muscle pain and acute kidney injury were far more suggestive of rhabdomyolysis.

DISCUSSION

Rhabdomyolysis is a serious complication of statin treatment. Both higher statin doses and pharmacokinetic factors can raise statin levels, leading to this serious muscle-related syndrome.^4,5 Co-administration of statins with drugs that are strong inhibitors of cytochrome P450 (CYP) 3A4 (the main cytochrome P450 isoform that metabolizes most statins) can increase statin levels several fold.^6,7 The trigger for our patient’s statin-induced rhabdomyolysis was fluconazole, a known moderate inhibitor of CYP3A4, which is comparatively weaker than certain potent azoles like itraconazole or ketoconazole.^7-10 Doses of fluconazole generally ≥200 mg/d are needed to produce clinical interactions with CYP3A4 substrates.⁷ There are only 3 reported cases of fluconazole-simvastatin–induced rhabdomyolysis (TABLE 1).^11-13

The Food and Drug Administration advises against simvastatin co-prescription with itraconazole and ketoconazole, but doesn’t mention fluconazole in its Drug Safety communication on simvastatin.¹⁴

Lexicomp places the simvastatin-fluconazole drug interaction into category C, which means that the agents can interact in a clinically significant manner (and a monitoring plan should be implemented), but that the benefits of concomitant use usually outweigh the risks.¹⁵

How our patient’s case differs from previous cases

Several features distinguish our patient’s scenario from previous cases. First, unlike other cases in which both drugs were stopped, only simvastatin was discontinued in our patient. Simvastatin and fluconazole have a half-life of 3 hours⁶ and 32 hours,⁷ respectively, suggesting that when simvastatin has fully cleared, fluconazole’s concentration will not even have halved. Thus, fluconazole was safely continued to treat the patient’s osteomyelitis.

Second, compared to previous case reports, our patient was taking a lower dose of simvastatin (20 mg). A 20-mg dose can make the drug interaction easier to miss; pharmacists are more likely to inform the physician of a potential drug interaction when the dose of a statin is ≥40 mg compared to when it is <40 mg (odds ratio=1.89; 95% confidence interval, 0.98-3.63).¹⁶

Researchers involved in the British randomized trial SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) sought to evaluate any added benefit to a higher dose of simvastatin in post-myocardial infarction patients. Among approximately 12,000 patients in the trial, there were 7 cases of rhabdomyolysis for the 80-mg simvastatin group and none for the 20-mg group.⁵ Another large case-control study showed that a 40-mg simvastatin dose was 5 times more likely to cause rhabdomyolysis than a 20-mg dose.¹⁷ Yet, based on our patient’s case, even 20 mg/d simvastatin should not decrease physician suspicion for rhabdomyolysis if patients are also taking a CYP3A4 inhibitor.

Third, the simvastatin-fluconazole co-administration time in our patient was 12 weeks, which is longer than previously reported (TABLE 1^11-13). Azole inhibition of CYP450 occurs relatively rapidly, but that does not mean that rhabdomyolysis will always occur immediately. For example, in cases of statin monotherapy, rhabdomyolysis secondary to statin biochemical toxicity can occur up to 1050 (mean=348) days after the drug’s initiation.¹⁸

Avoiding a drug-drug interaction in your patient

Physicians can use pharmacokinetic profiles to choose among different statins and azoles to help avoid a drug interaction (TABLE 2^6,7,10,19). Pravastatin’s serum concentration, for example, is not influenced by CYP3A4 inhibitors such as itraconazole¹¹ because pravastatin is metabolized by sulfation⁶ and not by the CYP450 system. Rosuvastatin and pitavastatin are minimally metabolized by the CYP450 system.^19,20

Even 20 mg/d simvastatin should not diminish your suspicion for rhabdomyolysis if a patient is taking a CYP3A4 inhibitor.

Among approximately 2700 statin-treated outpatients,⁴ the prevalence of potentially harmful statin interactions with other drugs (including CYP3A4 inhibitors), was significantly higher among patients treated with simvastatin or atorvastatin (CYP3A4-metabolized statins), than among patients treated with fluvastatin (CYP2C9-metabolized statin) or pravastatin (metabolized by sulfation). Apart from drug-drug interactions, other risk factors for statin-induced rhabdomyolysis include use of lipophilic statins, advanced age, and female gender.²¹

We discontinued our patient’s simvastatin on the day she was admitted to the hospital, but continued with the fluconazole throughout her hospitalization. Her CK level continued to rise, peaked on hospital Day 3 at 32,886 U/L, and then progressively decreased. The patient’s weakness and pain improved and her acute kidney injury resolved with hydration. She was discharged on hospital Day 7 on oral fluconazole, but no statin, and her muscle symptoms have since resolved.

THE TAKEAWAY

When hyperlipidemic patients have to take an azole for an extended period (eg, cancer prophylaxis or chronic osteomyelitis) and the azole is a strong CYP450 inhibitor (eg, itraconazole), switching to a statin that is not primarily metabolized by the CYP450 system (eg, pravastatin, pitavastatin) is wise. If the azole is a moderate CYP450 inhibitor (eg, fluconazole), we suggest that therapy should be closely monitored. In the case of short-term azole treatment (eg, such as for oral candidiasis), the statin should be stopped or the dose reduced by at least 50% (eg, from 40 or 20 mg to 10 mg).⁶

Prescriber knowledge is sometimes a limiting factor in identifying clinically significant interactions.²² This is especially pertinent in a case like this one, where a lower statin dose may result in a lower chance of the pharmacist alerting the prescribing physician¹⁶ and when an azole is used that is a comparatively weaker CYP450 inhibitor than other azoles such as itraconazole. Even in the era of electronic medical records, approximately 90% of drug interaction alerts are overridden by physicians, and alert fatigue is pronounced.²³

The intricacies and pharmacokinetic principles of this case should contribute to greater provider familiarity with even low-dose simvastatin-fluconazole interactions and help prevent iatrogenic complications such as rhabdomyolysis.

THE CASE

A 76-year-old Caucasian woman presented to the emergency department with a 7-day history of weakness and pain in her arms and legs. She had a history of Candida albicans vertebral osteomyelitis that had been treated for 3 months with fluconazole; non-Hodgkin lymphoma that had been in remission for 6 months; diabetes mellitus; hyperlipidemia; and hypothyroidism. The woman had dark urine, but denied chills, fever, respiratory symptoms, bowel or bladder leakage, falls/trauma, or grapefruit juice intake.

Her current medications included oral fluconazole 400 mg/d, simvastatin 20 mg/d, levothyroxine 88 mcg/d, pregabalin 75 mg/d, metformin 1000 mg twice daily, 6 units of subcutaneous insulin glargine at bedtime, and 2 units of insulin lispro with each meal. During the examination, we noted marked proximal muscle weakness, significant tenderness in all extremities, and diminished deep tendon reflexes. The patient had no saddle anesthesia, impaired rectal tone, or sensory abnormalities.

THE DIAGNOSIS

Magnetic resonance imaging of the patient’s spine confirmed multilevel discitis and osteomyelitis (T7-T9, L5-S1) with no cord compression. Laboratory data included a creatinine level of 1.42 mg/dL (the patient’s baseline was 0.8 mg/dL); a creatine kinase (CK) level of 8876 U/L (normal range, 0-220 U/L); a thyroid-stimulating hormone (TSH) level of 9.35 mIU/L (normal range, 0.4-5.5 mIU/L); and an erythrocyte sedimentation rate of 27 mm/hr (normal range, 0-31 mm/hr).

The patient received aggressive fluid hydration, orally and intravenously. On Day 2, the patient’s serum myoglobin level was 14,301 ng/mL (normal range, 30-90 ng/mL) and her aldolase level was 87.6 U/L (normal range, 1.5-8.5 U/L).

Zeroing in on the cause. There were no signs of drug abuse or use of other non-statin culprit medications that could have caused the patient’s rhabdomyolysis. She also did not describe any triggers of rhabdomyolysis, such as trauma, viral infection, metabolic disturbances, or temperature dysregulation. We believed the most likely cause of our patient’s signs and symptoms was statin-induced rhabdomyolysis, likely due to an interaction between simvastatin and fluconazole. We considered hypothyroidism-induced rhabdomyolysis, but thought it was unlikely because the patient had a mildly increased TSH level on admission, and one would expect to see levels higher than 100 mIU/L.^1-3

We also considered viral myositis in the differential, but it was an unlikely culprit because the patient lacked any history of fever or respiratory or gastrointestinal symptoms. And while paraneoplastic polymyositis could have caused the patient’s weakness, the marked muscle pain and acute kidney injury were far more suggestive of rhabdomyolysis.

DISCUSSION

Rhabdomyolysis is a serious complication of statin treatment. Both higher statin doses and pharmacokinetic factors can raise statin levels, leading to this serious muscle-related syndrome.^4,5 Co-administration of statins with drugs that are strong inhibitors of cytochrome P450 (CYP) 3A4 (the main cytochrome P450 isoform that metabolizes most statins) can increase statin levels several fold.^6,7 The trigger for our patient’s statin-induced rhabdomyolysis was fluconazole, a known moderate inhibitor of CYP3A4, which is comparatively weaker than certain potent azoles like itraconazole or ketoconazole.^7-10 Doses of fluconazole generally ≥200 mg/d are needed to produce clinical interactions with CYP3A4 substrates.⁷ There are only 3 reported cases of fluconazole-simvastatin–induced rhabdomyolysis (TABLE 1).^11-13

The Food and Drug Administration advises against simvastatin co-prescription with itraconazole and ketoconazole, but doesn’t mention fluconazole in its Drug Safety communication on simvastatin.¹⁴

Lexicomp places the simvastatin-fluconazole drug interaction into category C, which means that the agents can interact in a clinically significant manner (and a monitoring plan should be implemented), but that the benefits of concomitant use usually outweigh the risks.¹⁵

How our patient’s case differs from previous cases

Several features distinguish our patient’s scenario from previous cases. First, unlike other cases in which both drugs were stopped, only simvastatin was discontinued in our patient. Simvastatin and fluconazole have a half-life of 3 hours⁶ and 32 hours,⁷ respectively, suggesting that when simvastatin has fully cleared, fluconazole’s concentration will not even have halved. Thus, fluconazole was safely continued to treat the patient’s osteomyelitis.

Second, compared to previous case reports, our patient was taking a lower dose of simvastatin (20 mg). A 20-mg dose can make the drug interaction easier to miss; pharmacists are more likely to inform the physician of a potential drug interaction when the dose of a statin is ≥40 mg compared to when it is <40 mg (odds ratio=1.89; 95% confidence interval, 0.98-3.63).¹⁶

Researchers involved in the British randomized trial SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) sought to evaluate any added benefit to a higher dose of simvastatin in post-myocardial infarction patients. Among approximately 12,000 patients in the trial, there were 7 cases of rhabdomyolysis for the 80-mg simvastatin group and none for the 20-mg group.⁵ Another large case-control study showed that a 40-mg simvastatin dose was 5 times more likely to cause rhabdomyolysis than a 20-mg dose.¹⁷ Yet, based on our patient’s case, even 20 mg/d simvastatin should not decrease physician suspicion for rhabdomyolysis if patients are also taking a CYP3A4 inhibitor.

Third, the simvastatin-fluconazole co-administration time in our patient was 12 weeks, which is longer than previously reported (TABLE 1^11-13). Azole inhibition of CYP450 occurs relatively rapidly, but that does not mean that rhabdomyolysis will always occur immediately. For example, in cases of statin monotherapy, rhabdomyolysis secondary to statin biochemical toxicity can occur up to 1050 (mean=348) days after the drug’s initiation.¹⁸

Avoiding a drug-drug interaction in your patient

Physicians can use pharmacokinetic profiles to choose among different statins and azoles to help avoid a drug interaction (TABLE 2^6,7,10,19). Pravastatin’s serum concentration, for example, is not influenced by CYP3A4 inhibitors such as itraconazole¹¹ because pravastatin is metabolized by sulfation⁶ and not by the CYP450 system. Rosuvastatin and pitavastatin are minimally metabolized by the CYP450 system.^19,20

Even 20 mg/d simvastatin should not diminish your suspicion for rhabdomyolysis if a patient is taking a CYP3A4 inhibitor.

Among approximately 2700 statin-treated outpatients,⁴ the prevalence of potentially harmful statin interactions with other drugs (including CYP3A4 inhibitors), was significantly higher among patients treated with simvastatin or atorvastatin (CYP3A4-metabolized statins), than among patients treated with fluvastatin (CYP2C9-metabolized statin) or pravastatin (metabolized by sulfation). Apart from drug-drug interactions, other risk factors for statin-induced rhabdomyolysis include use of lipophilic statins, advanced age, and female gender.²¹

We discontinued our patient’s simvastatin on the day she was admitted to the hospital, but continued with the fluconazole throughout her hospitalization. Her CK level continued to rise, peaked on hospital Day 3 at 32,886 U/L, and then progressively decreased. The patient’s weakness and pain improved and her acute kidney injury resolved with hydration. She was discharged on hospital Day 7 on oral fluconazole, but no statin, and her muscle symptoms have since resolved.

THE TAKEAWAY

When hyperlipidemic patients have to take an azole for an extended period (eg, cancer prophylaxis or chronic osteomyelitis) and the azole is a strong CYP450 inhibitor (eg, itraconazole), switching to a statin that is not primarily metabolized by the CYP450 system (eg, pravastatin, pitavastatin) is wise. If the azole is a moderate CYP450 inhibitor (eg, fluconazole), we suggest that therapy should be closely monitored. In the case of short-term azole treatment (eg, such as for oral candidiasis), the statin should be stopped or the dose reduced by at least 50% (eg, from 40 or 20 mg to 10 mg).⁶

Prescriber knowledge is sometimes a limiting factor in identifying clinically significant interactions.²² This is especially pertinent in a case like this one, where a lower statin dose may result in a lower chance of the pharmacist alerting the prescribing physician¹⁶ and when an azole is used that is a comparatively weaker CYP450 inhibitor than other azoles such as itraconazole. Even in the era of electronic medical records, approximately 90% of drug interaction alerts are overridden by physicians, and alert fatigue is pronounced.²³

The intricacies and pharmacokinetic principles of this case should contribute to greater provider familiarity with even low-dose simvastatin-fluconazole interactions and help prevent iatrogenic complications such as rhabdomyolysis.

The Advisory Committee on Immunization Practices (ACIP) met 3 times in 2016 and introduced or revised recommendations on influenza, meningococcal, human papillomavirus (HPV), cholera, and hepatitis B vaccines. This Practice Alert highlights the most important new recommendations, except those for influenza vaccines, which were described in a previous Practice Alert.¹ (See the summary of how this year’s flu season compares to last year’s.)

Meningococcal vaccine: Now recommended for HIV-positive patients

Meningococcal conjugate vaccine (serogroups A, C, W, and Y) is recommended for all adolescents ages 11 to 12 as a single dose with a booster at age 16.² It is also recommended for adults and for children (starting at age 2 months) who have high-risk conditions such as functional or anatomic asplenia or complement deficiencies. Others at high risk include microbiologists routinely exposed to isolates of Neisseria meningitidis and those traveling to areas of high meningococcal incidence. ACIP recently added human immunodeficiency virus (HIV) infection to the list of high-risk conditions.³

Two meningococcal conjugate vaccines are available in the United States: Menactra, (Sanofi Pasteur), licensed for use in individuals ages 9 months to 55 years; and Menveo (GlaxoSmithKline), licensed for use in individuals ages 2 months to 55 years. Menveo is the preferred vaccine for children younger than 2 years infected with HIV. However, if Menactra is used, give it at least 4 weeks after completing all pneumococcal conjugate vaccine doses and either before or concomitantly with diphtheria and tetanus toxoid and acellular pertussis vaccine (DTaP). All individuals who are HIV positive should receive a multi-dose primary series and booster doses. The number of primary doses and timing of boosters depends on the product used and the ages of those vaccinated (TABLE³).

Although neither meningococcal conjugate vaccine product is licensed for use in individuals 56 years or older, ACIP recommends using one of the products for HIV-infected individuals in this age group because the only meningococcal vaccine licensed for use in adults 56 or older, meningococcal polysaccharide vaccine (MPSV4, Menomune, Sanofi Pasteur), has not been studied in patients with HIV infection.

Serogroup B. Two vaccine products provide short-term protection against meningococcal serogroup B: MenB-FHbp (Trumenba, Wyeth Pharmaceuticals, Inc.) and MenB-4C (Bexsero, GlaxoSmithKline). In 2015, ACIP made a “B” recommendation for the use of these vaccines in individuals 16 to 23 years of age, with the preferred age range being 16 to 18.⁴ A “B” recommendation means that while ACIP does not advise routine use of the vaccines in this age group, the vaccines can be administered to those who desire them. ACIP has recommended routine use of these products only for individuals 10 years and older who are at high risk for meningococcal disease.⁵

Trumenba was approved as a 3-dose vaccine, administered at 0, 2, and 6 months. Bexsero requires 2 doses given at least one month apart. At its October 2016 meeting, ACIP approved a 2-dose Trumenba schedule, at 0 and 6 months, when administered to those not at risk for meningococcal disease.⁶ However, during an outbreak, and for those at high risk for meningococcal disease, adhere to the original 3-dose schedule.

HPV vaccine: Now a 2-dose schedule for younger patients

The only HPV vaccine available in the United States is the 9-valent HPV vaccine (9vHPV), Gardasil 9. It is approved for both males and females ages 9 to 26 years. ACIP recommends it for both sexes at ages 11 or 12, and advises catch-up doses for men through age 21 and women through age 26. It also recommends vaccination through age 26 for men who have sex with men and men with HIV/acquired immunodeficiency syndrome (AIDS). Children with a history of being sexually abused or assaulted should begin vaccination at age 9 years.

The HPV vaccine is approved for a 3-dose schedule at 0, 1 to 2, and 6 months. At its October 2016 meeting, ACIP approved a 2-dose schedule (0, 6-12 months) for those starting the vaccine before their 15th birthday.⁷ Those starting the vaccine after their 15th birthday, and individuals at any age with an immune-compromising condition, should receive 3 doses. It is hoped that a 2-dose schedule will help to increase the uptake of this safe, effective, and underused vaccine.

Cholera: A new vaccine is available

In June 2016, the FDA approved a live, attenuated, single-dose, oral vaccine (Vaxchora, PaxVax, Inc.) for the prevention of cholera in adults ages 18 to 64 years. It is the only cholera vaccine approved in the United States.

Cholera occurs at low rates among travelers to areas where the disease is endemic. The key to prevention is food and water precautions, and thus the vaccine is not recommended for most travelers—only for those who are at increased risk of exposure to cholera or who have a medical condition that predisposes them to a poor response to medical care if cholera is contracted.⁸ Risk increases with long-term or frequent travel to endemic areas where safe food and water is not always available. Examples of compromising medical conditions include a blood type O, low gastric acidity, and heart or kidney disease.

Duration of the vaccine’s effectiveness is unknown, given a lack of data beyond 6 months. No recommendation for revaccination has been made, and this issue will be assessed as more data are collected. Other unknowns about the vaccine include its effectiveness among immune-suppressed individuals and pregnant women, as well as for those who live in cholera endemic areas or were previously vaccinated with another cholera vaccine.

Hepatitis B: Vaccinate newborns sooner

The incidence of hepatitis B virus (HBV) infection has declined by more than 90% since the introduction of a vaccine in 1982.⁹ However, about 19,000 new cases still arise each year,¹⁰ and about 950 of these are acquired by babies born to HBV-infected mothers.¹¹ About 90% of these infected newborns will develop chronic HBV infection¹² and, if untreated, incur its long-term risks of cirrhosis and liver failure. Hepatitis B vaccine given soon after birth is 75% effective in preventing perinatal HBV infection, and hepatitis B immune globulin (HBIG) is 71% effective.¹³ Used together, the 2 are 94% effective.¹³

Current recommendations for the prevention of HBV include:⁹

• Screen all pregnant women for hepatitis B surface antigen (HBsAg), and use HBIG and hepatitis B vaccines within 12 hours of birth for all newborns whose mothers are HBsAg positive or have an unknown HBsAg status.
• Administer the 3-dose hepatitis B vaccine to all other infants.
• Routinely vaccinate previously unvaccinated children and adolescents.
• Routinely vaccinate adults who are non-immune and at risk for HBV infection.

At its October 2016 meeting, ACIP adopted a comprehensive update of all HBV prevention recommendations. (This will be the subject of a future Practice Alert.) Included was a revision of a previously permissive recommendation that allowed the first dose of hepatitis B vaccine for newborns to be given within 2 months of hospital discharge. The new recommendation⁹ states that newborns of mothers known to be HBsAg negative should be vaccinated within 24 hours (if weight is ≥2000 g) or at age one month or at hospital discharge (if weight is <2000 g).

The first dose should be given within 12 hours of birth to all newborns whose mothers are HBsAg positive or have an unknown HBsAg status.⁹

Immunization schedules

Every year ACIP updates the adult and child immunization schedules to incorporate the changes from the previous year. These can be found on the ACIP Web site at https://www.cdc.gov/vaccines/schedules/hcp/index.html. This Web site remains the most authoritative and accurate source of information on vaccines and immunizations for both professionals and the public.

The Advisory Committee on Immunization Practices (ACIP) met 3 times in 2016 and introduced or revised recommendations on influenza, meningococcal, human papillomavirus (HPV), cholera, and hepatitis B vaccines. This Practice Alert highlights the most important new recommendations, except those for influenza vaccines, which were described in a previous Practice Alert.¹ (See the summary of how this year’s flu season compares to last year’s.)

Meningococcal vaccine: Now recommended for HIV-positive patients

Meningococcal conjugate vaccine (serogroups A, C, W, and Y) is recommended for all adolescents ages 11 to 12 as a single dose with a booster at age 16.² It is also recommended for adults and for children (starting at age 2 months) who have high-risk conditions such as functional or anatomic asplenia or complement deficiencies. Others at high risk include microbiologists routinely exposed to isolates of Neisseria meningitidis and those traveling to areas of high meningococcal incidence. ACIP recently added human immunodeficiency virus (HIV) infection to the list of high-risk conditions.³

Two meningococcal conjugate vaccines are available in the United States: Menactra, (Sanofi Pasteur), licensed for use in individuals ages 9 months to 55 years; and Menveo (GlaxoSmithKline), licensed for use in individuals ages 2 months to 55 years. Menveo is the preferred vaccine for children younger than 2 years infected with HIV. However, if Menactra is used, give it at least 4 weeks after completing all pneumococcal conjugate vaccine doses and either before or concomitantly with diphtheria and tetanus toxoid and acellular pertussis vaccine (DTaP). All individuals who are HIV positive should receive a multi-dose primary series and booster doses. The number of primary doses and timing of boosters depends on the product used and the ages of those vaccinated (TABLE³).

Although neither meningococcal conjugate vaccine product is licensed for use in individuals 56 years or older, ACIP recommends using one of the products for HIV-infected individuals in this age group because the only meningococcal vaccine licensed for use in adults 56 or older, meningococcal polysaccharide vaccine (MPSV4, Menomune, Sanofi Pasteur), has not been studied in patients with HIV infection.

Serogroup B. Two vaccine products provide short-term protection against meningococcal serogroup B: MenB-FHbp (Trumenba, Wyeth Pharmaceuticals, Inc.) and MenB-4C (Bexsero, GlaxoSmithKline). In 2015, ACIP made a “B” recommendation for the use of these vaccines in individuals 16 to 23 years of age, with the preferred age range being 16 to 18.⁴ A “B” recommendation means that while ACIP does not advise routine use of the vaccines in this age group, the vaccines can be administered to those who desire them. ACIP has recommended routine use of these products only for individuals 10 years and older who are at high risk for meningococcal disease.⁵

Trumenba was approved as a 3-dose vaccine, administered at 0, 2, and 6 months. Bexsero requires 2 doses given at least one month apart. At its October 2016 meeting, ACIP approved a 2-dose Trumenba schedule, at 0 and 6 months, when administered to those not at risk for meningococcal disease.⁶ However, during an outbreak, and for those at high risk for meningococcal disease, adhere to the original 3-dose schedule.

HPV vaccine: Now a 2-dose schedule for younger patients

The only HPV vaccine available in the United States is the 9-valent HPV vaccine (9vHPV), Gardasil 9. It is approved for both males and females ages 9 to 26 years. ACIP recommends it for both sexes at ages 11 or 12, and advises catch-up doses for men through age 21 and women through age 26. It also recommends vaccination through age 26 for men who have sex with men and men with HIV/acquired immunodeficiency syndrome (AIDS). Children with a history of being sexually abused or assaulted should begin vaccination at age 9 years.

The HPV vaccine is approved for a 3-dose schedule at 0, 1 to 2, and 6 months. At its October 2016 meeting, ACIP approved a 2-dose schedule (0, 6-12 months) for those starting the vaccine before their 15th birthday.⁷ Those starting the vaccine after their 15th birthday, and individuals at any age with an immune-compromising condition, should receive 3 doses. It is hoped that a 2-dose schedule will help to increase the uptake of this safe, effective, and underused vaccine.

Cholera: A new vaccine is available

In June 2016, the FDA approved a live, attenuated, single-dose, oral vaccine (Vaxchora, PaxVax, Inc.) for the prevention of cholera in adults ages 18 to 64 years. It is the only cholera vaccine approved in the United States.

Cholera occurs at low rates among travelers to areas where the disease is endemic. The key to prevention is food and water precautions, and thus the vaccine is not recommended for most travelers—only for those who are at increased risk of exposure to cholera or who have a medical condition that predisposes them to a poor response to medical care if cholera is contracted.⁸ Risk increases with long-term or frequent travel to endemic areas where safe food and water is not always available. Examples of compromising medical conditions include a blood type O, low gastric acidity, and heart or kidney disease.

Duration of the vaccine’s effectiveness is unknown, given a lack of data beyond 6 months. No recommendation for revaccination has been made, and this issue will be assessed as more data are collected. Other unknowns about the vaccine include its effectiveness among immune-suppressed individuals and pregnant women, as well as for those who live in cholera endemic areas or were previously vaccinated with another cholera vaccine.

Hepatitis B: Vaccinate newborns sooner

The incidence of hepatitis B virus (HBV) infection has declined by more than 90% since the introduction of a vaccine in 1982.⁹ However, about 19,000 new cases still arise each year,¹⁰ and about 950 of these are acquired by babies born to HBV-infected mothers.¹¹ About 90% of these infected newborns will develop chronic HBV infection¹² and, if untreated, incur its long-term risks of cirrhosis and liver failure. Hepatitis B vaccine given soon after birth is 75% effective in preventing perinatal HBV infection, and hepatitis B immune globulin (HBIG) is 71% effective.¹³ Used together, the 2 are 94% effective.¹³

Current recommendations for the prevention of HBV include:⁹

• Screen all pregnant women for hepatitis B surface antigen (HBsAg), and use HBIG and hepatitis B vaccines within 12 hours of birth for all newborns whose mothers are HBsAg positive or have an unknown HBsAg status.
• Administer the 3-dose hepatitis B vaccine to all other infants.
• Routinely vaccinate previously unvaccinated children and adolescents.
• Routinely vaccinate adults who are non-immune and at risk for HBV infection.

At its October 2016 meeting, ACIP adopted a comprehensive update of all HBV prevention recommendations. (This will be the subject of a future Practice Alert.) Included was a revision of a previously permissive recommendation that allowed the first dose of hepatitis B vaccine for newborns to be given within 2 months of hospital discharge. The new recommendation⁹ states that newborns of mothers known to be HBsAg negative should be vaccinated within 24 hours (if weight is ≥2000 g) or at age one month or at hospital discharge (if weight is <2000 g).

The first dose should be given within 12 hours of birth to all newborns whose mothers are HBsAg positive or have an unknown HBsAg status.⁹

Immunization schedules

Every year ACIP updates the adult and child immunization schedules to incorporate the changes from the previous year. These can be found on the ACIP Web site at https://www.cdc.gov/vaccines/schedules/hcp/index.html. This Web site remains the most authoritative and accurate source of information on vaccines and immunizations for both professionals and the public.

The Advisory Committee on Immunization Practices (ACIP) met 3 times in 2016 and introduced or revised recommendations on influenza, meningococcal, human papillomavirus (HPV), cholera, and hepatitis B vaccines. This Practice Alert highlights the most important new recommendations, except those for influenza vaccines, which were described in a previous Practice Alert.¹ (See the summary of how this year’s flu season compares to last year’s.)

Meningococcal vaccine: Now recommended for HIV-positive patients

Meningococcal conjugate vaccine (serogroups A, C, W, and Y) is recommended for all adolescents ages 11 to 12 as a single dose with a booster at age 16.² It is also recommended for adults and for children (starting at age 2 months) who have high-risk conditions such as functional or anatomic asplenia or complement deficiencies. Others at high risk include microbiologists routinely exposed to isolates of Neisseria meningitidis and those traveling to areas of high meningococcal incidence. ACIP recently added human immunodeficiency virus (HIV) infection to the list of high-risk conditions.³

Two meningococcal conjugate vaccines are available in the United States: Menactra, (Sanofi Pasteur), licensed for use in individuals ages 9 months to 55 years; and Menveo (GlaxoSmithKline), licensed for use in individuals ages 2 months to 55 years. Menveo is the preferred vaccine for children younger than 2 years infected with HIV. However, if Menactra is used, give it at least 4 weeks after completing all pneumococcal conjugate vaccine doses and either before or concomitantly with diphtheria and tetanus toxoid and acellular pertussis vaccine (DTaP). All individuals who are HIV positive should receive a multi-dose primary series and booster doses. The number of primary doses and timing of boosters depends on the product used and the ages of those vaccinated (TABLE³).

Although neither meningococcal conjugate vaccine product is licensed for use in individuals 56 years or older, ACIP recommends using one of the products for HIV-infected individuals in this age group because the only meningococcal vaccine licensed for use in adults 56 or older, meningococcal polysaccharide vaccine (MPSV4, Menomune, Sanofi Pasteur), has not been studied in patients with HIV infection.

Serogroup B. Two vaccine products provide short-term protection against meningococcal serogroup B: MenB-FHbp (Trumenba, Wyeth Pharmaceuticals, Inc.) and MenB-4C (Bexsero, GlaxoSmithKline). In 2015, ACIP made a “B” recommendation for the use of these vaccines in individuals 16 to 23 years of age, with the preferred age range being 16 to 18.⁴ A “B” recommendation means that while ACIP does not advise routine use of the vaccines in this age group, the vaccines can be administered to those who desire them. ACIP has recommended routine use of these products only for individuals 10 years and older who are at high risk for meningococcal disease.⁵

Trumenba was approved as a 3-dose vaccine, administered at 0, 2, and 6 months. Bexsero requires 2 doses given at least one month apart. At its October 2016 meeting, ACIP approved a 2-dose Trumenba schedule, at 0 and 6 months, when administered to those not at risk for meningococcal disease.⁶ However, during an outbreak, and for those at high risk for meningococcal disease, adhere to the original 3-dose schedule.

HPV vaccine: Now a 2-dose schedule for younger patients

The only HPV vaccine available in the United States is the 9-valent HPV vaccine (9vHPV), Gardasil 9. It is approved for both males and females ages 9 to 26 years. ACIP recommends it for both sexes at ages 11 or 12, and advises catch-up doses for men through age 21 and women through age 26. It also recommends vaccination through age 26 for men who have sex with men and men with HIV/acquired immunodeficiency syndrome (AIDS). Children with a history of being sexually abused or assaulted should begin vaccination at age 9 years.

The HPV vaccine is approved for a 3-dose schedule at 0, 1 to 2, and 6 months. At its October 2016 meeting, ACIP approved a 2-dose schedule (0, 6-12 months) for those starting the vaccine before their 15th birthday.⁷ Those starting the vaccine after their 15th birthday, and individuals at any age with an immune-compromising condition, should receive 3 doses. It is hoped that a 2-dose schedule will help to increase the uptake of this safe, effective, and underused vaccine.

Cholera: A new vaccine is available

In June 2016, the FDA approved a live, attenuated, single-dose, oral vaccine (Vaxchora, PaxVax, Inc.) for the prevention of cholera in adults ages 18 to 64 years. It is the only cholera vaccine approved in the United States.

Cholera occurs at low rates among travelers to areas where the disease is endemic. The key to prevention is food and water precautions, and thus the vaccine is not recommended for most travelers—only for those who are at increased risk of exposure to cholera or who have a medical condition that predisposes them to a poor response to medical care if cholera is contracted.⁸ Risk increases with long-term or frequent travel to endemic areas where safe food and water is not always available. Examples of compromising medical conditions include a blood type O, low gastric acidity, and heart or kidney disease.

Duration of the vaccine’s effectiveness is unknown, given a lack of data beyond 6 months. No recommendation for revaccination has been made, and this issue will be assessed as more data are collected. Other unknowns about the vaccine include its effectiveness among immune-suppressed individuals and pregnant women, as well as for those who live in cholera endemic areas or were previously vaccinated with another cholera vaccine.

Hepatitis B: Vaccinate newborns sooner

The incidence of hepatitis B virus (HBV) infection has declined by more than 90% since the introduction of a vaccine in 1982.⁹ However, about 19,000 new cases still arise each year,¹⁰ and about 950 of these are acquired by babies born to HBV-infected mothers.¹¹ About 90% of these infected newborns will develop chronic HBV infection¹² and, if untreated, incur its long-term risks of cirrhosis and liver failure. Hepatitis B vaccine given soon after birth is 75% effective in preventing perinatal HBV infection, and hepatitis B immune globulin (HBIG) is 71% effective.¹³ Used together, the 2 are 94% effective.¹³

Current recommendations for the prevention of HBV include:⁹

• Screen all pregnant women for hepatitis B surface antigen (HBsAg), and use HBIG and hepatitis B vaccines within 12 hours of birth for all newborns whose mothers are HBsAg positive or have an unknown HBsAg status.
• Administer the 3-dose hepatitis B vaccine to all other infants.
• Routinely vaccinate previously unvaccinated children and adolescents.
• Routinely vaccinate adults who are non-immune and at risk for HBV infection.

At its October 2016 meeting, ACIP adopted a comprehensive update of all HBV prevention recommendations. (This will be the subject of a future Practice Alert.) Included was a revision of a previously permissive recommendation that allowed the first dose of hepatitis B vaccine for newborns to be given within 2 months of hospital discharge. The new recommendation⁹ states that newborns of mothers known to be HBsAg negative should be vaccinated within 24 hours (if weight is ≥2000 g) or at age one month or at hospital discharge (if weight is <2000 g).

The first dose should be given within 12 hours of birth to all newborns whose mothers are HBsAg positive or have an unknown HBsAg status.⁹

Immunization schedules

Every year ACIP updates the adult and child immunization schedules to incorporate the changes from the previous year. These can be found on the ACIP Web site at https://www.cdc.gov/vaccines/schedules/hcp/index.html. This Web site remains the most authoritative and accurate source of information on vaccines and immunizations for both professionals and the public.

CASE › A 52-year-old right-hand-dominant white man arrived at our clinic complaining that he was unable to straighten his right ring finger. He had no associated pain or numbness, and had not injured his hand. The patient had type 2 diabetes that was controlled with metformin. He had no history of surgery or drug allergies, did not smoke, and said he drank 2 to 3 alcoholic beverages per day. He was a car salesman and was self-conscious when shaking hands with customers. On physical examination, we noted that he held his right ring finger at roughly 45 degrees of flexion at the metacarpophalangeal joint; a painless cord-like structure was palpable on the palmar surface of that joint. His left hand had no abnormalities.

If this were your patient, how would you proceed?

Dupuytren’s disease (DD) is a disabling fibroproliferative disorder of the hand for which there is no cure. While the exact cause of DD is unknown, it has been linked to a number of risk factors, including smoking, alcohol consumption, and diabetes. It affects about 5% of the US population, and up to 70% of affected individuals may initially seek treatment from a primary care physician.¹ The disease is also referred to as Dupuytren’s contracture, which describes the flexion contractures of fingers at the end stage of the disease. Palmar fibromatosis is yet another name for the disorder.

DD refers to a spectrum of presentations ranging from nodules to cords to discernible contractures, and it is not known which patients with early Dupuytren changes will progress to severe contracture. With recognition of early changes, nonsurgical intervention is possible, such as collagenase injection or percutaneous fasciotomy, and can slow the progression of DD, restore function, and avoid or delay surgical intervention. DD is a clinically challenging disorder. Treatment for an affected area may resolve symptoms, only to have them recur in that location or another.

How underlying pathology correlates with clinical findings

DD affects the palmar fascia, a thick triangular-shaped sheet of dense fibrous collagenous connective tissue that lies deep to the dermis and superficial to the flexor tendons of the hand with fibers extending both into the skin and into the deep tissue. The palmar fascia secures the skin during gripping and twisting motions, and it bifurcates into distal extensions, called pretendinous bands, that overlay and mimic the flexor tendons.

Clinical findings reflect the progression of underlying pathology. The earliest manifestation of DD is painless dimpling of the skin on the palmar surface of the hand.² Over time, the underlying fibrosis with increased collagen deposition can progress, leading to development of nodules and eventually, cords, which are sometimes mistaken for flexor tendons. Dupuytren-like fibrotic tissue can occur on the sole of the foot (Ledderhose disease) and penis (Peyronie’s disease).^2,3 In patients with these coexisting conditions, prognosis is generally worse.⁴ With the hands, bilateral involvement is common, although it is usually more severe in one hand. The ring finger is the digit most frequently involved, followed by the little finger, middle finger, and index finger. The thumb is rarely affected.³

As the disease progresses and cords contract, the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints develop flexion contractures. The distal interphalangeal (DIP) joint, rarely involved, instead exhibits a hyperextension contracture. Digital flexion contractures are often disabling, interfering with daily activities such as picking up a glass, shaking hands, or putting one's hand in a pants pocket. Many patients seek medical attention only after a palpable nodule, cord, or flexion contracture becomes apparent (FIGURE 1).

In a study of 326 patients who reported Dupuytren’s symptoms, the most common symptoms that led them to seek treatment were, in descending order, a hard bump (48%), a ropelike growth (12%), dimpling (11%), and finger contractures (10%). Only 9% of patients seeking treatment for hand symptoms associated with DD had received a diagnosis of DD from their initial medical encounter, causing an unnecessary delay in treatment.¹

Who is at increased risk for DD?

DD is most often seen in elderly white men of European descent.⁵ In the United States, the prevalence of the disease is roughly 5%,¹ compared with 4% to 39% in northwestern Europe (eg, Iceland).⁶ The male-to-female ratio of DD ranges from 6:1 to 15:1.⁷ The prevalence of DD appears to increase with age. The prevalence in men and women is similar up to age 45 years, after which the rate is much greater in males.⁷

DD is associated with many risk factors including smoking, alcohol consumption, vascular insufficiency, epilepsy, hyperlipidemia, manual labor, occupations with exposure to vibration, hand trauma, and even hand surgery such as carpal tunnel release or trigger finger release.^8-11 It is also associated with diabetes; particularly type 1 insulin-dependent diabetes.¹² There may also be an association with frozen shoulder.^12,13

The need for surgical treatment of DD becomes more likely with a history of cigarette smoking and heavy alcohol consumption. There seems to be an association with epilepsy, most likely from anti-epileptic drugs.¹⁴ Rheumatoid arthritis is the only condition that has been associated with a lower incidence of DD, possibly because of the use of anti-inflammatory drugs.¹⁵ There are genetic differences between patients with and without DD, although a “Dupuytren’s gene” has not been identified.

Rule out possible DD mimics

The differential diagnosis for flexion contracture of the MCP or PIP joints seen in Dupuytren’s disease includes stenosing flexor tenosynovitis, or trigger finger. Other conditions that can mimic DD are ulnar claw hand, trauma scars, intrinsic joint diseases such as degenerative or rheumatoid arthritis (RA), diabetic cheiroarthropathy, camptodactyly, and Volkmann’s contracture. Trauma scars—especially longitudinal scars—have a tendency to contract and develop keloid formation.

It's not known which patients with early Dupuytren changes will progress to severe contracture.

Stenosing flexor tenosynovitis and ulnar claw hand are distinguishable from DD by full or nearly full active or passive extension of the affected digit, whereas DD is a true contracture of the joint that does not allow full extension. A careful history can rule out previous injury to the area. Although intrinsic joint disease, such as RA, can cause finger contractures, the joints are usually enlarged, painful, and associated with characteristic radiologic findings.

Unlike DD, diabetic cheiroarthropathy often involves all of the digits except for the thumb, and is often associated with a waxy appearance of the skin. Camptodactyly is an autosomal dominant disorder that more often presents in childhood and can be caused by a number of congenital syndromes. Volkmann’s contracture can manifest as a claw-like deformity of the hand caused by undiagnosed compartment syndrome of the forearm.

Assess the severity of DD

In your evaluation, first identify palmar or digital fibromatosis presenting as a nodule or a cord. Second, estimate the degree of MCP and PIP joint contractures. A common measure of contracture is the Hueston tabletop test. Ask the patient to place the palm of the hand on a flat surface. If the patient is unable to completely flatten the hand against the surface, presume a positive result (FIGURE 2).¹⁶

An accurate measure of the degree of flexion can be accomplished with a goniometer. For a simple assessment of severity, have the patient place each affected finger along the convexity of a spoon. If adjoining surfaces are flush, assume that the contracture is at least 30 degrees (FIGURE 3). The severity of DD can also be graded according to the Tubiana classification system (TABLE¹⁷), wherein the total deformity or contracture score is the sum of the angles of all 3 digital joints of the finger.

A look at the treatment options

Once the diagnosis of DD is made, reassure the patient that the disease is not cancerous, although it may be progressive. Advise patients, too, that several treatment options (detailed below) are available, but that surgery is the mainstay of treatment. (Of note: Despite what would seem logical, stretching a cord to straighten the finger is not recommended, as it may actually worsen the condition.¹⁸)

Options for early DD. Corticosteroids such as triamcinolone may have a role as an adjunct for early DD by reducing the size and firmness of the Dupuytren’s nodules and possibly slowing the progression of the disease. However, in one study of 63 patients, half of the individuals experienced reactivation of disease between one and 3 years.¹⁹

Radiotherapy has been studied as a potential treatment for early DD and for patients unable to undergo surgery. Radiation does have a biologic effect on nodular DD, but has no effect on the cords that cause the joint contracture. In a long-term follow-up study of 135 patients treated with radiotherapy, disease remained stable in 59% of patients, improved in 10%, and progressed in 31%.²⁰ Results were better for early stage disease. This modality is not used for more advanced cases.

Surgery is the primary method by which to restore function and minimize complications. In the past, referral was recom­mended for MCP joint contractures >30 degrees or for any involvment of the PIP joint, because involvement of the latter carries a worse prognosis and may not be fully correctable, even with surgery.²¹ However, treatment may also be warranted in cases of functional disability—regardless of the degree of contracture (eg, for pain associated with a prominent nodule or cord when gripping objects).

Although fasciectomies have shown the best efficacy and lowest recurrence rates, complications are more likely with these procedures.Depending on disease progression and the surgeon’s preference, the most popular procedures are fasciotomies and fasciectomies. Surgical options for contractures—in increasing order of invasiveness and amounts of fascia removed—are fasciotomy (needle, open), fasciectomy (partial, radical), and dermofasciectomy.

Needle fasciotomy is an outpatient procedure performed under local block. The surgeon uses a needle bevel to transect the diseased cord at multiple puncture sites.

Open fasciotomy is also an outpatient procedure involving an incision that allows direct visualization of the cord and internal structures before dividing the fascia. Percutaneous and open fasciotomies are more successful for MCP joint contractures and less successful for PIP joint contractures.

With partial fasciectomy, only the grossly affected fascia is removed.

With radical fasciectomy, the entire palmar fascia is removed, regardless of which areas are grossly diseased.

Dermofasciectomy removes diseased fascia and the overlying skin, with a skin graft applied to heal the wound.

Another option: Collagenase injection. In February 2010, the US Food and Drug Administration approved collagenase clostridium histolyticum (Xiaflex) as the first drug specifically indicated for the treatment of Dupuytren’s contracture. Collagenase is injected directly into the fascial cord, cleaving its collagen component and progressively softening and breaking down the cord. If not properly injected, collagenase may injure neurovascular structures and may rupture tendons.

So how do the treatment options compare?

We found no randomized prospective trials comparing treatment options for DD, but there are a number of trials that shed light on a variety of the available options.

Treatment success. In general, partial fasciectomies have shown the greatest success in reducing contractures and maintaining the lowest recurrence rates. Correction of contracture to ≤5 degrees was seen in 94% of MCP joint contractures treated with partial fasciectomy, in 77% of MCP joints treated with collagenase, and in 55% of MCP joints treated with percutaneous needle fasciotomies.^22,23 PIP joint contracture correction was not as successful: Correction of contracture to ≤5 degrees was seen in 47% of those treated with partial fasciectomy, 40% treated with collagenase, and 26% treated with needle fasciotomy.^22,23

Recurrence rates. When recurrence was defined as loss of passive extension >30 degrees, the recurrence rate for MCP joint contractures with partial fasciectomy was 21%, compared with 85% for needle fasciotomy.²² In a similar review, recurrence rates for partial fasciectomy ranged from 12% to 39% compared with 50% to 58% for needle fasciotomy.²⁴ With collagenase injection, 5-year data have shown an overall recurrence rate of 32%, with a recurrence of 26% at the MCP joint and 46% at the PIP joint.²⁵ In this trial, recurrence was defined as more than 30% worsening of flexion.²⁵

Complications. Although fasciectomies have shown the best efficacy and lowest recurrence rates, complications such as infection, neurapraxia, and digital nerve injury are more likely with these procedures.^26,27

Early recognition and referral to a hand specialist for the treatment of DD may allow the use of less invasive techniques and improved functional results.

CASE › Absent a history of trauma and features typical of other hand/digit disorders, we diagnosed Dupuytren’s disease in this patient. Potential treatments included partial fasciectomy and collagenase injection. After discussing the risks and benefits of each of these procedures, the patient elected to undergo a partial fasciectomy. The surgery was uncomplicated and the abnormality was corrected to within 5 degrees of full extension. At the patient’s one-year follow-up visit, there was no evidence of recurrence.

CASE › A 52-year-old right-hand-dominant white man arrived at our clinic complaining that he was unable to straighten his right ring finger. He had no associated pain or numbness, and had not injured his hand. The patient had type 2 diabetes that was controlled with metformin. He had no history of surgery or drug allergies, did not smoke, and said he drank 2 to 3 alcoholic beverages per day. He was a car salesman and was self-conscious when shaking hands with customers. On physical examination, we noted that he held his right ring finger at roughly 45 degrees of flexion at the metacarpophalangeal joint; a painless cord-like structure was palpable on the palmar surface of that joint. His left hand had no abnormalities.

If this were your patient, how would you proceed?

Dupuytren’s disease (DD) is a disabling fibroproliferative disorder of the hand for which there is no cure. While the exact cause of DD is unknown, it has been linked to a number of risk factors, including smoking, alcohol consumption, and diabetes. It affects about 5% of the US population, and up to 70% of affected individuals may initially seek treatment from a primary care physician.¹ The disease is also referred to as Dupuytren’s contracture, which describes the flexion contractures of fingers at the end stage of the disease. Palmar fibromatosis is yet another name for the disorder.

DD refers to a spectrum of presentations ranging from nodules to cords to discernible contractures, and it is not known which patients with early Dupuytren changes will progress to severe contracture. With recognition of early changes, nonsurgical intervention is possible, such as collagenase injection or percutaneous fasciotomy, and can slow the progression of DD, restore function, and avoid or delay surgical intervention. DD is a clinically challenging disorder. Treatment for an affected area may resolve symptoms, only to have them recur in that location or another.

How underlying pathology correlates with clinical findings

DD affects the palmar fascia, a thick triangular-shaped sheet of dense fibrous collagenous connective tissue that lies deep to the dermis and superficial to the flexor tendons of the hand with fibers extending both into the skin and into the deep tissue. The palmar fascia secures the skin during gripping and twisting motions, and it bifurcates into distal extensions, called pretendinous bands, that overlay and mimic the flexor tendons.

Clinical findings reflect the progression of underlying pathology. The earliest manifestation of DD is painless dimpling of the skin on the palmar surface of the hand.² Over time, the underlying fibrosis with increased collagen deposition can progress, leading to development of nodules and eventually, cords, which are sometimes mistaken for flexor tendons. Dupuytren-like fibrotic tissue can occur on the sole of the foot (Ledderhose disease) and penis (Peyronie’s disease).^2,3 In patients with these coexisting conditions, prognosis is generally worse.⁴ With the hands, bilateral involvement is common, although it is usually more severe in one hand. The ring finger is the digit most frequently involved, followed by the little finger, middle finger, and index finger. The thumb is rarely affected.³

As the disease progresses and cords contract, the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints develop flexion contractures. The distal interphalangeal (DIP) joint, rarely involved, instead exhibits a hyperextension contracture. Digital flexion contractures are often disabling, interfering with daily activities such as picking up a glass, shaking hands, or putting one's hand in a pants pocket. Many patients seek medical attention only after a palpable nodule, cord, or flexion contracture becomes apparent (FIGURE 1).

In a study of 326 patients who reported Dupuytren’s symptoms, the most common symptoms that led them to seek treatment were, in descending order, a hard bump (48%), a ropelike growth (12%), dimpling (11%), and finger contractures (10%). Only 9% of patients seeking treatment for hand symptoms associated with DD had received a diagnosis of DD from their initial medical encounter, causing an unnecessary delay in treatment.¹

Who is at increased risk for DD?

DD is most often seen in elderly white men of European descent.⁵ In the United States, the prevalence of the disease is roughly 5%,¹ compared with 4% to 39% in northwestern Europe (eg, Iceland).⁶ The male-to-female ratio of DD ranges from 6:1 to 15:1.⁷ The prevalence of DD appears to increase with age. The prevalence in men and women is similar up to age 45 years, after which the rate is much greater in males.⁷

DD is associated with many risk factors including smoking, alcohol consumption, vascular insufficiency, epilepsy, hyperlipidemia, manual labor, occupations with exposure to vibration, hand trauma, and even hand surgery such as carpal tunnel release or trigger finger release.^8-11 It is also associated with diabetes; particularly type 1 insulin-dependent diabetes.¹² There may also be an association with frozen shoulder.^12,13

The need for surgical treatment of DD becomes more likely with a history of cigarette smoking and heavy alcohol consumption. There seems to be an association with epilepsy, most likely from anti-epileptic drugs.¹⁴ Rheumatoid arthritis is the only condition that has been associated with a lower incidence of DD, possibly because of the use of anti-inflammatory drugs.¹⁵ There are genetic differences between patients with and without DD, although a “Dupuytren’s gene” has not been identified.

Rule out possible DD mimics

The differential diagnosis for flexion contracture of the MCP or PIP joints seen in Dupuytren’s disease includes stenosing flexor tenosynovitis, or trigger finger. Other conditions that can mimic DD are ulnar claw hand, trauma scars, intrinsic joint diseases such as degenerative or rheumatoid arthritis (RA), diabetic cheiroarthropathy, camptodactyly, and Volkmann’s contracture. Trauma scars—especially longitudinal scars—have a tendency to contract and develop keloid formation.

It's not known which patients with early Dupuytren changes will progress to severe contracture.

Stenosing flexor tenosynovitis and ulnar claw hand are distinguishable from DD by full or nearly full active or passive extension of the affected digit, whereas DD is a true contracture of the joint that does not allow full extension. A careful history can rule out previous injury to the area. Although intrinsic joint disease, such as RA, can cause finger contractures, the joints are usually enlarged, painful, and associated with characteristic radiologic findings.

Unlike DD, diabetic cheiroarthropathy often involves all of the digits except for the thumb, and is often associated with a waxy appearance of the skin. Camptodactyly is an autosomal dominant disorder that more often presents in childhood and can be caused by a number of congenital syndromes. Volkmann’s contracture can manifest as a claw-like deformity of the hand caused by undiagnosed compartment syndrome of the forearm.

Assess the severity of DD

In your evaluation, first identify palmar or digital fibromatosis presenting as a nodule or a cord. Second, estimate the degree of MCP and PIP joint contractures. A common measure of contracture is the Hueston tabletop test. Ask the patient to place the palm of the hand on a flat surface. If the patient is unable to completely flatten the hand against the surface, presume a positive result (FIGURE 2).¹⁶

An accurate measure of the degree of flexion can be accomplished with a goniometer. For a simple assessment of severity, have the patient place each affected finger along the convexity of a spoon. If adjoining surfaces are flush, assume that the contracture is at least 30 degrees (FIGURE 3). The severity of DD can also be graded according to the Tubiana classification system (TABLE¹⁷), wherein the total deformity or contracture score is the sum of the angles of all 3 digital joints of the finger.

A look at the treatment options

Once the diagnosis of DD is made, reassure the patient that the disease is not cancerous, although it may be progressive. Advise patients, too, that several treatment options (detailed below) are available, but that surgery is the mainstay of treatment. (Of note: Despite what would seem logical, stretching a cord to straighten the finger is not recommended, as it may actually worsen the condition.¹⁸)

Options for early DD. Corticosteroids such as triamcinolone may have a role as an adjunct for early DD by reducing the size and firmness of the Dupuytren’s nodules and possibly slowing the progression of the disease. However, in one study of 63 patients, half of the individuals experienced reactivation of disease between one and 3 years.¹⁹

Radiotherapy has been studied as a potential treatment for early DD and for patients unable to undergo surgery. Radiation does have a biologic effect on nodular DD, but has no effect on the cords that cause the joint contracture. In a long-term follow-up study of 135 patients treated with radiotherapy, disease remained stable in 59% of patients, improved in 10%, and progressed in 31%.²⁰ Results were better for early stage disease. This modality is not used for more advanced cases.

Surgery is the primary method by which to restore function and minimize complications. In the past, referral was recom­mended for MCP joint contractures >30 degrees or for any involvment of the PIP joint, because involvement of the latter carries a worse prognosis and may not be fully correctable, even with surgery.²¹ However, treatment may also be warranted in cases of functional disability—regardless of the degree of contracture (eg, for pain associated with a prominent nodule or cord when gripping objects).

Although fasciectomies have shown the best efficacy and lowest recurrence rates, complications are more likely with these procedures.Depending on disease progression and the surgeon’s preference, the most popular procedures are fasciotomies and fasciectomies. Surgical options for contractures—in increasing order of invasiveness and amounts of fascia removed—are fasciotomy (needle, open), fasciectomy (partial, radical), and dermofasciectomy.

Needle fasciotomy is an outpatient procedure performed under local block. The surgeon uses a needle bevel to transect the diseased cord at multiple puncture sites.

Open fasciotomy is also an outpatient procedure involving an incision that allows direct visualization of the cord and internal structures before dividing the fascia. Percutaneous and open fasciotomies are more successful for MCP joint contractures and less successful for PIP joint contractures.

With partial fasciectomy, only the grossly affected fascia is removed.

With radical fasciectomy, the entire palmar fascia is removed, regardless of which areas are grossly diseased.

Dermofasciectomy removes diseased fascia and the overlying skin, with a skin graft applied to heal the wound.

Another option: Collagenase injection. In February 2010, the US Food and Drug Administration approved collagenase clostridium histolyticum (Xiaflex) as the first drug specifically indicated for the treatment of Dupuytren’s contracture. Collagenase is injected directly into the fascial cord, cleaving its collagen component and progressively softening and breaking down the cord. If not properly injected, collagenase may injure neurovascular structures and may rupture tendons.

So how do the treatment options compare?

We found no randomized prospective trials comparing treatment options for DD, but there are a number of trials that shed light on a variety of the available options.

Treatment success. In general, partial fasciectomies have shown the greatest success in reducing contractures and maintaining the lowest recurrence rates. Correction of contracture to ≤5 degrees was seen in 94% of MCP joint contractures treated with partial fasciectomy, in 77% of MCP joints treated with collagenase, and in 55% of MCP joints treated with percutaneous needle fasciotomies.^22,23 PIP joint contracture correction was not as successful: Correction of contracture to ≤5 degrees was seen in 47% of those treated with partial fasciectomy, 40% treated with collagenase, and 26% treated with needle fasciotomy.^22,23

Recurrence rates. When recurrence was defined as loss of passive extension >30 degrees, the recurrence rate for MCP joint contractures with partial fasciectomy was 21%, compared with 85% for needle fasciotomy.²² In a similar review, recurrence rates for partial fasciectomy ranged from 12% to 39% compared with 50% to 58% for needle fasciotomy.²⁴ With collagenase injection, 5-year data have shown an overall recurrence rate of 32%, with a recurrence of 26% at the MCP joint and 46% at the PIP joint.²⁵ In this trial, recurrence was defined as more than 30% worsening of flexion.²⁵

Complications. Although fasciectomies have shown the best efficacy and lowest recurrence rates, complications such as infection, neurapraxia, and digital nerve injury are more likely with these procedures.^26,27

Early recognition and referral to a hand specialist for the treatment of DD may allow the use of less invasive techniques and improved functional results.

CASE › Absent a history of trauma and features typical of other hand/digit disorders, we diagnosed Dupuytren’s disease in this patient. Potential treatments included partial fasciectomy and collagenase injection. After discussing the risks and benefits of each of these procedures, the patient elected to undergo a partial fasciectomy. The surgery was uncomplicated and the abnormality was corrected to within 5 degrees of full extension. At the patient’s one-year follow-up visit, there was no evidence of recurrence.

CASE › A 52-year-old right-hand-dominant white man arrived at our clinic complaining that he was unable to straighten his right ring finger. He had no associated pain or numbness, and had not injured his hand. The patient had type 2 diabetes that was controlled with metformin. He had no history of surgery or drug allergies, did not smoke, and said he drank 2 to 3 alcoholic beverages per day. He was a car salesman and was self-conscious when shaking hands with customers. On physical examination, we noted that he held his right ring finger at roughly 45 degrees of flexion at the metacarpophalangeal joint; a painless cord-like structure was palpable on the palmar surface of that joint. His left hand had no abnormalities.

If this were your patient, how would you proceed?

Dupuytren’s disease (DD) is a disabling fibroproliferative disorder of the hand for which there is no cure. While the exact cause of DD is unknown, it has been linked to a number of risk factors, including smoking, alcohol consumption, and diabetes. It affects about 5% of the US population, and up to 70% of affected individuals may initially seek treatment from a primary care physician.¹ The disease is also referred to as Dupuytren’s contracture, which describes the flexion contractures of fingers at the end stage of the disease. Palmar fibromatosis is yet another name for the disorder.

DD refers to a spectrum of presentations ranging from nodules to cords to discernible contractures, and it is not known which patients with early Dupuytren changes will progress to severe contracture. With recognition of early changes, nonsurgical intervention is possible, such as collagenase injection or percutaneous fasciotomy, and can slow the progression of DD, restore function, and avoid or delay surgical intervention. DD is a clinically challenging disorder. Treatment for an affected area may resolve symptoms, only to have them recur in that location or another.

How underlying pathology correlates with clinical findings

DD affects the palmar fascia, a thick triangular-shaped sheet of dense fibrous collagenous connective tissue that lies deep to the dermis and superficial to the flexor tendons of the hand with fibers extending both into the skin and into the deep tissue. The palmar fascia secures the skin during gripping and twisting motions, and it bifurcates into distal extensions, called pretendinous bands, that overlay and mimic the flexor tendons.

Clinical findings reflect the progression of underlying pathology. The earliest manifestation of DD is painless dimpling of the skin on the palmar surface of the hand.² Over time, the underlying fibrosis with increased collagen deposition can progress, leading to development of nodules and eventually, cords, which are sometimes mistaken for flexor tendons. Dupuytren-like fibrotic tissue can occur on the sole of the foot (Ledderhose disease) and penis (Peyronie’s disease).^2,3 In patients with these coexisting conditions, prognosis is generally worse.⁴ With the hands, bilateral involvement is common, although it is usually more severe in one hand. The ring finger is the digit most frequently involved, followed by the little finger, middle finger, and index finger. The thumb is rarely affected.³

As the disease progresses and cords contract, the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints develop flexion contractures. The distal interphalangeal (DIP) joint, rarely involved, instead exhibits a hyperextension contracture. Digital flexion contractures are often disabling, interfering with daily activities such as picking up a glass, shaking hands, or putting one's hand in a pants pocket. Many patients seek medical attention only after a palpable nodule, cord, or flexion contracture becomes apparent (FIGURE 1).

In a study of 326 patients who reported Dupuytren’s symptoms, the most common symptoms that led them to seek treatment were, in descending order, a hard bump (48%), a ropelike growth (12%), dimpling (11%), and finger contractures (10%). Only 9% of patients seeking treatment for hand symptoms associated with DD had received a diagnosis of DD from their initial medical encounter, causing an unnecessary delay in treatment.¹

Who is at increased risk for DD?

DD is most often seen in elderly white men of European descent.⁵ In the United States, the prevalence of the disease is roughly 5%,¹ compared with 4% to 39% in northwestern Europe (eg, Iceland).⁶ The male-to-female ratio of DD ranges from 6:1 to 15:1.⁷ The prevalence of DD appears to increase with age. The prevalence in men and women is similar up to age 45 years, after which the rate is much greater in males.⁷

DD is associated with many risk factors including smoking, alcohol consumption, vascular insufficiency, epilepsy, hyperlipidemia, manual labor, occupations with exposure to vibration, hand trauma, and even hand surgery such as carpal tunnel release or trigger finger release.^8-11 It is also associated with diabetes; particularly type 1 insulin-dependent diabetes.¹² There may also be an association with frozen shoulder.^12,13

The need for surgical treatment of DD becomes more likely with a history of cigarette smoking and heavy alcohol consumption. There seems to be an association with epilepsy, most likely from anti-epileptic drugs.¹⁴ Rheumatoid arthritis is the only condition that has been associated with a lower incidence of DD, possibly because of the use of anti-inflammatory drugs.¹⁵ There are genetic differences between patients with and without DD, although a “Dupuytren’s gene” has not been identified.

Rule out possible DD mimics

The differential diagnosis for flexion contracture of the MCP or PIP joints seen in Dupuytren’s disease includes stenosing flexor tenosynovitis, or trigger finger. Other conditions that can mimic DD are ulnar claw hand, trauma scars, intrinsic joint diseases such as degenerative or rheumatoid arthritis (RA), diabetic cheiroarthropathy, camptodactyly, and Volkmann’s contracture. Trauma scars—especially longitudinal scars—have a tendency to contract and develop keloid formation.

It's not known which patients with early Dupuytren changes will progress to severe contracture.

Stenosing flexor tenosynovitis and ulnar claw hand are distinguishable from DD by full or nearly full active or passive extension of the affected digit, whereas DD is a true contracture of the joint that does not allow full extension. A careful history can rule out previous injury to the area. Although intrinsic joint disease, such as RA, can cause finger contractures, the joints are usually enlarged, painful, and associated with characteristic radiologic findings.

Unlike DD, diabetic cheiroarthropathy often involves all of the digits except for the thumb, and is often associated with a waxy appearance of the skin. Camptodactyly is an autosomal dominant disorder that more often presents in childhood and can be caused by a number of congenital syndromes. Volkmann’s contracture can manifest as a claw-like deformity of the hand caused by undiagnosed compartment syndrome of the forearm.

Assess the severity of DD

In your evaluation, first identify palmar or digital fibromatosis presenting as a nodule or a cord. Second, estimate the degree of MCP and PIP joint contractures. A common measure of contracture is the Hueston tabletop test. Ask the patient to place the palm of the hand on a flat surface. If the patient is unable to completely flatten the hand against the surface, presume a positive result (FIGURE 2).¹⁶

An accurate measure of the degree of flexion can be accomplished with a goniometer. For a simple assessment of severity, have the patient place each affected finger along the convexity of a spoon. If adjoining surfaces are flush, assume that the contracture is at least 30 degrees (FIGURE 3). The severity of DD can also be graded according to the Tubiana classification system (TABLE¹⁷), wherein the total deformity or contracture score is the sum of the angles of all 3 digital joints of the finger.

A look at the treatment options

Once the diagnosis of DD is made, reassure the patient that the disease is not cancerous, although it may be progressive. Advise patients, too, that several treatment options (detailed below) are available, but that surgery is the mainstay of treatment. (Of note: Despite what would seem logical, stretching a cord to straighten the finger is not recommended, as it may actually worsen the condition.¹⁸)

Options for early DD. Corticosteroids such as triamcinolone may have a role as an adjunct for early DD by reducing the size and firmness of the Dupuytren’s nodules and possibly slowing the progression of the disease. However, in one study of 63 patients, half of the individuals experienced reactivation of disease between one and 3 years.¹⁹

Radiotherapy has been studied as a potential treatment for early DD and for patients unable to undergo surgery. Radiation does have a biologic effect on nodular DD, but has no effect on the cords that cause the joint contracture. In a long-term follow-up study of 135 patients treated with radiotherapy, disease remained stable in 59% of patients, improved in 10%, and progressed in 31%.²⁰ Results were better for early stage disease. This modality is not used for more advanced cases.

Surgery is the primary method by which to restore function and minimize complications. In the past, referral was recom­mended for MCP joint contractures >30 degrees or for any involvment of the PIP joint, because involvement of the latter carries a worse prognosis and may not be fully correctable, even with surgery.²¹ However, treatment may also be warranted in cases of functional disability—regardless of the degree of contracture (eg, for pain associated with a prominent nodule or cord when gripping objects).

Although fasciectomies have shown the best efficacy and lowest recurrence rates, complications are more likely with these procedures.Depending on disease progression and the surgeon’s preference, the most popular procedures are fasciotomies and fasciectomies. Surgical options for contractures—in increasing order of invasiveness and amounts of fascia removed—are fasciotomy (needle, open), fasciectomy (partial, radical), and dermofasciectomy.

Needle fasciotomy is an outpatient procedure performed under local block. The surgeon uses a needle bevel to transect the diseased cord at multiple puncture sites.

Open fasciotomy is also an outpatient procedure involving an incision that allows direct visualization of the cord and internal structures before dividing the fascia. Percutaneous and open fasciotomies are more successful for MCP joint contractures and less successful for PIP joint contractures.

With partial fasciectomy, only the grossly affected fascia is removed.

With radical fasciectomy, the entire palmar fascia is removed, regardless of which areas are grossly diseased.

Dermofasciectomy removes diseased fascia and the overlying skin, with a skin graft applied to heal the wound.

Another option: Collagenase injection. In February 2010, the US Food and Drug Administration approved collagenase clostridium histolyticum (Xiaflex) as the first drug specifically indicated for the treatment of Dupuytren’s contracture. Collagenase is injected directly into the fascial cord, cleaving its collagen component and progressively softening and breaking down the cord. If not properly injected, collagenase may injure neurovascular structures and may rupture tendons.

So how do the treatment options compare?

We found no randomized prospective trials comparing treatment options for DD, but there are a number of trials that shed light on a variety of the available options.

Treatment success. In general, partial fasciectomies have shown the greatest success in reducing contractures and maintaining the lowest recurrence rates. Correction of contracture to ≤5 degrees was seen in 94% of MCP joint contractures treated with partial fasciectomy, in 77% of MCP joints treated with collagenase, and in 55% of MCP joints treated with percutaneous needle fasciotomies.^22,23 PIP joint contracture correction was not as successful: Correction of contracture to ≤5 degrees was seen in 47% of those treated with partial fasciectomy, 40% treated with collagenase, and 26% treated with needle fasciotomy.^22,23

Recurrence rates. When recurrence was defined as loss of passive extension >30 degrees, the recurrence rate for MCP joint contractures with partial fasciectomy was 21%, compared with 85% for needle fasciotomy.²² In a similar review, recurrence rates for partial fasciectomy ranged from 12% to 39% compared with 50% to 58% for needle fasciotomy.²⁴ With collagenase injection, 5-year data have shown an overall recurrence rate of 32%, with a recurrence of 26% at the MCP joint and 46% at the PIP joint.²⁵ In this trial, recurrence was defined as more than 30% worsening of flexion.²⁵

Complications. Although fasciectomies have shown the best efficacy and lowest recurrence rates, complications such as infection, neurapraxia, and digital nerve injury are more likely with these procedures.^26,27

Early recognition and referral to a hand specialist for the treatment of DD may allow the use of less invasive techniques and improved functional results.

CASE › Absent a history of trauma and features typical of other hand/digit disorders, we diagnosed Dupuytren’s disease in this patient. Potential treatments included partial fasciectomy and collagenase injection. After discussing the risks and benefits of each of these procedures, the patient elected to undergo a partial fasciectomy. The surgery was uncomplicated and the abnormality was corrected to within 5 degrees of full extension. At the patient’s one-year follow-up visit, there was no evidence of recurrence.

CASE 1 › Lola A is a 28-year-old woman with a history of muscular aches and joint pain throughout her body, fatigue, and mental fogginess. She has been seen by a rheumatologist and has been given a diagnosis of fibromyalgia, but 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 P 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 B is a 56-year-old construction worker who has been suffering from bouts of back pain for many years. The pain has become more debilitating over time; currently, it is constant, and Mr. B can hardly make it through his work day. He has been getting hydrocodone/acetaminophen from urgent care centers and emergency rooms, but he isn’t sure it is helping and is coming to you to assume his pain management.

Chronic pain (defined as pain >3 months 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 physicians (FPs) on the front lines of 2 epidemics: that of chronic pain itself and that of the abuse and misuse of opioid pain medications.

In an effort 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 Centers for Disease Control and Prevention,² have published guidelines on the use of opioids for non-malignant chronic pain. With these guidelines in mind—and in light of the latest evidence—we propose the paradigm that follows for the treatment of chronic pain. A critical aspect of this paradigm is determining the pathophysiology underlying 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 3 common chronic pain 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 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.

With central sensitization, pain is often accompanied by other systemic symptoms such as fatigue—often in the setting of little to no actual stimulation of the peripheral nociceptors.For most patients with chronic pain, regardless of their diagnosis, there is some degree of alteration in the processing of nociceptive signals by the central nervous system contributing to the experience of pain.⁴ This alteration is thought to be the result of peripheral nociceptive signaling persisting past the point of tissue healing, leading to a hypersensitivity of nerve fibers; the fibers then continue to respond to low, or even absent, sensory stimuli.

Central sensitization is the term used when this hypersensitivity develops in the superficial, deep, and ventral cord nerves. When this happens, pain is often accompanied by other systemic symptoms such as fatigue and slowed cognitive processing, often in the setting of little to no actual stimulation of the peripheral nociceptors.³ (For more on this, see “A new paradigm for pain?” J Fam Pract. 2016;65:598-605 or go to http://www.mdedge.com/jfponline/article/111257/pain/new-paradigm-pain.)

TABLE 1⁴ lists the possible mechanisms of pain, which can be broken down into 4 categories: peripheral nociceptive (inflammatory or mechanical), peripheral neuropathic (underlying damage to a peripheral nerve), central (referring to when the central nervous system is the primary entity involved in maintaining the pain), or any combination of the 3.

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 disproportional 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

FPs 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 those patients with a higher degree of centralization of pain (as measured by widespread pain index and modified fibromyalgia screening scales⁶) were less likely to report improvement in the affected body part and in overall body pain following the surgery.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 the treatment plan to the underlying mechanisms of pain

As with any chronic condition, a thorough work-up (complete with history, physical exam, and diagnostic testing, as appropriate) is indicated. In the setting of chronic pain, it’s important to identify both the primary mechanism, as well as secondary factors that may be contributing to the patient’s pain, before developing your treatment plan. These secondary factors may include co-occurring affect disorders,⁹ a history of trauma,¹⁰ poor sleep,¹¹ and tobacco use,¹² among others. 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 central nervous system’s role in chronic pain need to be considered.¹³

3 common conditions. Below we present evidence-based treatment approaches for 3 conditions that are typically associated with each of the major mechanisms of chronic pain generation: fibromyalgia (a central sensitization cause), OA (a peripheral nociceptive cause), and low back pain (a mixed pain state).

Fibromyalgia: A case of central sensitization

Fibromyalgia is a hallmark diagnosis for those patients in whom central sensitization is the dominant cause of pain. These patients usually present with widespread, diffuse pain, as well as somatic symptoms such as fatigue, memory difficulties, and poor sleep quality.⁸ When explaining the pain mechanism (ie, central sensitization) 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, 5 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;²⁰ low norepinephrine, serotonin,²¹ and gamma-aminobutyric acid [GABA]²²) play a role in central amplification. 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 in 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,^26,29 which have high degrees of efficacy with few adverse effects.

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

Identify any factors that might be contributing to your patient's pain, such as co-occurring affect disorders, a history of trauma, poor sleep, or tobacco use.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 (For more advice on managing fibromyalgia, see the related videos at http://bit.ly/2lPEt0f and http://bit.ly/2lmjEcn.)

Osteoarthritis: 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 7000 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,⁴⁰ and, in some patients, a centralized pain component. 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 3^42-61 for a summary of evidence-based treatment options.

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 low back pain), neuropathic (lumbar radiculopathy), and central sensitization pain.^62,63 Evidence for centralized pain is demonstrated in studies showing hyperalgesia,⁶⁴ augmented central pain processing,⁶⁵ involvement of the emotional brain,⁶⁶ and delayed recovery influenced by poor coping strategies.⁶⁷

When developing a treatment plan for a patient with chronic low back pain, 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; they also had higher levels of depression/anxiety and a lower level of physical function.

Because low back pain 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 (see “How effective are opioids for chronic low back pain?” J Fam Pract. 2015;64:584-584), 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 4^70-89 for a summary of evidence-based treatment options.

CASE 1 › Ms. A is started on amitriptyline 25 mg at bedtime, which improves her fatigue and cognitive symptoms. During monthly office visits, her FP 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 › Mr. P 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 nonsteroidal anti-inflammatory drugs (NSAIDs) has allowed Mr. P to maintain his function and his job.

CASE 3 › Because Mr. B was only taking the narcotics intermittently and wasn’t certain they were helping, CBT was sufficient to wean Mr. B 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.

CORRESPONDENCE
Jill Schneiderhan, MD, 24 Frank Lloyd Wright Dr., Lobby H, Suite 2300, Ann Arbor, MI 48105; [email protected].

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

CASE 1 › Lola A is a 28-year-old woman with a history of muscular aches and joint pain throughout her body, fatigue, and mental fogginess. She has been seen by a rheumatologist and has been given a diagnosis of fibromyalgia, but 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 P 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 B is a 56-year-old construction worker who has been suffering from bouts of back pain for many years. The pain has become more debilitating over time; currently, it is constant, and Mr. B can hardly make it through his work day. He has been getting hydrocodone/acetaminophen from urgent care centers and emergency rooms, but he isn’t sure it is helping and is coming to you to assume his pain management.

Chronic pain (defined as pain >3 months 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 physicians (FPs) on the front lines of 2 epidemics: that of chronic pain itself and that of the abuse and misuse of opioid pain medications.

In an effort 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 Centers for Disease Control and Prevention,² have published guidelines on the use of opioids for non-malignant chronic pain. With these guidelines in mind—and in light of the latest evidence—we propose the paradigm that follows for the treatment of chronic pain. A critical aspect of this paradigm is determining the pathophysiology underlying 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 3 common chronic pain 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 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.

With central sensitization, pain is often accompanied by other systemic symptoms such as fatigue—often in the setting of little to no actual stimulation of the peripheral nociceptors.For most patients with chronic pain, regardless of their diagnosis, there is some degree of alteration in the processing of nociceptive signals by the central nervous system contributing to the experience of pain.⁴ This alteration is thought to be the result of peripheral nociceptive signaling persisting past the point of tissue healing, leading to a hypersensitivity of nerve fibers; the fibers then continue to respond to low, or even absent, sensory stimuli.

Central sensitization is the term used when this hypersensitivity develops in the superficial, deep, and ventral cord nerves. When this happens, pain is often accompanied by other systemic symptoms such as fatigue and slowed cognitive processing, often in the setting of little to no actual stimulation of the peripheral nociceptors.³ (For more on this, see “A new paradigm for pain?” J Fam Pract. 2016;65:598-605 or go to http://www.mdedge.com/jfponline/article/111257/pain/new-paradigm-pain.)

TABLE 1⁴ lists the possible mechanisms of pain, which can be broken down into 4 categories: peripheral nociceptive (inflammatory or mechanical), peripheral neuropathic (underlying damage to a peripheral nerve), central (referring to when the central nervous system is the primary entity involved in maintaining the pain), or any combination of the 3.

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 disproportional 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

FPs 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 those patients with a higher degree of centralization of pain (as measured by widespread pain index and modified fibromyalgia screening scales⁶) were less likely to report improvement in the affected body part and in overall body pain following the surgery.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 the treatment plan to the underlying mechanisms of pain

As with any chronic condition, a thorough work-up (complete with history, physical exam, and diagnostic testing, as appropriate) is indicated. In the setting of chronic pain, it’s important to identify both the primary mechanism, as well as secondary factors that may be contributing to the patient’s pain, before developing your treatment plan. These secondary factors may include co-occurring affect disorders,⁹ a history of trauma,¹⁰ poor sleep,¹¹ and tobacco use,¹² among others. 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 central nervous system’s role in chronic pain need to be considered.¹³

3 common conditions. Below we present evidence-based treatment approaches for 3 conditions that are typically associated with each of the major mechanisms of chronic pain generation: fibromyalgia (a central sensitization cause), OA (a peripheral nociceptive cause), and low back pain (a mixed pain state).

Fibromyalgia: A case of central sensitization

Fibromyalgia is a hallmark diagnosis for those patients in whom central sensitization is the dominant cause of pain. These patients usually present with widespread, diffuse pain, as well as somatic symptoms such as fatigue, memory difficulties, and poor sleep quality.⁸ When explaining the pain mechanism (ie, central sensitization) 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, 5 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;²⁰ low norepinephrine, serotonin,²¹ and gamma-aminobutyric acid [GABA]²²) play a role in central amplification. 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 in 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,^26,29 which have high degrees of efficacy with few adverse effects.

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

Identify any factors that might be contributing to your patient's pain, such as co-occurring affect disorders, a history of trauma, poor sleep, or tobacco use.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 (For more advice on managing fibromyalgia, see the related videos at http://bit.ly/2lPEt0f and http://bit.ly/2lmjEcn.)

Osteoarthritis: 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 7000 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,⁴⁰ and, in some patients, a centralized pain component. 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 3^42-61 for a summary of evidence-based treatment options.

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 low back pain), neuropathic (lumbar radiculopathy), and central sensitization pain.^62,63 Evidence for centralized pain is demonstrated in studies showing hyperalgesia,⁶⁴ augmented central pain processing,⁶⁵ involvement of the emotional brain,⁶⁶ and delayed recovery influenced by poor coping strategies.⁶⁷

When developing a treatment plan for a patient with chronic low back pain, 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; they also had higher levels of depression/anxiety and a lower level of physical function.

Because low back pain 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 (see “How effective are opioids for chronic low back pain?” J Fam Pract. 2015;64:584-584), 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 4^70-89 for a summary of evidence-based treatment options.

CASE 1 › Ms. A is started on amitriptyline 25 mg at bedtime, which improves her fatigue and cognitive symptoms. During monthly office visits, her FP 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 › Mr. P 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 nonsteroidal anti-inflammatory drugs (NSAIDs) has allowed Mr. P to maintain his function and his job.

CASE 3 › Because Mr. B was only taking the narcotics intermittently and wasn’t certain they were helping, CBT was sufficient to wean Mr. B 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.

CORRESPONDENCE
Jill Schneiderhan, MD, 24 Frank Lloyd Wright Dr., Lobby H, Suite 2300, Ann Arbor, MI 48105; [email protected].

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

CASE 1 › Lola A is a 28-year-old woman with a history of muscular aches and joint pain throughout her body, fatigue, and mental fogginess. She has been seen by a rheumatologist and has been given a diagnosis of fibromyalgia, but 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 P 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 B is a 56-year-old construction worker who has been suffering from bouts of back pain for many years. The pain has become more debilitating over time; currently, it is constant, and Mr. B can hardly make it through his work day. He has been getting hydrocodone/acetaminophen from urgent care centers and emergency rooms, but he isn’t sure it is helping and is coming to you to assume his pain management.

Chronic pain (defined as pain >3 months 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 physicians (FPs) on the front lines of 2 epidemics: that of chronic pain itself and that of the abuse and misuse of opioid pain medications.

In an effort 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 Centers for Disease Control and Prevention,² have published guidelines on the use of opioids for non-malignant chronic pain. With these guidelines in mind—and in light of the latest evidence—we propose the paradigm that follows for the treatment of chronic pain. A critical aspect of this paradigm is determining the pathophysiology underlying 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 3 common chronic pain 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 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.

With central sensitization, pain is often accompanied by other systemic symptoms such as fatigue—often in the setting of little to no actual stimulation of the peripheral nociceptors.For most patients with chronic pain, regardless of their diagnosis, there is some degree of alteration in the processing of nociceptive signals by the central nervous system contributing to the experience of pain.⁴ This alteration is thought to be the result of peripheral nociceptive signaling persisting past the point of tissue healing, leading to a hypersensitivity of nerve fibers; the fibers then continue to respond to low, or even absent, sensory stimuli.

Central sensitization is the term used when this hypersensitivity develops in the superficial, deep, and ventral cord nerves. When this happens, pain is often accompanied by other systemic symptoms such as fatigue and slowed cognitive processing, often in the setting of little to no actual stimulation of the peripheral nociceptors.³ (For more on this, see “A new paradigm for pain?” J Fam Pract. 2016;65:598-605 or go to http://www.mdedge.com/jfponline/article/111257/pain/new-paradigm-pain.)

TABLE 1⁴ lists the possible mechanisms of pain, which can be broken down into 4 categories: peripheral nociceptive (inflammatory or mechanical), peripheral neuropathic (underlying damage to a peripheral nerve), central (referring to when the central nervous system is the primary entity involved in maintaining the pain), or any combination of the 3.

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 disproportional 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

FPs 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 those patients with a higher degree of centralization of pain (as measured by widespread pain index and modified fibromyalgia screening scales⁶) were less likely to report improvement in the affected body part and in overall body pain following the surgery.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 the treatment plan to the underlying mechanisms of pain

As with any chronic condition, a thorough work-up (complete with history, physical exam, and diagnostic testing, as appropriate) is indicated. In the setting of chronic pain, it’s important to identify both the primary mechanism, as well as secondary factors that may be contributing to the patient’s pain, before developing your treatment plan. These secondary factors may include co-occurring affect disorders,⁹ a history of trauma,¹⁰ poor sleep,¹¹ and tobacco use,¹² among others. 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 central nervous system’s role in chronic pain need to be considered.¹³

3 common conditions. Below we present evidence-based treatment approaches for 3 conditions that are typically associated with each of the major mechanisms of chronic pain generation: fibromyalgia (a central sensitization cause), OA (a peripheral nociceptive cause), and low back pain (a mixed pain state).

Fibromyalgia: A case of central sensitization

Fibromyalgia is a hallmark diagnosis for those patients in whom central sensitization is the dominant cause of pain. These patients usually present with widespread, diffuse pain, as well as somatic symptoms such as fatigue, memory difficulties, and poor sleep quality.⁸ When explaining the pain mechanism (ie, central sensitization) 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, 5 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;²⁰ low norepinephrine, serotonin,²¹ and gamma-aminobutyric acid [GABA]²²) play a role in central amplification. 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 in 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,^26,29 which have high degrees of efficacy with few adverse effects.

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

Identify any factors that might be contributing to your patient's pain, such as co-occurring affect disorders, a history of trauma, poor sleep, or tobacco use.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 (For more advice on managing fibromyalgia, see the related videos at http://bit.ly/2lPEt0f and http://bit.ly/2lmjEcn.)

Osteoarthritis: 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 7000 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,⁴⁰ and, in some patients, a centralized pain component. 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 3^42-61 for a summary of evidence-based treatment options.

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 low back pain), neuropathic (lumbar radiculopathy), and central sensitization pain.^62,63 Evidence for centralized pain is demonstrated in studies showing hyperalgesia,⁶⁴ augmented central pain processing,⁶⁵ involvement of the emotional brain,⁶⁶ and delayed recovery influenced by poor coping strategies.⁶⁷

When developing a treatment plan for a patient with chronic low back pain, 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; they also had higher levels of depression/anxiety and a lower level of physical function.

Because low back pain 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 (see “How effective are opioids for chronic low back pain?” J Fam Pract. 2015;64:584-584), 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 4^70-89 for a summary of evidence-based treatment options.

CASE 1 › Ms. A is started on amitriptyline 25 mg at bedtime, which improves her fatigue and cognitive symptoms. During monthly office visits, her FP 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 › Mr. P 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 nonsteroidal anti-inflammatory drugs (NSAIDs) has allowed Mr. P to maintain his function and his job.

CASE 3 › Because Mr. B was only taking the narcotics intermittently and wasn’t certain they were helping, CBT was sufficient to wean Mr. B 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.

CORRESPONDENCE
Jill Schneiderhan, MD, 24 Frank Lloyd Wright Dr., Lobby H, Suite 2300, Ann Arbor, MI 48105; [email protected].

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

New clinical practice advice has been issued for use of the functional lumen imaging probe (FLIP) to assess disorders of the upper gastrointestinal tract, with the main takeaway being the device’s potency in diagnosing achalasia.

“Although the strongest data appear to be focused on the management of achalasia, emerging evidence supports the clinical relevance of FLIP in the assessment of disease severity and as an outcome measure in [eosinophilic esophagitis (EoE)] intervention trials,” wrote the authors of the update, led by John E. Pandolfino, MD, of Northwestern University, Chicago. The report is in the March issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.
10.022).

*This story updated on 3/9/2017.

[email protected]

New clinical practice advice has been issued for use of the functional lumen imaging probe (FLIP) to assess disorders of the upper gastrointestinal tract, with the main takeaway being the device’s potency in diagnosing achalasia.

“Although the strongest data appear to be focused on the management of achalasia, emerging evidence supports the clinical relevance of FLIP in the assessment of disease severity and as an outcome measure in [eosinophilic esophagitis (EoE)] intervention trials,” wrote the authors of the update, led by John E. Pandolfino, MD, of Northwestern University, Chicago. The report is in the March issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.
10.022).

*This story updated on 3/9/2017.

[email protected]

New clinical practice advice has been issued for use of the functional lumen imaging probe (FLIP) to assess disorders of the upper gastrointestinal tract, with the main takeaway being the device’s potency in diagnosing achalasia.

“Although the strongest data appear to be focused on the management of achalasia, emerging evidence supports the clinical relevance of FLIP in the assessment of disease severity and as an outcome measure in [eosinophilic esophagitis (EoE)] intervention trials,” wrote the authors of the update, led by John E. Pandolfino, MD, of Northwestern University, Chicago. The report is in the March issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.
10.022).

*This story updated on 3/9/2017.

[email protected]

The AGA Institute has released a series of new best practice statements that gastroenterologists should use when considering a patient for endoscopic bariatric treatments or surgeries (EBTs).

“There is a need for less-invasive weight loss therapies that are more effective and durable than lifestyle interventions alone, less invasive and risky than bariatric surgery, and easily performed at a lower expense than that of surgery, thereby allowing improved access and application to a larger segment of the population with moderate obesity,” wrote the authors of the expert review, led by Barham K. Abu Dayyeh, MD of the Mayo Clinic in Rochester, Minn. The report is in the March issue of Gastroenterology (doi: 10.1053/j.gastro.2017.01.035). “[EBTs] potentially meet these criteria and may provide an effective treatment approach to obesity in selected patients.”

copyright kikkerdirk/Thinkstock

[email protected]

The AGA Institute has released a series of new best practice statements that gastroenterologists should use when considering a patient for endoscopic bariatric treatments or surgeries (EBTs).

“There is a need for less-invasive weight loss therapies that are more effective and durable than lifestyle interventions alone, less invasive and risky than bariatric surgery, and easily performed at a lower expense than that of surgery, thereby allowing improved access and application to a larger segment of the population with moderate obesity,” wrote the authors of the expert review, led by Barham K. Abu Dayyeh, MD of the Mayo Clinic in Rochester, Minn. The report is in the March issue of Gastroenterology (doi: 10.1053/j.gastro.2017.01.035). “[EBTs] potentially meet these criteria and may provide an effective treatment approach to obesity in selected patients.”

copyright kikkerdirk/Thinkstock

[email protected]

The AGA Institute has released a series of new best practice statements that gastroenterologists should use when considering a patient for endoscopic bariatric treatments or surgeries (EBTs).

“There is a need for less-invasive weight loss therapies that are more effective and durable than lifestyle interventions alone, less invasive and risky than bariatric surgery, and easily performed at a lower expense than that of surgery, thereby allowing improved access and application to a larger segment of the population with moderate obesity,” wrote the authors of the expert review, led by Barham K. Abu Dayyeh, MD of the Mayo Clinic in Rochester, Minn. The report is in the March issue of Gastroenterology (doi: 10.1053/j.gastro.2017.01.035). “[EBTs] potentially meet these criteria and may provide an effective treatment approach to obesity in selected patients.”

copyright kikkerdirk/Thinkstock

[email protected]

Updated best practice statements regarding the use of proton pump inhibitors first detail what types of patients should be using short and long-term PPIs.

“When PPIs are appropriately prescribed, their benefits are likely to outweigh their risks [but] when PPIs are inappropriately prescribed, modest risks become important because there is no potential benefit,” wrote the authors of the updated guidance, published in the March issue of Gastroenterology.

“There is currently insufficient evidence to recommend specific strategies for mitigating PPI adverse effects,” noted Daniel E. Freedberg, MD, of Columbia University, New York, and his colleagues.

PPIs should be used on a short-term basis for individuals with gastroesophageal reflux disease (GERD) or conditions such as erosive esophagitis. These patients can also use PPIs for maintenance and occasional symptom management, but those with uncomplicated GERD should be weaned off PPIs if they respond favorably to them.

If a patient is unable to be weaned off PPIs, then ambulatory esophageal pH and impedance monitoring should be done, as this will allow clinicians to determine if the patient has a functional syndrome or GERD. Lifelong PPI treatment should not be considered until this step is taken, according to the new best practice statements.

“Short-term PPIs are highly effective for uncomplicated GERD [but] because patients who cannot reduce PPIs face lifelong therapy, we would consider testing for an acid-related disorder in this situation,” the authors explained. “However, there is no high-quality evidence on which to base this recommendation.”

Patients who have symptomatic GERD or Barrett’s esophagus, either symptomatic or asymptomatic, should be on long-term PPI treatment. Patients who are at a higher risk for NSAID-induced ulcer bleeding should be taking PPIs if they continue to take NSAIDs.

When recommending long-term PPI treatment for a patient, the patient need not use probiotics on a regular basis; there appears to be no need to routinely check the patient’s bone mineral density, serum creatinine, magnesium, or vitamin B₁₂ level on a regular basis. In addition, they need not consume more than the Recommended Dietary Allowance of calcium, magnesium, or vitamin B₁₂.

Finally, the authors state that “specific PPI formulations should not be selected based on potential risks.” This is because no evidence has been found indicating that PPI formulations can be ranked in any way based on risk.

These recommendations come from the AGA’s Clinical Practice Updates Committee, which pored through studies published through July 2016 in the PubMed, EMbase, and Cochrane library databases. Expert opinions and quality assessments on each study contributed to forming these best practice statements.

“In sum, the best current strategies for mitigating the potential risks of long-term PPIs are to avoid prescribing them when they are not indicated and to reduce them to their minimum dose when they are indicated,” Dr. Freedberg and his colleagues concluded.

The researchers did not report any relevant financial disclosures.

Updated best practice statements regarding the use of proton pump inhibitors first detail what types of patients should be using short and long-term PPIs.

“When PPIs are appropriately prescribed, their benefits are likely to outweigh their risks [but] when PPIs are inappropriately prescribed, modest risks become important because there is no potential benefit,” wrote the authors of the updated guidance, published in the March issue of Gastroenterology.

“There is currently insufficient evidence to recommend specific strategies for mitigating PPI adverse effects,” noted Daniel E. Freedberg, MD, of Columbia University, New York, and his colleagues.

PPIs should be used on a short-term basis for individuals with gastroesophageal reflux disease (GERD) or conditions such as erosive esophagitis. These patients can also use PPIs for maintenance and occasional symptom management, but those with uncomplicated GERD should be weaned off PPIs if they respond favorably to them.

If a patient is unable to be weaned off PPIs, then ambulatory esophageal pH and impedance monitoring should be done, as this will allow clinicians to determine if the patient has a functional syndrome or GERD. Lifelong PPI treatment should not be considered until this step is taken, according to the new best practice statements.

“Short-term PPIs are highly effective for uncomplicated GERD [but] because patients who cannot reduce PPIs face lifelong therapy, we would consider testing for an acid-related disorder in this situation,” the authors explained. “However, there is no high-quality evidence on which to base this recommendation.”

Patients who have symptomatic GERD or Barrett’s esophagus, either symptomatic or asymptomatic, should be on long-term PPI treatment. Patients who are at a higher risk for NSAID-induced ulcer bleeding should be taking PPIs if they continue to take NSAIDs.

When recommending long-term PPI treatment for a patient, the patient need not use probiotics on a regular basis; there appears to be no need to routinely check the patient’s bone mineral density, serum creatinine, magnesium, or vitamin B₁₂ level on a regular basis. In addition, they need not consume more than the Recommended Dietary Allowance of calcium, magnesium, or vitamin B₁₂.

Finally, the authors state that “specific PPI formulations should not be selected based on potential risks.” This is because no evidence has been found indicating that PPI formulations can be ranked in any way based on risk.

These recommendations come from the AGA’s Clinical Practice Updates Committee, which pored through studies published through July 2016 in the PubMed, EMbase, and Cochrane library databases. Expert opinions and quality assessments on each study contributed to forming these best practice statements.

“In sum, the best current strategies for mitigating the potential risks of long-term PPIs are to avoid prescribing them when they are not indicated and to reduce them to their minimum dose when they are indicated,” Dr. Freedberg and his colleagues concluded.

The researchers did not report any relevant financial disclosures.

Updated best practice statements regarding the use of proton pump inhibitors first detail what types of patients should be using short and long-term PPIs.

“When PPIs are appropriately prescribed, their benefits are likely to outweigh their risks [but] when PPIs are inappropriately prescribed, modest risks become important because there is no potential benefit,” wrote the authors of the updated guidance, published in the March issue of Gastroenterology.

“There is currently insufficient evidence to recommend specific strategies for mitigating PPI adverse effects,” noted Daniel E. Freedberg, MD, of Columbia University, New York, and his colleagues.

PPIs should be used on a short-term basis for individuals with gastroesophageal reflux disease (GERD) or conditions such as erosive esophagitis. These patients can also use PPIs for maintenance and occasional symptom management, but those with uncomplicated GERD should be weaned off PPIs if they respond favorably to them.

If a patient is unable to be weaned off PPIs, then ambulatory esophageal pH and impedance monitoring should be done, as this will allow clinicians to determine if the patient has a functional syndrome or GERD. Lifelong PPI treatment should not be considered until this step is taken, according to the new best practice statements.

“Short-term PPIs are highly effective for uncomplicated GERD [but] because patients who cannot reduce PPIs face lifelong therapy, we would consider testing for an acid-related disorder in this situation,” the authors explained. “However, there is no high-quality evidence on which to base this recommendation.”

Patients who have symptomatic GERD or Barrett’s esophagus, either symptomatic or asymptomatic, should be on long-term PPI treatment. Patients who are at a higher risk for NSAID-induced ulcer bleeding should be taking PPIs if they continue to take NSAIDs.

When recommending long-term PPI treatment for a patient, the patient need not use probiotics on a regular basis; there appears to be no need to routinely check the patient’s bone mineral density, serum creatinine, magnesium, or vitamin B₁₂ level on a regular basis. In addition, they need not consume more than the Recommended Dietary Allowance of calcium, magnesium, or vitamin B₁₂.

Finally, the authors state that “specific PPI formulations should not be selected based on potential risks.” This is because no evidence has been found indicating that PPI formulations can be ranked in any way based on risk.

These recommendations come from the AGA’s Clinical Practice Updates Committee, which pored through studies published through July 2016 in the PubMed, EMbase, and Cochrane library databases. Expert opinions and quality assessments on each study contributed to forming these best practice statements.

“In sum, the best current strategies for mitigating the potential risks of long-term PPIs are to avoid prescribing them when they are not indicated and to reduce them to their minimum dose when they are indicated,” Dr. Freedberg and his colleagues concluded.

The researchers did not report any relevant financial disclosures.

Q2: Answer: B

This patient, with no imaging or laboratory findings to suggest cirrhosis, most likely has noncirrhotic portal hypertension (NCPH). There is now a well-described association between HIV and NCPH with the prevalence of NCPH in HIV estimated to be –0.5% to 1%. Patients typically are unaware of any underlying liver disease until presentation with variceal bleeding. Variceal bleeding is a much more common manifestation of NCPH than ascites. Clinical presentation with normal hepatic enzymes and normal hepatic synthetic function is a very typical feature in these patients.  Although the exact etiology is not fully understood, NCPH in HIV is likely related to HAART, particularly didanosine use, hypercoagulability, microbial translocation from the gut, and direct effects of HIV. NCPH is a presinusoidal lesion, and liver biopsy may reveal paucity of portal vasculature and focal obliteration of small portal veins. Portal vein thrombosis in patients with HIV and NCPH is common and has been observed in 25%-75% of patients.  
 

Reference

1. Vispo E., Morello J., Rodriguez-Novoa S., Soriano V. Noncirrhotic portal hypertension in HIV infection. Curr Opin Infect Dis. 2011;24:12-8.
2. Khanna R., Sarin S.K. Noncirrhotic portal hypertension – Diagnosis and management. J Hepatol. 2014;60:421-41. 
 

Q2: Answer: B

This patient, with no imaging or laboratory findings to suggest cirrhosis, most likely has noncirrhotic portal hypertension (NCPH). There is now a well-described association between HIV and NCPH with the prevalence of NCPH in HIV estimated to be –0.5% to 1%. Patients typically are unaware of any underlying liver disease until presentation with variceal bleeding. Variceal bleeding is a much more common manifestation of NCPH than ascites. Clinical presentation with normal hepatic enzymes and normal hepatic synthetic function is a very typical feature in these patients.  Although the exact etiology is not fully understood, NCPH in HIV is likely related to HAART, particularly didanosine use, hypercoagulability, microbial translocation from the gut, and direct effects of HIV. NCPH is a presinusoidal lesion, and liver biopsy may reveal paucity of portal vasculature and focal obliteration of small portal veins. Portal vein thrombosis in patients with HIV and NCPH is common and has been observed in 25%-75% of patients.  
 

Reference

1. Vispo E., Morello J., Rodriguez-Novoa S., Soriano V. Noncirrhotic portal hypertension in HIV infection. Curr Opin Infect Dis. 2011;24:12-8.
2. Khanna R., Sarin S.K. Noncirrhotic portal hypertension – Diagnosis and management. J Hepatol. 2014;60:421-41. 
 

Q2: Answer: B

This patient, with no imaging or laboratory findings to suggest cirrhosis, most likely has noncirrhotic portal hypertension (NCPH). There is now a well-described association between HIV and NCPH with the prevalence of NCPH in HIV estimated to be –0.5% to 1%. Patients typically are unaware of any underlying liver disease until presentation with variceal bleeding. Variceal bleeding is a much more common manifestation of NCPH than ascites. Clinical presentation with normal hepatic enzymes and normal hepatic synthetic function is a very typical feature in these patients.  Although the exact etiology is not fully understood, NCPH in HIV is likely related to HAART, particularly didanosine use, hypercoagulability, microbial translocation from the gut, and direct effects of HIV. NCPH is a presinusoidal lesion, and liver biopsy may reveal paucity of portal vasculature and focal obliteration of small portal veins. Portal vein thrombosis in patients with HIV and NCPH is common and has been observed in 25%-75% of patients.  
 

Reference

1. Vispo E., Morello J., Rodriguez-Novoa S., Soriano V. Noncirrhotic portal hypertension in HIV infection. Curr Opin Infect Dis. 2011;24:12-8.
2. Khanna R., Sarin S.K. Noncirrhotic portal hypertension – Diagnosis and management. J Hepatol. 2014;60:421-41. 
 

Q1: Answer: A

Critique: This is a classic presentation of eosinophilic esophagitis (EoE). As many as half of older children with food impactions suffer from EoE. EoE is characterized by a severe, eosinophilic infiltration of the esophagus that may respond to acid inhibition, systemic or topical steroid therapy, or removal of dietary allergens. Epidemiologic studies suggest a rising incidence in the United States in both children and adults, with at least one case occurring in every 10,000 children each year. Treatment is aimed at alleviating symptoms and healing esophageal inflammation. Allergy testing should be performed at the time of diagnosis; however, radioallergosorbent  tests and skin-prick tests are often negative, and only half of affected children have a antecedent history of other allergic symptoms. 

A five-food elimination diet can be helpful for many affected children and adults, although adherence to the diet can be difficult. There is a group of affected children who respond to high doses of proton pump inhibitors, and most patients respond to either systemic or topical steroid therapy. Even with therapy, some patients go on to develop esophageal strictures and may need serial or repeated dilatations.  

While eosinophilic infiltration and inflammation may be present with gastroesophageal reflux disease and associated esophagitis, the number of eosinophils seen in this boy’s biopsies is much more consistent with EoE. Moreover, stricture formation as a result of peptic esophagitis in a child this age would be extremely rare. While inflammatory bowel disease may be associated with eosinophilic infiltration of the intestinal tract, isolated esophageal Crohn’s disease would be extraordinarily rare.Our patient has no history of any immune deficiency or steroid use that would predispose to fungal esophagitis. Achalasia typically presents with gradually worsening symptoms, and the obstruction would be at the lower esophageal sphincter, not in the mid-esophagus.  
 

Reference

<sup>1. Liacouras C., Furuta G., Hirano I., et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol. 2011;128:3-20. 
2. Furuta G., Liacouras C., Collins M., et al. Eosinophilic esophagitis in children and adults: A systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133:1342-63.</sup>

Q1: Answer: A

Critique: This is a classic presentation of eosinophilic esophagitis (EoE). As many as half of older children with food impactions suffer from EoE. EoE is characterized by a severe, eosinophilic infiltration of the esophagus that may respond to acid inhibition, systemic or topical steroid therapy, or removal of dietary allergens. Epidemiologic studies suggest a rising incidence in the United States in both children and adults, with at least one case occurring in every 10,000 children each year. Treatment is aimed at alleviating symptoms and healing esophageal inflammation. Allergy testing should be performed at the time of diagnosis; however, radioallergosorbent  tests and skin-prick tests are often negative, and only half of affected children have a antecedent history of other allergic symptoms. 

A five-food elimination diet can be helpful for many affected children and adults, although adherence to the diet can be difficult. There is a group of affected children who respond to high doses of proton pump inhibitors, and most patients respond to either systemic or topical steroid therapy. Even with therapy, some patients go on to develop esophageal strictures and may need serial or repeated dilatations.  

While eosinophilic infiltration and inflammation may be present with gastroesophageal reflux disease and associated esophagitis, the number of eosinophils seen in this boy’s biopsies is much more consistent with EoE. Moreover, stricture formation as a result of peptic esophagitis in a child this age would be extremely rare. While inflammatory bowel disease may be associated with eosinophilic infiltration of the intestinal tract, isolated esophageal Crohn’s disease would be extraordinarily rare.Our patient has no history of any immune deficiency or steroid use that would predispose to fungal esophagitis. Achalasia typically presents with gradually worsening symptoms, and the obstruction would be at the lower esophageal sphincter, not in the mid-esophagus.  
 

Reference

<sup>1. Liacouras C., Furuta G., Hirano I., et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol. 2011;128:3-20. 
2. Furuta G., Liacouras C., Collins M., et al. Eosinophilic esophagitis in children and adults: A systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133:1342-63.</sup>

Q1: Answer: A

Critique: This is a classic presentation of eosinophilic esophagitis (EoE). As many as half of older children with food impactions suffer from EoE. EoE is characterized by a severe, eosinophilic infiltration of the esophagus that may respond to acid inhibition, systemic or topical steroid therapy, or removal of dietary allergens. Epidemiologic studies suggest a rising incidence in the United States in both children and adults, with at least one case occurring in every 10,000 children each year. Treatment is aimed at alleviating symptoms and healing esophageal inflammation. Allergy testing should be performed at the time of diagnosis; however, radioallergosorbent  tests and skin-prick tests are often negative, and only half of affected children have a antecedent history of other allergic symptoms. 

A five-food elimination diet can be helpful for many affected children and adults, although adherence to the diet can be difficult. There is a group of affected children who respond to high doses of proton pump inhibitors, and most patients respond to either systemic or topical steroid therapy. Even with therapy, some patients go on to develop esophageal strictures and may need serial or repeated dilatations.  

While eosinophilic infiltration and inflammation may be present with gastroesophageal reflux disease and associated esophagitis, the number of eosinophils seen in this boy’s biopsies is much more consistent with EoE. Moreover, stricture formation as a result of peptic esophagitis in a child this age would be extremely rare. While inflammatory bowel disease may be associated with eosinophilic infiltration of the intestinal tract, isolated esophageal Crohn’s disease would be extraordinarily rare.Our patient has no history of any immune deficiency or steroid use that would predispose to fungal esophagitis. Achalasia typically presents with gradually worsening symptoms, and the obstruction would be at the lower esophageal sphincter, not in the mid-esophagus.  
 

Reference

<sup>1. Liacouras C., Furuta G., Hirano I., et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol. 2011;128:3-20. 
2. Furuta G., Liacouras C., Collins M., et al. Eosinophilic esophagitis in children and adults: A systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133:1342-63.</sup>