For more than 75 years, pediatrics has sought sound guidelines for prescribing maintenance intravenous fluid (mIVF) for children. In 1957, Holliday and Segar (H&S)¹ introduced a breakthrough method for estimating mIVF needs. Their guidelines for calculating free-water and electrolyte needs for mIVF gained wide-spread acceptance and became the standard of care for decades.

Over the last two decades, awareness has grown around the occurrence of rare, life-threatening hyponatremic conditions, especially hyponatremic encephalopathy, in hospitalized children. Concomitantly, an increasing awareness shows that serum levels of antidiuretic hormone (ADH) are often elevated in sick children and triggered by nonosmotic conditions (pain, vomiting, perioperative state, meningitis, and pulmonary disease). This situation led to heightened concern of clinicians and investigators who assumed that hospitalized patients would exhibit reduced tolerance for hypotonic mIVF the mainstay of the H&S method. The possibility that the H&S method could be a significant contributing factor to the development of hyponatremic encephalopathy in hospitalized children became a research topic. This research speculated that even mildly reduced serum sodium levels might be a marker for the much rarer condition of hyponatremic encephalopathy. A number of hospitalists also switched from quarter-normal to half-normal saline in mIVF.

The substitution of hypotonic fluids with isotonic fluids (eg, 0.9% normal saline or lactated Ringer’s) is the current front-runner alternative to increase sodium delivery. The hypothesis is that the delivery of additional sodium, while maintaining the same H&S method volume/rate of fluid delivery, will protect against life-threatening hyponatremic events.

The challenge we face is whether we are moving from mIVF therapy, which features a long track record of success and an excellent safety profile, to a safer or more effective therapeutic approach. We should consider the burden of proof which should be satisfied to support creating new guidelines which center on changing from hypotonic mIVF to isotonic mIVF.

Is there sufficient scientific proof that isotonic mIVF is safer and/or more effective than hypotonic mIVF in preventing life-threatening hyponatremic events?

Is there compelling biologic plausibility for this change for patients with risk factors that are associated with elevated serum ADH levels?

What is the magnitude of the benefit?

What is the magnitude of unintended harms?

We offer our perspective on each of these questions.

The primary difficulty with addressing the adverse events of catastrophic hyponatremia (encephalopathy, seizures, cerebral edema, and death) is their rarity. The events stand out when they occur, prompting mortality and morbidity (M&M) conferences to blunder into action. But that action is not evidence-based, even if a rationale mentions a meta-analysis, because the rationales lack estimates of the number needed to treat (NNT) to prevent one catastrophic event. Estimates of the NNT to prevent mild hypernatremia are not useful. Furthermore, estimates of the number needed to harm (NNH) via unintended consequences of infusing extra sodium chloride are unavailable. True evidence-based medicine (EBM) is rigorous in requiring NNT and NNH. Anything less is considered M&M-based medicine masquerading as EBM.

No technical jargon distinguishes the profound and catastrophic events from the common, mild hyponatremia frequently observed in ill toddlers upon admission. As an analogy, in dealing with fever, astute pediatricians recognize that a moderate fever of 103.4 °F is not halfway to a heatstroke of 108 °F. Fever is not a near miss for heatstroke. Physicians do not recommend acetaminophen to prevent heatstroke, although many parents act that way.

No published randomized controlled trials (RCTs) showed the incidence of these catastrophic hyponatremic events. In the meta-analysis of 10 disparate and uncoordinated trials in 2014,² no serious adverse events were noted among the 1,000 patients involved. Since then, newer RCTs have added another 1,000 patients to the meta-analysis pool, but still no serious adverse event has been observed.

The H&S method features 60 years of proven safety and remains the appropriate estimate when composing long-term parenteral nutrition. No recommendation is perfect for all situations. Many hospitalized children will exhibit an increased level of ADH. A very small fraction of those children will present a sufficiently elevated ADH level long enough to risk creating profound hyponatremia. An approximation is in the order of magnitude of 1 per 100,000 pediatric medical admissions and 1 per 10,000 postoperative patients. With 3 million pediatric admissions yearly in the United States, such numbers mean that large children’s hospitals might see one or two catastrophic adverse events each decade due to mIVF in previously healthy children. The risk in chronically ill children and in the ICU will be higher. The potential for causing unintended greater harm amongst the other millions of patients is high, requiring application of the precautionary principle.

Thus, EBM and RCTs are poor methodologies for quality improvement of this issue. Assigning surrogate measures, such as moderate hyponatremia or even mild hyponatremia, to increase sensitivity and incidence for research purposes lacks a validated scientific link to the much rarer profound hyponatremic events. The resulting nonvalid extrapolation is precisely what true EBM seeks to avoid. A serum sodium of 132 mEq/L is not a near miss. The NNT to prevent the catastrophic events is unknown. Indeed, no paper advocating adoption of isotonic mIVF has even ventured an approximation.

The RCTs are also, therefore, underpowered to identify harms from using normal saline as a maintenance fluid. A few studies mention hypernatremia, but serum sodium is not a statistical variable. Renal physiology predicts that kidneys can easily handle excess infused sodium and can protect against hypernatremia. However, the extra chloride load risks creating hyperchloremic acidosis, particularly when a patient with respiratory insufficiency cannot compensate by lowering pCO₂ through increased minute ventilation. Edema is another risk. Both respiratory insufficiency and edema already occur more frequently (by orders of magnitude) in hospitalized patients on any mIVF than the profound hyponatremia events in hospitalized patients on hypotonic mIVF. For instance, about 1% of hospitalized infants with bronchiolitis are ventilated for respiratory failure. If hyperchloremic acidosis unintentionally caused by isotonic mIVF slightly increases the frequency of intubation, then such result far outweighs any benefit from reducing catastrophic hyponatremic events. Difficulty will also arise in detecting this unintended increase in the rate of intubation compared with the current background frequency. Detecting these unintended harms becomes impossible if the RCT is underpowered by 100-fold due to utilizing a surrogate measure, such as serum sodium <135 mEq/L, as the dependent variable instead of measuring serious hyponatremic adverse events.

All claims that “no evidence of harm” was found from using normal saline as mIVF are type II statistical errors. There is little chance of detecting any harm with a grossly underpowered study or a meta-analysis of 10 such studies. Simply put, EBM is impossible to use for events that occur less than 1 per 10,000 patients using RCTs with 1,000 patients. No usable safety data are available for normal saline as mIVF in any published RCT. As the RCTs are underpowered, one should rely on science to guide therapy, rather than on invalid statistics.

Using the precautionary principle, hypothetically, adding extra sodium chloride to maintenance fluids should be considered in the same manner as adding any other drug. Based on the current evidence, would the Food and Drug Administration approve the drug intravenous sodium chloride for the prevention of hyponatremia induced by maintenance fluids? An increasing evidence of a minimal beneficial effect is observed, but no evidence of safety nor physiology is available. A new drug application for using normal saline as a default maintenance fluid would be soundly rejected by an FDA panel, just as it has been rejected by the majority of pediatric hospitalists throughout the past 15 years since the idea was proposed in 2003.

With the lack of compelling statistical evidence to guide practice, clinicians often rely on biologic plausibility. Relatively recent studies have revealed that many sick children develop elevated blood levels of ADH due to nonosmotic and nonhemodynamic triggers. Fortunately, we also possess a strong body of knowledge around management of children with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). We understand that elevated levels of ADH in the blood causes an increase in the resorption of free water from the renal collecting tubules. No increase in loss of renal sodium nor chloride is associated with this hormonal influence. The resultant hyponatremia is due to excess free-water retention and not the excess loss of sodium or chloride. To manage this condition, patients are not given a salt shaker and then allowed to drink ad libitum. The standard and well-accepted management of patients with SIADH is the restriction of free-water intake because this step addresses the dysfunctional renal process. Administering sodium chloride to a child with SIADH might possibly slow down the progression of hyponatremia but would also expand the total fluid volumes of the patient and would indirectly deal with a problem that could be addressed directly.

Understandably, in an intensive care setting, when hemodynamics is dicey, and when fluid-restriction could risk hypovolemia, employing a volume-expanding solution for mIVF therapy might be reasonable. However, in an ICU setting, SIADH is routinely treated with free-water restriction, and careful calculations of an individual patient’s fluid and electrolyte losses and needs are made.

In conclusion, we recognize the motivation for questioning the H&S method for mIVF as our field surveilles more than a half-century of accumulated experience with this method and the advances in our understanding of physiology and pathophysiology. However, we believe that the current body of evidence fails to substantiate the proposed recommendations.³ The avoidance of laboratory-detectable decreases in serum sodium levels is an unproven marker for the development of life-threatening hyponatremic events. Concerns for untoward effects (eg, excessive volume expansion and effects of hyperchloremia toward acidosis) and the exploration of alternative approaches (eg, modifications in volumes/rates of fluid delivery) have been inadequately explored. The proposed changes in practice may provide no mitigation in the rare events we hope to avoid, may fail to serve all subpopulations within the proposed scope of patients, and will likely create unintended new problems.

Disclosures

Dr. Powell and Dr. Zaoutis have nothing to disclose.

For more than 75 years, pediatrics has sought sound guidelines for prescribing maintenance intravenous fluid (mIVF) for children. In 1957, Holliday and Segar (H&S)¹ introduced a breakthrough method for estimating mIVF needs. Their guidelines for calculating free-water and electrolyte needs for mIVF gained wide-spread acceptance and became the standard of care for decades.

Over the last two decades, awareness has grown around the occurrence of rare, life-threatening hyponatremic conditions, especially hyponatremic encephalopathy, in hospitalized children. Concomitantly, an increasing awareness shows that serum levels of antidiuretic hormone (ADH) are often elevated in sick children and triggered by nonosmotic conditions (pain, vomiting, perioperative state, meningitis, and pulmonary disease). This situation led to heightened concern of clinicians and investigators who assumed that hospitalized patients would exhibit reduced tolerance for hypotonic mIVF the mainstay of the H&S method. The possibility that the H&S method could be a significant contributing factor to the development of hyponatremic encephalopathy in hospitalized children became a research topic. This research speculated that even mildly reduced serum sodium levels might be a marker for the much rarer condition of hyponatremic encephalopathy. A number of hospitalists also switched from quarter-normal to half-normal saline in mIVF.

The substitution of hypotonic fluids with isotonic fluids (eg, 0.9% normal saline or lactated Ringer’s) is the current front-runner alternative to increase sodium delivery. The hypothesis is that the delivery of additional sodium, while maintaining the same H&S method volume/rate of fluid delivery, will protect against life-threatening hyponatremic events.

The challenge we face is whether we are moving from mIVF therapy, which features a long track record of success and an excellent safety profile, to a safer or more effective therapeutic approach. We should consider the burden of proof which should be satisfied to support creating new guidelines which center on changing from hypotonic mIVF to isotonic mIVF.

Is there sufficient scientific proof that isotonic mIVF is safer and/or more effective than hypotonic mIVF in preventing life-threatening hyponatremic events?

Is there compelling biologic plausibility for this change for patients with risk factors that are associated with elevated serum ADH levels?

What is the magnitude of the benefit?

What is the magnitude of unintended harms?

We offer our perspective on each of these questions.

The primary difficulty with addressing the adverse events of catastrophic hyponatremia (encephalopathy, seizures, cerebral edema, and death) is their rarity. The events stand out when they occur, prompting mortality and morbidity (M&M) conferences to blunder into action. But that action is not evidence-based, even if a rationale mentions a meta-analysis, because the rationales lack estimates of the number needed to treat (NNT) to prevent one catastrophic event. Estimates of the NNT to prevent mild hypernatremia are not useful. Furthermore, estimates of the number needed to harm (NNH) via unintended consequences of infusing extra sodium chloride are unavailable. True evidence-based medicine (EBM) is rigorous in requiring NNT and NNH. Anything less is considered M&M-based medicine masquerading as EBM.

No technical jargon distinguishes the profound and catastrophic events from the common, mild hyponatremia frequently observed in ill toddlers upon admission. As an analogy, in dealing with fever, astute pediatricians recognize that a moderate fever of 103.4 °F is not halfway to a heatstroke of 108 °F. Fever is not a near miss for heatstroke. Physicians do not recommend acetaminophen to prevent heatstroke, although many parents act that way.

No published randomized controlled trials (RCTs) showed the incidence of these catastrophic hyponatremic events. In the meta-analysis of 10 disparate and uncoordinated trials in 2014,² no serious adverse events were noted among the 1,000 patients involved. Since then, newer RCTs have added another 1,000 patients to the meta-analysis pool, but still no serious adverse event has been observed.

The H&S method features 60 years of proven safety and remains the appropriate estimate when composing long-term parenteral nutrition. No recommendation is perfect for all situations. Many hospitalized children will exhibit an increased level of ADH. A very small fraction of those children will present a sufficiently elevated ADH level long enough to risk creating profound hyponatremia. An approximation is in the order of magnitude of 1 per 100,000 pediatric medical admissions and 1 per 10,000 postoperative patients. With 3 million pediatric admissions yearly in the United States, such numbers mean that large children’s hospitals might see one or two catastrophic adverse events each decade due to mIVF in previously healthy children. The risk in chronically ill children and in the ICU will be higher. The potential for causing unintended greater harm amongst the other millions of patients is high, requiring application of the precautionary principle.

Thus, EBM and RCTs are poor methodologies for quality improvement of this issue. Assigning surrogate measures, such as moderate hyponatremia or even mild hyponatremia, to increase sensitivity and incidence for research purposes lacks a validated scientific link to the much rarer profound hyponatremic events. The resulting nonvalid extrapolation is precisely what true EBM seeks to avoid. A serum sodium of 132 mEq/L is not a near miss. The NNT to prevent the catastrophic events is unknown. Indeed, no paper advocating adoption of isotonic mIVF has even ventured an approximation.

The RCTs are also, therefore, underpowered to identify harms from using normal saline as a maintenance fluid. A few studies mention hypernatremia, but serum sodium is not a statistical variable. Renal physiology predicts that kidneys can easily handle excess infused sodium and can protect against hypernatremia. However, the extra chloride load risks creating hyperchloremic acidosis, particularly when a patient with respiratory insufficiency cannot compensate by lowering pCO₂ through increased minute ventilation. Edema is another risk. Both respiratory insufficiency and edema already occur more frequently (by orders of magnitude) in hospitalized patients on any mIVF than the profound hyponatremia events in hospitalized patients on hypotonic mIVF. For instance, about 1% of hospitalized infants with bronchiolitis are ventilated for respiratory failure. If hyperchloremic acidosis unintentionally caused by isotonic mIVF slightly increases the frequency of intubation, then such result far outweighs any benefit from reducing catastrophic hyponatremic events. Difficulty will also arise in detecting this unintended increase in the rate of intubation compared with the current background frequency. Detecting these unintended harms becomes impossible if the RCT is underpowered by 100-fold due to utilizing a surrogate measure, such as serum sodium <135 mEq/L, as the dependent variable instead of measuring serious hyponatremic adverse events.

All claims that “no evidence of harm” was found from using normal saline as mIVF are type II statistical errors. There is little chance of detecting any harm with a grossly underpowered study or a meta-analysis of 10 such studies. Simply put, EBM is impossible to use for events that occur less than 1 per 10,000 patients using RCTs with 1,000 patients. No usable safety data are available for normal saline as mIVF in any published RCT. As the RCTs are underpowered, one should rely on science to guide therapy, rather than on invalid statistics.

Using the precautionary principle, hypothetically, adding extra sodium chloride to maintenance fluids should be considered in the same manner as adding any other drug. Based on the current evidence, would the Food and Drug Administration approve the drug intravenous sodium chloride for the prevention of hyponatremia induced by maintenance fluids? An increasing evidence of a minimal beneficial effect is observed, but no evidence of safety nor physiology is available. A new drug application for using normal saline as a default maintenance fluid would be soundly rejected by an FDA panel, just as it has been rejected by the majority of pediatric hospitalists throughout the past 15 years since the idea was proposed in 2003.

With the lack of compelling statistical evidence to guide practice, clinicians often rely on biologic plausibility. Relatively recent studies have revealed that many sick children develop elevated blood levels of ADH due to nonosmotic and nonhemodynamic triggers. Fortunately, we also possess a strong body of knowledge around management of children with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). We understand that elevated levels of ADH in the blood causes an increase in the resorption of free water from the renal collecting tubules. No increase in loss of renal sodium nor chloride is associated with this hormonal influence. The resultant hyponatremia is due to excess free-water retention and not the excess loss of sodium or chloride. To manage this condition, patients are not given a salt shaker and then allowed to drink ad libitum. The standard and well-accepted management of patients with SIADH is the restriction of free-water intake because this step addresses the dysfunctional renal process. Administering sodium chloride to a child with SIADH might possibly slow down the progression of hyponatremia but would also expand the total fluid volumes of the patient and would indirectly deal with a problem that could be addressed directly.

Understandably, in an intensive care setting, when hemodynamics is dicey, and when fluid-restriction could risk hypovolemia, employing a volume-expanding solution for mIVF therapy might be reasonable. However, in an ICU setting, SIADH is routinely treated with free-water restriction, and careful calculations of an individual patient’s fluid and electrolyte losses and needs are made.

In conclusion, we recognize the motivation for questioning the H&S method for mIVF as our field surveilles more than a half-century of accumulated experience with this method and the advances in our understanding of physiology and pathophysiology. However, we believe that the current body of evidence fails to substantiate the proposed recommendations.³ The avoidance of laboratory-detectable decreases in serum sodium levels is an unproven marker for the development of life-threatening hyponatremic events. Concerns for untoward effects (eg, excessive volume expansion and effects of hyperchloremia toward acidosis) and the exploration of alternative approaches (eg, modifications in volumes/rates of fluid delivery) have been inadequately explored. The proposed changes in practice may provide no mitigation in the rare events we hope to avoid, may fail to serve all subpopulations within the proposed scope of patients, and will likely create unintended new problems.

Disclosures

Dr. Powell and Dr. Zaoutis have nothing to disclose.

For more than 75 years, pediatrics has sought sound guidelines for prescribing maintenance intravenous fluid (mIVF) for children. In 1957, Holliday and Segar (H&S)¹ introduced a breakthrough method for estimating mIVF needs. Their guidelines for calculating free-water and electrolyte needs for mIVF gained wide-spread acceptance and became the standard of care for decades.

Over the last two decades, awareness has grown around the occurrence of rare, life-threatening hyponatremic conditions, especially hyponatremic encephalopathy, in hospitalized children. Concomitantly, an increasing awareness shows that serum levels of antidiuretic hormone (ADH) are often elevated in sick children and triggered by nonosmotic conditions (pain, vomiting, perioperative state, meningitis, and pulmonary disease). This situation led to heightened concern of clinicians and investigators who assumed that hospitalized patients would exhibit reduced tolerance for hypotonic mIVF the mainstay of the H&S method. The possibility that the H&S method could be a significant contributing factor to the development of hyponatremic encephalopathy in hospitalized children became a research topic. This research speculated that even mildly reduced serum sodium levels might be a marker for the much rarer condition of hyponatremic encephalopathy. A number of hospitalists also switched from quarter-normal to half-normal saline in mIVF.

The substitution of hypotonic fluids with isotonic fluids (eg, 0.9% normal saline or lactated Ringer’s) is the current front-runner alternative to increase sodium delivery. The hypothesis is that the delivery of additional sodium, while maintaining the same H&S method volume/rate of fluid delivery, will protect against life-threatening hyponatremic events.

The challenge we face is whether we are moving from mIVF therapy, which features a long track record of success and an excellent safety profile, to a safer or more effective therapeutic approach. We should consider the burden of proof which should be satisfied to support creating new guidelines which center on changing from hypotonic mIVF to isotonic mIVF.

Is there sufficient scientific proof that isotonic mIVF is safer and/or more effective than hypotonic mIVF in preventing life-threatening hyponatremic events?

Is there compelling biologic plausibility for this change for patients with risk factors that are associated with elevated serum ADH levels?

What is the magnitude of the benefit?

What is the magnitude of unintended harms?

We offer our perspective on each of these questions.

The primary difficulty with addressing the adverse events of catastrophic hyponatremia (encephalopathy, seizures, cerebral edema, and death) is their rarity. The events stand out when they occur, prompting mortality and morbidity (M&M) conferences to blunder into action. But that action is not evidence-based, even if a rationale mentions a meta-analysis, because the rationales lack estimates of the number needed to treat (NNT) to prevent one catastrophic event. Estimates of the NNT to prevent mild hypernatremia are not useful. Furthermore, estimates of the number needed to harm (NNH) via unintended consequences of infusing extra sodium chloride are unavailable. True evidence-based medicine (EBM) is rigorous in requiring NNT and NNH. Anything less is considered M&M-based medicine masquerading as EBM.

No technical jargon distinguishes the profound and catastrophic events from the common, mild hyponatremia frequently observed in ill toddlers upon admission. As an analogy, in dealing with fever, astute pediatricians recognize that a moderate fever of 103.4 °F is not halfway to a heatstroke of 108 °F. Fever is not a near miss for heatstroke. Physicians do not recommend acetaminophen to prevent heatstroke, although many parents act that way.

No published randomized controlled trials (RCTs) showed the incidence of these catastrophic hyponatremic events. In the meta-analysis of 10 disparate and uncoordinated trials in 2014,² no serious adverse events were noted among the 1,000 patients involved. Since then, newer RCTs have added another 1,000 patients to the meta-analysis pool, but still no serious adverse event has been observed.

The H&S method features 60 years of proven safety and remains the appropriate estimate when composing long-term parenteral nutrition. No recommendation is perfect for all situations. Many hospitalized children will exhibit an increased level of ADH. A very small fraction of those children will present a sufficiently elevated ADH level long enough to risk creating profound hyponatremia. An approximation is in the order of magnitude of 1 per 100,000 pediatric medical admissions and 1 per 10,000 postoperative patients. With 3 million pediatric admissions yearly in the United States, such numbers mean that large children’s hospitals might see one or two catastrophic adverse events each decade due to mIVF in previously healthy children. The risk in chronically ill children and in the ICU will be higher. The potential for causing unintended greater harm amongst the other millions of patients is high, requiring application of the precautionary principle.

Thus, EBM and RCTs are poor methodologies for quality improvement of this issue. Assigning surrogate measures, such as moderate hyponatremia or even mild hyponatremia, to increase sensitivity and incidence for research purposes lacks a validated scientific link to the much rarer profound hyponatremic events. The resulting nonvalid extrapolation is precisely what true EBM seeks to avoid. A serum sodium of 132 mEq/L is not a near miss. The NNT to prevent the catastrophic events is unknown. Indeed, no paper advocating adoption of isotonic mIVF has even ventured an approximation.

The RCTs are also, therefore, underpowered to identify harms from using normal saline as a maintenance fluid. A few studies mention hypernatremia, but serum sodium is not a statistical variable. Renal physiology predicts that kidneys can easily handle excess infused sodium and can protect against hypernatremia. However, the extra chloride load risks creating hyperchloremic acidosis, particularly when a patient with respiratory insufficiency cannot compensate by lowering pCO₂ through increased minute ventilation. Edema is another risk. Both respiratory insufficiency and edema already occur more frequently (by orders of magnitude) in hospitalized patients on any mIVF than the profound hyponatremia events in hospitalized patients on hypotonic mIVF. For instance, about 1% of hospitalized infants with bronchiolitis are ventilated for respiratory failure. If hyperchloremic acidosis unintentionally caused by isotonic mIVF slightly increases the frequency of intubation, then such result far outweighs any benefit from reducing catastrophic hyponatremic events. Difficulty will also arise in detecting this unintended increase in the rate of intubation compared with the current background frequency. Detecting these unintended harms becomes impossible if the RCT is underpowered by 100-fold due to utilizing a surrogate measure, such as serum sodium <135 mEq/L, as the dependent variable instead of measuring serious hyponatremic adverse events.

All claims that “no evidence of harm” was found from using normal saline as mIVF are type II statistical errors. There is little chance of detecting any harm with a grossly underpowered study or a meta-analysis of 10 such studies. Simply put, EBM is impossible to use for events that occur less than 1 per 10,000 patients using RCTs with 1,000 patients. No usable safety data are available for normal saline as mIVF in any published RCT. As the RCTs are underpowered, one should rely on science to guide therapy, rather than on invalid statistics.

Using the precautionary principle, hypothetically, adding extra sodium chloride to maintenance fluids should be considered in the same manner as adding any other drug. Based on the current evidence, would the Food and Drug Administration approve the drug intravenous sodium chloride for the prevention of hyponatremia induced by maintenance fluids? An increasing evidence of a minimal beneficial effect is observed, but no evidence of safety nor physiology is available. A new drug application for using normal saline as a default maintenance fluid would be soundly rejected by an FDA panel, just as it has been rejected by the majority of pediatric hospitalists throughout the past 15 years since the idea was proposed in 2003.

With the lack of compelling statistical evidence to guide practice, clinicians often rely on biologic plausibility. Relatively recent studies have revealed that many sick children develop elevated blood levels of ADH due to nonosmotic and nonhemodynamic triggers. Fortunately, we also possess a strong body of knowledge around management of children with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). We understand that elevated levels of ADH in the blood causes an increase in the resorption of free water from the renal collecting tubules. No increase in loss of renal sodium nor chloride is associated with this hormonal influence. The resultant hyponatremia is due to excess free-water retention and not the excess loss of sodium or chloride. To manage this condition, patients are not given a salt shaker and then allowed to drink ad libitum. The standard and well-accepted management of patients with SIADH is the restriction of free-water intake because this step addresses the dysfunctional renal process. Administering sodium chloride to a child with SIADH might possibly slow down the progression of hyponatremia but would also expand the total fluid volumes of the patient and would indirectly deal with a problem that could be addressed directly.

Understandably, in an intensive care setting, when hemodynamics is dicey, and when fluid-restriction could risk hypovolemia, employing a volume-expanding solution for mIVF therapy might be reasonable. However, in an ICU setting, SIADH is routinely treated with free-water restriction, and careful calculations of an individual patient’s fluid and electrolyte losses and needs are made.

In conclusion, we recognize the motivation for questioning the H&S method for mIVF as our field surveilles more than a half-century of accumulated experience with this method and the advances in our understanding of physiology and pathophysiology. However, we believe that the current body of evidence fails to substantiate the proposed recommendations.³ The avoidance of laboratory-detectable decreases in serum sodium levels is an unproven marker for the development of life-threatening hyponatremic events. Concerns for untoward effects (eg, excessive volume expansion and effects of hyperchloremia toward acidosis) and the exploration of alternative approaches (eg, modifications in volumes/rates of fluid delivery) have been inadequately explored. The proposed changes in practice may provide no mitigation in the rare events we hope to avoid, may fail to serve all subpopulations within the proposed scope of patients, and will likely create unintended new problems.

Disclosures

Dr. Powell and Dr. Zaoutis have nothing to disclose.

Click here to access the September 2018 Digital Edition.

Table of Contents

• Huddling for High-Performing
• Flexible Bronchoscopic Removal of 3 Foreign Objects
• Improved Transitional Care Through an Innovative Hospitalist Model
• Reducing Prescribing of Benzodiazepines in Older Veterans
• Outcomes of Palliative Care Consults With Hospitalized Veterans
• Transforming Primary Care Clinical Learning Environments to Optimize Education, Outcomes, and Satisfaction

Click here to access the September 2018 Digital Edition.

Table of Contents

• Huddling for High-Performing
• Flexible Bronchoscopic Removal of 3 Foreign Objects
• Improved Transitional Care Through an Innovative Hospitalist Model
• Reducing Prescribing of Benzodiazepines in Older Veterans
• Outcomes of Palliative Care Consults With Hospitalized Veterans
• Transforming Primary Care Clinical Learning Environments to Optimize Education, Outcomes, and Satisfaction

Click here to access the September 2018 Digital Edition.

Table of Contents

• Huddling for High-Performing
• Flexible Bronchoscopic Removal of 3 Foreign Objects
• Improved Transitional Care Through an Innovative Hospitalist Model
• Reducing Prescribing of Benzodiazepines in Older Veterans
• Outcomes of Palliative Care Consults With Hospitalized Veterans
• Transforming Primary Care Clinical Learning Environments to Optimize Education, Outcomes, and Satisfaction

The use of pharmacogenetic testing to help drive decisions for medication management of patients with psychiatric illnesses is growing. It’s becoming increasingly common for patients or the parents of pediatric patients to request pharmacogenetic testing or to bring the results of prior testing to their appointment. In these situations, patients may ask clinicians to consider the recommendations from these testing reports, which rarely provide guidance specific to pediatric patients. However, this can be difficult for clinicians who did not receive education in pharmacogenetics and may not be familiar with the evidence or options for pharmacogenetic testing. Many of the pharmacogenetic associations identified thus far have been discovered in adults, but studies in pediatric patients are relatively rare. This article reviews pharmacogenetic testing and the evidence supporting it, and describes implementation of routine pharmacogenetics testing at a children’s hospital.

CASE
Testing leads to dose adjustment, improvement

Ms. R, age 16, presents with treatment-resistant major depressive disorder that is characterized by a significant neurovegetative burden and prominent anhedonia, as well as intermittent suicidal ideation without intent or plan. She reportedly did not improve after multiple medication trials, including citalopram (maximum dose 30 mg/d, treatment duration 8 weeks, good compliance), sertraline (maximum dose 150 mg/d, treatment duration 10 weeks, good compliance), fluoxetine (maximum dose 40 mg/d, treatment duration 8 weeks, good compliance, mild improvement in neurovegetative symptoms and depressed mood), and duloxetine (maximum dose 90 mg/d, treatment duration 6 weeks, good compliance, mild benefit but intolerable nausea).

Augmentation strategies included risperidone, 1 mg/d at bedtime, but it failed to ameliorate her depressive symptoms. At the time of pharmacogenetic testing, she is taking aripiprazole, 2 mg/d at bedtime, and venlafaxine ER, 37.5 mg/d. Some benefit was noted, but her symptoms recrudesced within several weeks. Because both of these medications are metabolized by the cytochrome P450 (CYP) 2D6 enzyme, Ms. R is tested for CYP2D6 variants and is determined to be a CYP2D6 ultra-rapid metabolizer. Her venlafaxine ER is quickly titrated from 37.5 to 112.5 mg/d and aripiprazole is titrated from 2 to 10 mg/d. The patient’s anergia, amotivation, and mood improve.

_

Drug metabolism and genetic variants

It is common for patients with psychiatric disorders to receive trials of multiple psychotropic medications prior to identifying one that reduces symptom burden without producing intolerable adverse effects. Due to the high frequency of toxicity-related adverse effects (observed in 20% to 70% of patients),¹ these medications are frequently initiated at low doses and titrated slowly until the patient either experiences an intolerable adverse effect or achieves symptomatic remission.^1,2 The practice of slow titration at the start of treatment increases the risk of undertreatment in many patients, and may ultimately lead to a medication change due to the lack of response.

Many of the medications used to treat psychiatric illnesses are primarily metabolized by 2 CYP enzymes expressed in the liver, encoded by the CYP2D6 and CYP2C19 genes³ (Table 1^3-7 and Table 2^3,6,7). These drug-metabolizing enzymes affect the pharmacokinetics of many medications. Some medications are converted to an active form by these enzymes, and some are inactivated. The contributions of CYP enzymes to the pharmacokinetics of neuro­psychiatric medications have been well-described; however, there is less evidence on whether variants in these genes are associated with treatment efficacy, especially in pediatric patients.^8,9 CYP2D6 enzyme activity reaches adult levels soon after birth, but children may have higher CYP2C19 activity than adults.⁴ CYP3A4 also contributes to the metabolism of many medications; however, there is only weak evidence that genetic variants in CYP3A4 contribute to variability in the pharmacokinetics of these medications, and there are currently no dosing guidelines based on pharmacogenetics available for this gene.¹⁰

As is common in the pharmacogenetic field, genotypes are denoted with a “star allele” (eg, *2) rather than positional nomenclature (eg, c.681G>A). The normal allele is usually designated as *1, and this result is given in the absence of the tested alleles. There is no consensus on the minimum set of alleles to be tested for most genes,¹¹ so commercially available tests vary widely in what alleles are tested (and therefore what they exclude before calling a normal allele).¹² The metabolizer phenotype for a patient is determined by taking into account the activity of each of the patient’s 2 alleles (eg, *1/*2). A patient is categorized as a poor-, intermediate-, normal- (extensive-), or ultra-rapid metabolizer. Generally, the allele definitions are widely agreed upon (what genetic variant or variants comprise the *2 allele) due to nomenclature committees for each gene; however, because there are no standards for interpretation, the interpretation of the activity of the alleles and conversion to metabolizer phenotype varies among clinics.¹³

Continue to: Guidelines help with genotype-guided dosing

Each CPIC guideline specifically addresses use in pediatric patients, indicating that there are relatively few studies in pediatrics, but “it may be appropriate to extrapolate these recommendations to adolescents or possibly younger children with close monitoring.”⁴ The DPWG guidelines do not mention whether or not the recommendations are applicable to children. Neither CPIC nor the DPWG provides guidance on when to test; however, the French National Network of Pharmacogenetics (Réseau national de pharmacogénétique) recommends CYP2D6 and CYP2C19 genotyping before initiating antidepressant treatment, especially in patients with a high risk of toxicity.¹⁶

In the case above, Ms. R was determined to be a CYP2D6 ultra-rapid metabolizer. Because she showed some initial response to aripiprazole and venlafaxine ER, which are both metabolized by CYP2D6, these medications were very quickly titrated up, and the increased dosages produced the desired response. Venlafaxine is metabolized to the active metabolite O-desmethylvenlafaxine by CYP2D6. The DPWG recommends increasing the dose of venlafaxine in CYP2D6 ultra-rapid metabolizers to 150% of the normal dose based on the decreased serum concentrations of venlafaxine and O-desmethylvenlafaxine in these patients.⁶ Aripiprazole is also metabolized by CYP2D6; however, the FDA and DPWG give no recommendations for ultra-rapid metabolizers, but do recommend reducing the dose of aripiprazole in CYP2D6 poor metabolizers.

Multiple studies in adults have analyzed the association between pharmacokinetic (CYP2D6 and CYP2C19) or pharmacodynamic genes (SLC6A4, HTR2A, and GRIK4) and outcomes,¹⁷ including some large clinical trials that conducted genome-wide association studies^18-20 and meta-analyses across multiple studies.^21,22 Most pharmacogenetic studies in psychiatric patients are small, and very few have included pediatric patients. However, with more interest in neuropsychiatric pharmacogenetics, these studies are becoming more common.^23-26

Continue to: Limited evidence from studies of commercially available tests

Several pharmacogenetic tests are commercially available, including some that focus on providing information that can be used specifically when prescribing psychiatric medications, such as the GeneSight Psychotropic test, CNSdose, Genomind, and Neuropharmagen.

In an industry-sponsored, nonrandomized clinical trial that included patients for whom prescribing decisions were made based on the GeneSight test, outcomes in adults were improved compared with treatment as usual,²⁷ inpatient stays were shorter,²⁸ and pharmacy costs were reduced.²⁹ In one of these studies, the authors noted that the traditional, single-gene analysis was not associated with improved outcomes, whereas the multiple gene combination (pharmacokinetic and pharmacodynamic genes) was associated with improved outcomes among patients with depression.²⁷ However, when GeneSightwas compared with treatment as usual in a small randomized trial, there was not a significant association between use of the test and improved outcomes among patients with treatment-resistant depression.³⁰ The results of a much larger randomized trial (N = 1,167) are available³¹ and expected to be published, but patients younger than age 18 were excluded from this study.³² A retrospective study conducted in adult psychiatric patients found that patients whose treatment followed recommendations of a pharmacogenetic test including 20 genes were almost 4 times more likely to improve than patients whose treatment did not follow the recommendations.³³

Pharmacogenetic testing at our pediatric inpatient unit

The Cincinnati Children’s Division of Child and Adolescent Psychiatry is the largest psychiatric inpatient service in a U.S. pediatric hospital. Starting in 2004, we adopted pharmacogenetically-guided dosing of psychiatric medications.³⁴ CYP2D6 and CYP2C19 were chosen for testing because the enzymes encoded by these genes metabolize many of the antidepressants and antipsychotics that patients admitted to our unit will receive, and the clinicians wanted all available tools to help improve the care of these patients. To date, the Genetic Pharmacology Service (GPS) has performed >25,000 tests for variants in CYP2D6 and CYP2C19 as part of inpatient care. Patients provide a specimen (blood or buccal swab) at the time of admission to inpatient psychiatry, genotyping is performed onsite by the Molecular Genetics Laboratory (certified by the College of American Pathologists [CAP]/Clinical Laboratory Improvement Amendments [CLIA]) and the results are posted to the medical record within 2 business days. The report contains the patient’s alleles for CYP2D6 and CYP2C19, the genotype-predicted metabolizer phenotype, and dosing recommendations for 19 drugs (provided as a percentage of the standard dose). Insurance is billed for the test, and reimbursement is usually received when the test is performed as part of an inpatient stay.

The GPS team performed a retrospective chart review after the first panel was implemented in 2005.²³ The study included 279 patients who were receiving a medication metabolized by one of the 2 genes tested. The poor metabolizers had the highest efficacy and highest number of adverse drug reactions, while ultra-rapid metabolizers had the lowest efficacy and lowest number of adverse reactions during their initial inpatient stay. In patients not treated with medications metabolized by CYP2D6 or CYP2C19, there was no association between metabolizer status and efficacy or adverse drug reactions. In this retrospective study, there was no association between metabolizer status and length of stay.

Overcoming the challenges

One challenge with many of the pharmacogenetic tests is interpretation of the results. The reports can span more than 20 pages, and clinicians may not have time to thoroughly read and understand how best to use all of this information. Sometimes the reports can make it seem like the first-line medication for the patient’s condition is not the best choice, but it could work well when dosed appropriately based on the patient’s genotype. Each commercially available test has a different way of presenting results,¹³ so when choosing a pharmacogenetic test, one should be sure to see a sample report. Vo et al³⁵ recently reviewed factors to consider when choosing a pharmacogenetic test.

Continue to: Because patients and families also have difficulty understanding the reports...

Because patients and families also have difficulty understanding the reports, we created patient education sheets,³⁶ written at an eighth grade level with feedback from parents and modeled on those provided by St. Jude Children’s Research Hospital.³⁷ St. Jude Children’s Research Hospital also has pharmacogenetic competencies that pharmacists and nurses must pass.^38,39 The following is a sample explanation that one of our nurses uses to educate parents on what is being tested and what effect the results will have on the treatment plan.

“During your child’s stay we will be completing a genetic test to help us understand how he/she processes the types of medications that we may be likely to start during their hospitalization. This does not tell us which medication will be best—unfortunately within the field of psychiatry there is still some unavoidable trial and error; rather, what it will do is tell us how to make sure that the dosing is at a level that would be safe for the way your child’s body breaks down the medicine, so that he/she can get the intended benefit of the medicine’s effects, while decreasing the risk of uncomfortable side effects, where possible.”

Other challenges in pharmacogenetic testing are the cost, disease risk, and concern about how genetic information will be used. Because these tests are often not covered by health insurance, some commercial pharmacogenetic testing companies offer an out-of-pocket maximum in the $250 to $350 range to reduce the cost to the patient. Some pharmacogenetic testing companies also test for genes associated with disease, so if a clinician orders the test, he or she may be responsible for sharing that information with the patient. For most pharmacogenetic testing companies, the turn-around time is 2 to 10 days. Genetic information is protected by federal laws, including Genetic Information Nondiscrimination Act (GINA) and Health Insurance Portability and Accountability Act (HIPAA).

The choice of psychotropic medication is complex, and although we would like pharmacogenetics to be the only answer to why every patient does or does not respond to a medication, it is not. Response to medication is influenced by age, comorbidities, illness severity, illness duration, compliance, gender, concomitant medications, and potentially more.⁴⁰ Pharmacogenetics is another tool at the clinician’s disposal to help in choosing a medication and dose. There is a clear association between CYP2D6 and CYP2C19 and exposure to many antidepressants and antipsychotics (reviewed by Stingl et al³); however, the link between exposure and response is much weaker. It may be strengthened by the inclusion of pharmacodynamic information (the level of expression of the drug target), which can be influenced by genetic variants.⁴¹ At the present time, the most evidence exists for testing CYP2D6 and CYP2C19, and the CPIC^4,5,15 and DWPG⁶ guidelines provide evidence-based recommendations for how to adjust medication dosages based on the results.

There is clearly much more research that needs to be done in the field of neuropsychi­atric pharmacogenetics, especially in pediatric populations. As we see increased utilization of pharmacogenetic tests in psychiatry, there is also a need for pharmaco­genetic education of patients, families, nurses, pharmacists, and psychiatrists. Several good pharmacogenetic resources that contain up-to-date summaries of the available evidence linking pharmacogenetic variants to medication response, implementation resources, and educational resources are available. These include CPIC (www.cpicpgx.org), PharmGKB (www.pharmgkb.org), and the IGNITE Spark Toolbox (https://ignite-genomics.org/spark-toolbox/clinicians/).

Acknowledgements

The author thanks Jen Milau, APRN, for the case study and sample explanation, and Jeffrey Strawn, MD, FAACP, Ethan Poweleit, and Stacey Aldrich, MS, for help with preparing this manuscript.

The use of pharmacogenetic testing to help drive decisions for medication management of patients with psychiatric illnesses is growing. It’s becoming increasingly common for patients or the parents of pediatric patients to request pharmacogenetic testing or to bring the results of prior testing to their appointment. In these situations, patients may ask clinicians to consider the recommendations from these testing reports, which rarely provide guidance specific to pediatric patients. However, this can be difficult for clinicians who did not receive education in pharmacogenetics and may not be familiar with the evidence or options for pharmacogenetic testing. Many of the pharmacogenetic associations identified thus far have been discovered in adults, but studies in pediatric patients are relatively rare. This article reviews pharmacogenetic testing and the evidence supporting it, and describes implementation of routine pharmacogenetics testing at a children’s hospital.

CASE
Testing leads to dose adjustment, improvement

Ms. R, age 16, presents with treatment-resistant major depressive disorder that is characterized by a significant neurovegetative burden and prominent anhedonia, as well as intermittent suicidal ideation without intent or plan. She reportedly did not improve after multiple medication trials, including citalopram (maximum dose 30 mg/d, treatment duration 8 weeks, good compliance), sertraline (maximum dose 150 mg/d, treatment duration 10 weeks, good compliance), fluoxetine (maximum dose 40 mg/d, treatment duration 8 weeks, good compliance, mild improvement in neurovegetative symptoms and depressed mood), and duloxetine (maximum dose 90 mg/d, treatment duration 6 weeks, good compliance, mild benefit but intolerable nausea).

Augmentation strategies included risperidone, 1 mg/d at bedtime, but it failed to ameliorate her depressive symptoms. At the time of pharmacogenetic testing, she is taking aripiprazole, 2 mg/d at bedtime, and venlafaxine ER, 37.5 mg/d. Some benefit was noted, but her symptoms recrudesced within several weeks. Because both of these medications are metabolized by the cytochrome P450 (CYP) 2D6 enzyme, Ms. R is tested for CYP2D6 variants and is determined to be a CYP2D6 ultra-rapid metabolizer. Her venlafaxine ER is quickly titrated from 37.5 to 112.5 mg/d and aripiprazole is titrated from 2 to 10 mg/d. The patient’s anergia, amotivation, and mood improve.

_

Drug metabolism and genetic variants

It is common for patients with psychiatric disorders to receive trials of multiple psychotropic medications prior to identifying one that reduces symptom burden without producing intolerable adverse effects. Due to the high frequency of toxicity-related adverse effects (observed in 20% to 70% of patients),¹ these medications are frequently initiated at low doses and titrated slowly until the patient either experiences an intolerable adverse effect or achieves symptomatic remission.^1,2 The practice of slow titration at the start of treatment increases the risk of undertreatment in many patients, and may ultimately lead to a medication change due to the lack of response.

Many of the medications used to treat psychiatric illnesses are primarily metabolized by 2 CYP enzymes expressed in the liver, encoded by the CYP2D6 and CYP2C19 genes³ (Table 1^3-7 and Table 2^3,6,7). These drug-metabolizing enzymes affect the pharmacokinetics of many medications. Some medications are converted to an active form by these enzymes, and some are inactivated. The contributions of CYP enzymes to the pharmacokinetics of neuro­psychiatric medications have been well-described; however, there is less evidence on whether variants in these genes are associated with treatment efficacy, especially in pediatric patients.^8,9 CYP2D6 enzyme activity reaches adult levels soon after birth, but children may have higher CYP2C19 activity than adults.⁴ CYP3A4 also contributes to the metabolism of many medications; however, there is only weak evidence that genetic variants in CYP3A4 contribute to variability in the pharmacokinetics of these medications, and there are currently no dosing guidelines based on pharmacogenetics available for this gene.¹⁰

As is common in the pharmacogenetic field, genotypes are denoted with a “star allele” (eg, *2) rather than positional nomenclature (eg, c.681G>A). The normal allele is usually designated as *1, and this result is given in the absence of the tested alleles. There is no consensus on the minimum set of alleles to be tested for most genes,¹¹ so commercially available tests vary widely in what alleles are tested (and therefore what they exclude before calling a normal allele).¹² The metabolizer phenotype for a patient is determined by taking into account the activity of each of the patient’s 2 alleles (eg, *1/*2). A patient is categorized as a poor-, intermediate-, normal- (extensive-), or ultra-rapid metabolizer. Generally, the allele definitions are widely agreed upon (what genetic variant or variants comprise the *2 allele) due to nomenclature committees for each gene; however, because there are no standards for interpretation, the interpretation of the activity of the alleles and conversion to metabolizer phenotype varies among clinics.¹³

Continue to: Guidelines help with genotype-guided dosing

Each CPIC guideline specifically addresses use in pediatric patients, indicating that there are relatively few studies in pediatrics, but “it may be appropriate to extrapolate these recommendations to adolescents or possibly younger children with close monitoring.”⁴ The DPWG guidelines do not mention whether or not the recommendations are applicable to children. Neither CPIC nor the DPWG provides guidance on when to test; however, the French National Network of Pharmacogenetics (Réseau national de pharmacogénétique) recommends CYP2D6 and CYP2C19 genotyping before initiating antidepressant treatment, especially in patients with a high risk of toxicity.¹⁶

In the case above, Ms. R was determined to be a CYP2D6 ultra-rapid metabolizer. Because she showed some initial response to aripiprazole and venlafaxine ER, which are both metabolized by CYP2D6, these medications were very quickly titrated up, and the increased dosages produced the desired response. Venlafaxine is metabolized to the active metabolite O-desmethylvenlafaxine by CYP2D6. The DPWG recommends increasing the dose of venlafaxine in CYP2D6 ultra-rapid metabolizers to 150% of the normal dose based on the decreased serum concentrations of venlafaxine and O-desmethylvenlafaxine in these patients.⁶ Aripiprazole is also metabolized by CYP2D6; however, the FDA and DPWG give no recommendations for ultra-rapid metabolizers, but do recommend reducing the dose of aripiprazole in CYP2D6 poor metabolizers.

Multiple studies in adults have analyzed the association between pharmacokinetic (CYP2D6 and CYP2C19) or pharmacodynamic genes (SLC6A4, HTR2A, and GRIK4) and outcomes,¹⁷ including some large clinical trials that conducted genome-wide association studies^18-20 and meta-analyses across multiple studies.^21,22 Most pharmacogenetic studies in psychiatric patients are small, and very few have included pediatric patients. However, with more interest in neuropsychiatric pharmacogenetics, these studies are becoming more common.^23-26

Continue to: Limited evidence from studies of commercially available tests

Several pharmacogenetic tests are commercially available, including some that focus on providing information that can be used specifically when prescribing psychiatric medications, such as the GeneSight Psychotropic test, CNSdose, Genomind, and Neuropharmagen.

In an industry-sponsored, nonrandomized clinical trial that included patients for whom prescribing decisions were made based on the GeneSight test, outcomes in adults were improved compared with treatment as usual,²⁷ inpatient stays were shorter,²⁸ and pharmacy costs were reduced.²⁹ In one of these studies, the authors noted that the traditional, single-gene analysis was not associated with improved outcomes, whereas the multiple gene combination (pharmacokinetic and pharmacodynamic genes) was associated with improved outcomes among patients with depression.²⁷ However, when GeneSightwas compared with treatment as usual in a small randomized trial, there was not a significant association between use of the test and improved outcomes among patients with treatment-resistant depression.³⁰ The results of a much larger randomized trial (N = 1,167) are available³¹ and expected to be published, but patients younger than age 18 were excluded from this study.³² A retrospective study conducted in adult psychiatric patients found that patients whose treatment followed recommendations of a pharmacogenetic test including 20 genes were almost 4 times more likely to improve than patients whose treatment did not follow the recommendations.³³

Pharmacogenetic testing at our pediatric inpatient unit

The Cincinnati Children’s Division of Child and Adolescent Psychiatry is the largest psychiatric inpatient service in a U.S. pediatric hospital. Starting in 2004, we adopted pharmacogenetically-guided dosing of psychiatric medications.³⁴ CYP2D6 and CYP2C19 were chosen for testing because the enzymes encoded by these genes metabolize many of the antidepressants and antipsychotics that patients admitted to our unit will receive, and the clinicians wanted all available tools to help improve the care of these patients. To date, the Genetic Pharmacology Service (GPS) has performed >25,000 tests for variants in CYP2D6 and CYP2C19 as part of inpatient care. Patients provide a specimen (blood or buccal swab) at the time of admission to inpatient psychiatry, genotyping is performed onsite by the Molecular Genetics Laboratory (certified by the College of American Pathologists [CAP]/Clinical Laboratory Improvement Amendments [CLIA]) and the results are posted to the medical record within 2 business days. The report contains the patient’s alleles for CYP2D6 and CYP2C19, the genotype-predicted metabolizer phenotype, and dosing recommendations for 19 drugs (provided as a percentage of the standard dose). Insurance is billed for the test, and reimbursement is usually received when the test is performed as part of an inpatient stay.

The GPS team performed a retrospective chart review after the first panel was implemented in 2005.²³ The study included 279 patients who were receiving a medication metabolized by one of the 2 genes tested. The poor metabolizers had the highest efficacy and highest number of adverse drug reactions, while ultra-rapid metabolizers had the lowest efficacy and lowest number of adverse reactions during their initial inpatient stay. In patients not treated with medications metabolized by CYP2D6 or CYP2C19, there was no association between metabolizer status and efficacy or adverse drug reactions. In this retrospective study, there was no association between metabolizer status and length of stay.

Overcoming the challenges

One challenge with many of the pharmacogenetic tests is interpretation of the results. The reports can span more than 20 pages, and clinicians may not have time to thoroughly read and understand how best to use all of this information. Sometimes the reports can make it seem like the first-line medication for the patient’s condition is not the best choice, but it could work well when dosed appropriately based on the patient’s genotype. Each commercially available test has a different way of presenting results,¹³ so when choosing a pharmacogenetic test, one should be sure to see a sample report. Vo et al³⁵ recently reviewed factors to consider when choosing a pharmacogenetic test.

Continue to: Because patients and families also have difficulty understanding the reports...

Because patients and families also have difficulty understanding the reports, we created patient education sheets,³⁶ written at an eighth grade level with feedback from parents and modeled on those provided by St. Jude Children’s Research Hospital.³⁷ St. Jude Children’s Research Hospital also has pharmacogenetic competencies that pharmacists and nurses must pass.^38,39 The following is a sample explanation that one of our nurses uses to educate parents on what is being tested and what effect the results will have on the treatment plan.

“During your child’s stay we will be completing a genetic test to help us understand how he/she processes the types of medications that we may be likely to start during their hospitalization. This does not tell us which medication will be best—unfortunately within the field of psychiatry there is still some unavoidable trial and error; rather, what it will do is tell us how to make sure that the dosing is at a level that would be safe for the way your child’s body breaks down the medicine, so that he/she can get the intended benefit of the medicine’s effects, while decreasing the risk of uncomfortable side effects, where possible.”

Other challenges in pharmacogenetic testing are the cost, disease risk, and concern about how genetic information will be used. Because these tests are often not covered by health insurance, some commercial pharmacogenetic testing companies offer an out-of-pocket maximum in the $250 to $350 range to reduce the cost to the patient. Some pharmacogenetic testing companies also test for genes associated with disease, so if a clinician orders the test, he or she may be responsible for sharing that information with the patient. For most pharmacogenetic testing companies, the turn-around time is 2 to 10 days. Genetic information is protected by federal laws, including Genetic Information Nondiscrimination Act (GINA) and Health Insurance Portability and Accountability Act (HIPAA).

The choice of psychotropic medication is complex, and although we would like pharmacogenetics to be the only answer to why every patient does or does not respond to a medication, it is not. Response to medication is influenced by age, comorbidities, illness severity, illness duration, compliance, gender, concomitant medications, and potentially more.⁴⁰ Pharmacogenetics is another tool at the clinician’s disposal to help in choosing a medication and dose. There is a clear association between CYP2D6 and CYP2C19 and exposure to many antidepressants and antipsychotics (reviewed by Stingl et al³); however, the link between exposure and response is much weaker. It may be strengthened by the inclusion of pharmacodynamic information (the level of expression of the drug target), which can be influenced by genetic variants.⁴¹ At the present time, the most evidence exists for testing CYP2D6 and CYP2C19, and the CPIC^4,5,15 and DWPG⁶ guidelines provide evidence-based recommendations for how to adjust medication dosages based on the results.

There is clearly much more research that needs to be done in the field of neuropsychi­atric pharmacogenetics, especially in pediatric populations. As we see increased utilization of pharmacogenetic tests in psychiatry, there is also a need for pharmaco­genetic education of patients, families, nurses, pharmacists, and psychiatrists. Several good pharmacogenetic resources that contain up-to-date summaries of the available evidence linking pharmacogenetic variants to medication response, implementation resources, and educational resources are available. These include CPIC (www.cpicpgx.org), PharmGKB (www.pharmgkb.org), and the IGNITE Spark Toolbox (https://ignite-genomics.org/spark-toolbox/clinicians/).

Acknowledgements

The author thanks Jen Milau, APRN, for the case study and sample explanation, and Jeffrey Strawn, MD, FAACP, Ethan Poweleit, and Stacey Aldrich, MS, for help with preparing this manuscript.

The use of pharmacogenetic testing to help drive decisions for medication management of patients with psychiatric illnesses is growing. It’s becoming increasingly common for patients or the parents of pediatric patients to request pharmacogenetic testing or to bring the results of prior testing to their appointment. In these situations, patients may ask clinicians to consider the recommendations from these testing reports, which rarely provide guidance specific to pediatric patients. However, this can be difficult for clinicians who did not receive education in pharmacogenetics and may not be familiar with the evidence or options for pharmacogenetic testing. Many of the pharmacogenetic associations identified thus far have been discovered in adults, but studies in pediatric patients are relatively rare. This article reviews pharmacogenetic testing and the evidence supporting it, and describes implementation of routine pharmacogenetics testing at a children’s hospital.

CASE
Testing leads to dose adjustment, improvement

Ms. R, age 16, presents with treatment-resistant major depressive disorder that is characterized by a significant neurovegetative burden and prominent anhedonia, as well as intermittent suicidal ideation without intent or plan. She reportedly did not improve after multiple medication trials, including citalopram (maximum dose 30 mg/d, treatment duration 8 weeks, good compliance), sertraline (maximum dose 150 mg/d, treatment duration 10 weeks, good compliance), fluoxetine (maximum dose 40 mg/d, treatment duration 8 weeks, good compliance, mild improvement in neurovegetative symptoms and depressed mood), and duloxetine (maximum dose 90 mg/d, treatment duration 6 weeks, good compliance, mild benefit but intolerable nausea).

Augmentation strategies included risperidone, 1 mg/d at bedtime, but it failed to ameliorate her depressive symptoms. At the time of pharmacogenetic testing, she is taking aripiprazole, 2 mg/d at bedtime, and venlafaxine ER, 37.5 mg/d. Some benefit was noted, but her symptoms recrudesced within several weeks. Because both of these medications are metabolized by the cytochrome P450 (CYP) 2D6 enzyme, Ms. R is tested for CYP2D6 variants and is determined to be a CYP2D6 ultra-rapid metabolizer. Her venlafaxine ER is quickly titrated from 37.5 to 112.5 mg/d and aripiprazole is titrated from 2 to 10 mg/d. The patient’s anergia, amotivation, and mood improve.

_

Drug metabolism and genetic variants

It is common for patients with psychiatric disorders to receive trials of multiple psychotropic medications prior to identifying one that reduces symptom burden without producing intolerable adverse effects. Due to the high frequency of toxicity-related adverse effects (observed in 20% to 70% of patients),¹ these medications are frequently initiated at low doses and titrated slowly until the patient either experiences an intolerable adverse effect or achieves symptomatic remission.^1,2 The practice of slow titration at the start of treatment increases the risk of undertreatment in many patients, and may ultimately lead to a medication change due to the lack of response.

Many of the medications used to treat psychiatric illnesses are primarily metabolized by 2 CYP enzymes expressed in the liver, encoded by the CYP2D6 and CYP2C19 genes³ (Table 1^3-7 and Table 2^3,6,7). These drug-metabolizing enzymes affect the pharmacokinetics of many medications. Some medications are converted to an active form by these enzymes, and some are inactivated. The contributions of CYP enzymes to the pharmacokinetics of neuro­psychiatric medications have been well-described; however, there is less evidence on whether variants in these genes are associated with treatment efficacy, especially in pediatric patients.^8,9 CYP2D6 enzyme activity reaches adult levels soon after birth, but children may have higher CYP2C19 activity than adults.⁴ CYP3A4 also contributes to the metabolism of many medications; however, there is only weak evidence that genetic variants in CYP3A4 contribute to variability in the pharmacokinetics of these medications, and there are currently no dosing guidelines based on pharmacogenetics available for this gene.¹⁰

As is common in the pharmacogenetic field, genotypes are denoted with a “star allele” (eg, *2) rather than positional nomenclature (eg, c.681G>A). The normal allele is usually designated as *1, and this result is given in the absence of the tested alleles. There is no consensus on the minimum set of alleles to be tested for most genes,¹¹ so commercially available tests vary widely in what alleles are tested (and therefore what they exclude before calling a normal allele).¹² The metabolizer phenotype for a patient is determined by taking into account the activity of each of the patient’s 2 alleles (eg, *1/*2). A patient is categorized as a poor-, intermediate-, normal- (extensive-), or ultra-rapid metabolizer. Generally, the allele definitions are widely agreed upon (what genetic variant or variants comprise the *2 allele) due to nomenclature committees for each gene; however, because there are no standards for interpretation, the interpretation of the activity of the alleles and conversion to metabolizer phenotype varies among clinics.¹³

Continue to: Guidelines help with genotype-guided dosing

Each CPIC guideline specifically addresses use in pediatric patients, indicating that there are relatively few studies in pediatrics, but “it may be appropriate to extrapolate these recommendations to adolescents or possibly younger children with close monitoring.”⁴ The DPWG guidelines do not mention whether or not the recommendations are applicable to children. Neither CPIC nor the DPWG provides guidance on when to test; however, the French National Network of Pharmacogenetics (Réseau national de pharmacogénétique) recommends CYP2D6 and CYP2C19 genotyping before initiating antidepressant treatment, especially in patients with a high risk of toxicity.¹⁶

In the case above, Ms. R was determined to be a CYP2D6 ultra-rapid metabolizer. Because she showed some initial response to aripiprazole and venlafaxine ER, which are both metabolized by CYP2D6, these medications were very quickly titrated up, and the increased dosages produced the desired response. Venlafaxine is metabolized to the active metabolite O-desmethylvenlafaxine by CYP2D6. The DPWG recommends increasing the dose of venlafaxine in CYP2D6 ultra-rapid metabolizers to 150% of the normal dose based on the decreased serum concentrations of venlafaxine and O-desmethylvenlafaxine in these patients.⁶ Aripiprazole is also metabolized by CYP2D6; however, the FDA and DPWG give no recommendations for ultra-rapid metabolizers, but do recommend reducing the dose of aripiprazole in CYP2D6 poor metabolizers.

Multiple studies in adults have analyzed the association between pharmacokinetic (CYP2D6 and CYP2C19) or pharmacodynamic genes (SLC6A4, HTR2A, and GRIK4) and outcomes,¹⁷ including some large clinical trials that conducted genome-wide association studies^18-20 and meta-analyses across multiple studies.^21,22 Most pharmacogenetic studies in psychiatric patients are small, and very few have included pediatric patients. However, with more interest in neuropsychiatric pharmacogenetics, these studies are becoming more common.^23-26

Continue to: Limited evidence from studies of commercially available tests

Several pharmacogenetic tests are commercially available, including some that focus on providing information that can be used specifically when prescribing psychiatric medications, such as the GeneSight Psychotropic test, CNSdose, Genomind, and Neuropharmagen.

In an industry-sponsored, nonrandomized clinical trial that included patients for whom prescribing decisions were made based on the GeneSight test, outcomes in adults were improved compared with treatment as usual,²⁷ inpatient stays were shorter,²⁸ and pharmacy costs were reduced.²⁹ In one of these studies, the authors noted that the traditional, single-gene analysis was not associated with improved outcomes, whereas the multiple gene combination (pharmacokinetic and pharmacodynamic genes) was associated with improved outcomes among patients with depression.²⁷ However, when GeneSightwas compared with treatment as usual in a small randomized trial, there was not a significant association between use of the test and improved outcomes among patients with treatment-resistant depression.³⁰ The results of a much larger randomized trial (N = 1,167) are available³¹ and expected to be published, but patients younger than age 18 were excluded from this study.³² A retrospective study conducted in adult psychiatric patients found that patients whose treatment followed recommendations of a pharmacogenetic test including 20 genes were almost 4 times more likely to improve than patients whose treatment did not follow the recommendations.³³

Pharmacogenetic testing at our pediatric inpatient unit

The Cincinnati Children’s Division of Child and Adolescent Psychiatry is the largest psychiatric inpatient service in a U.S. pediatric hospital. Starting in 2004, we adopted pharmacogenetically-guided dosing of psychiatric medications.³⁴ CYP2D6 and CYP2C19 were chosen for testing because the enzymes encoded by these genes metabolize many of the antidepressants and antipsychotics that patients admitted to our unit will receive, and the clinicians wanted all available tools to help improve the care of these patients. To date, the Genetic Pharmacology Service (GPS) has performed >25,000 tests for variants in CYP2D6 and CYP2C19 as part of inpatient care. Patients provide a specimen (blood or buccal swab) at the time of admission to inpatient psychiatry, genotyping is performed onsite by the Molecular Genetics Laboratory (certified by the College of American Pathologists [CAP]/Clinical Laboratory Improvement Amendments [CLIA]) and the results are posted to the medical record within 2 business days. The report contains the patient’s alleles for CYP2D6 and CYP2C19, the genotype-predicted metabolizer phenotype, and dosing recommendations for 19 drugs (provided as a percentage of the standard dose). Insurance is billed for the test, and reimbursement is usually received when the test is performed as part of an inpatient stay.

The GPS team performed a retrospective chart review after the first panel was implemented in 2005.²³ The study included 279 patients who were receiving a medication metabolized by one of the 2 genes tested. The poor metabolizers had the highest efficacy and highest number of adverse drug reactions, while ultra-rapid metabolizers had the lowest efficacy and lowest number of adverse reactions during their initial inpatient stay. In patients not treated with medications metabolized by CYP2D6 or CYP2C19, there was no association between metabolizer status and efficacy or adverse drug reactions. In this retrospective study, there was no association between metabolizer status and length of stay.

Overcoming the challenges

One challenge with many of the pharmacogenetic tests is interpretation of the results. The reports can span more than 20 pages, and clinicians may not have time to thoroughly read and understand how best to use all of this information. Sometimes the reports can make it seem like the first-line medication for the patient’s condition is not the best choice, but it could work well when dosed appropriately based on the patient’s genotype. Each commercially available test has a different way of presenting results,¹³ so when choosing a pharmacogenetic test, one should be sure to see a sample report. Vo et al³⁵ recently reviewed factors to consider when choosing a pharmacogenetic test.

Continue to: Because patients and families also have difficulty understanding the reports...

Because patients and families also have difficulty understanding the reports, we created patient education sheets,³⁶ written at an eighth grade level with feedback from parents and modeled on those provided by St. Jude Children’s Research Hospital.³⁷ St. Jude Children’s Research Hospital also has pharmacogenetic competencies that pharmacists and nurses must pass.^38,39 The following is a sample explanation that one of our nurses uses to educate parents on what is being tested and what effect the results will have on the treatment plan.

“During your child’s stay we will be completing a genetic test to help us understand how he/she processes the types of medications that we may be likely to start during their hospitalization. This does not tell us which medication will be best—unfortunately within the field of psychiatry there is still some unavoidable trial and error; rather, what it will do is tell us how to make sure that the dosing is at a level that would be safe for the way your child’s body breaks down the medicine, so that he/she can get the intended benefit of the medicine’s effects, while decreasing the risk of uncomfortable side effects, where possible.”

Other challenges in pharmacogenetic testing are the cost, disease risk, and concern about how genetic information will be used. Because these tests are often not covered by health insurance, some commercial pharmacogenetic testing companies offer an out-of-pocket maximum in the $250 to $350 range to reduce the cost to the patient. Some pharmacogenetic testing companies also test for genes associated with disease, so if a clinician orders the test, he or she may be responsible for sharing that information with the patient. For most pharmacogenetic testing companies, the turn-around time is 2 to 10 days. Genetic information is protected by federal laws, including Genetic Information Nondiscrimination Act (GINA) and Health Insurance Portability and Accountability Act (HIPAA).

The choice of psychotropic medication is complex, and although we would like pharmacogenetics to be the only answer to why every patient does or does not respond to a medication, it is not. Response to medication is influenced by age, comorbidities, illness severity, illness duration, compliance, gender, concomitant medications, and potentially more.⁴⁰ Pharmacogenetics is another tool at the clinician’s disposal to help in choosing a medication and dose. There is a clear association between CYP2D6 and CYP2C19 and exposure to many antidepressants and antipsychotics (reviewed by Stingl et al³); however, the link between exposure and response is much weaker. It may be strengthened by the inclusion of pharmacodynamic information (the level of expression of the drug target), which can be influenced by genetic variants.⁴¹ At the present time, the most evidence exists for testing CYP2D6 and CYP2C19, and the CPIC^4,5,15 and DWPG⁶ guidelines provide evidence-based recommendations for how to adjust medication dosages based on the results.

There is clearly much more research that needs to be done in the field of neuropsychi­atric pharmacogenetics, especially in pediatric populations. As we see increased utilization of pharmacogenetic tests in psychiatry, there is also a need for pharmaco­genetic education of patients, families, nurses, pharmacists, and psychiatrists. Several good pharmacogenetic resources that contain up-to-date summaries of the available evidence linking pharmacogenetic variants to medication response, implementation resources, and educational resources are available. These include CPIC (www.cpicpgx.org), PharmGKB (www.pharmgkb.org), and the IGNITE Spark Toolbox (https://ignite-genomics.org/spark-toolbox/clinicians/).

Acknowledgements

The author thanks Jen Milau, APRN, for the case study and sample explanation, and Jeffrey Strawn, MD, FAACP, Ethan Poweleit, and Stacey Aldrich, MS, for help with preparing this manuscript.

Photo courtesy of Janssen

The European Commission (EC) has approved a new indication for daratumumab (Darzalex®).

The drug is now authorized for use in combination with bortezomib, melphalan, and prednisone (VMP) to treat adults with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplant.

Daratumumab was previously approved by the EC for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, to treat adults with MM who have received at least one prior therapy.

In addition, daratumumab is EC-approved as monotherapy for adults with relapsed and refractory MM whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on their last therapy.

The EC’s latest approval for daratumumab is based on results from the phase 3 ALCYONE (MMY3007) study.

Results from this study were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.

ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant. Patients were randomized to receive VMP or daratumumab plus VMP (D-VMP).

The overall response rates were 91% in the D-VMP arm and 74% in the VMP arm (P<0.0001). Rates of complete response were 43% and 24%, respectively. Rates of minimal residual disease negativity were 22% and 6%, respectively.

The median progression-free survival (PFS) was not reached in the D-VMP arm and was 18.1 months in the VMP arm. The 12-month PFS was 87% and 76%, respectively. The 18-month PFS was 72% and 50%, respectively.

The most common treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).

Infusion-related reactions occurred in 28% of patients in the D-VMP arm and 0% of those in the VMP arm.

The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. In both arms, most infections resolved.

The most common grade 3/4 treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).

The rate of discontinuation due to adverse events was 5% in the D-VMP arm and 9% in the VMP arm.

Photo courtesy of Janssen

The European Commission (EC) has approved a new indication for daratumumab (Darzalex®).

The drug is now authorized for use in combination with bortezomib, melphalan, and prednisone (VMP) to treat adults with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplant.

Daratumumab was previously approved by the EC for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, to treat adults with MM who have received at least one prior therapy.

In addition, daratumumab is EC-approved as monotherapy for adults with relapsed and refractory MM whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on their last therapy.

The EC’s latest approval for daratumumab is based on results from the phase 3 ALCYONE (MMY3007) study.

Results from this study were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.

ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant. Patients were randomized to receive VMP or daratumumab plus VMP (D-VMP).

The overall response rates were 91% in the D-VMP arm and 74% in the VMP arm (P<0.0001). Rates of complete response were 43% and 24%, respectively. Rates of minimal residual disease negativity were 22% and 6%, respectively.

The median progression-free survival (PFS) was not reached in the D-VMP arm and was 18.1 months in the VMP arm. The 12-month PFS was 87% and 76%, respectively. The 18-month PFS was 72% and 50%, respectively.

The most common treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).

Infusion-related reactions occurred in 28% of patients in the D-VMP arm and 0% of those in the VMP arm.

The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. In both arms, most infections resolved.

The most common grade 3/4 treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).

The rate of discontinuation due to adverse events was 5% in the D-VMP arm and 9% in the VMP arm.

Photo courtesy of Janssen

The European Commission (EC) has approved a new indication for daratumumab (Darzalex®).

The drug is now authorized for use in combination with bortezomib, melphalan, and prednisone (VMP) to treat adults with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplant.

Daratumumab was previously approved by the EC for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, to treat adults with MM who have received at least one prior therapy.

In addition, daratumumab is EC-approved as monotherapy for adults with relapsed and refractory MM whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on their last therapy.

The EC’s latest approval for daratumumab is based on results from the phase 3 ALCYONE (MMY3007) study.

Results from this study were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.

ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant. Patients were randomized to receive VMP or daratumumab plus VMP (D-VMP).

The overall response rates were 91% in the D-VMP arm and 74% in the VMP arm (P<0.0001). Rates of complete response were 43% and 24%, respectively. Rates of minimal residual disease negativity were 22% and 6%, respectively.

The median progression-free survival (PFS) was not reached in the D-VMP arm and was 18.1 months in the VMP arm. The 12-month PFS was 87% and 76%, respectively. The 18-month PFS was 72% and 50%, respectively.

The most common treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).

Infusion-related reactions occurred in 28% of patients in the D-VMP arm and 0% of those in the VMP arm.

The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. In both arms, most infections resolved.

The most common grade 3/4 treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).

The rate of discontinuation due to adverse events was 5% in the D-VMP arm and 9% in the VMP arm.

Here are 4 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Alcohol use during breastfeeding linked to cognitive harms in children

To take the posttest, go to: https://bit.ly/2vJyUDc
Expires July 30, 2019

2. Cigarette smoking epidemic among HCV-infected individuals

To take the posttest, go to: https://bit.ly/2B00JwX
Expires June 26, 2019

3. Pancreatic surveillance identified resectable cancers

To take the posttest, go to: https://bit.ly/2vuSKmj
Expires July 30, 2019

4. Autoimmune connective tissue disease predicted by interferon status, family history

To take the posttest, go to: https://bit.ly/2OkZHNS
Expires July 30, 2019

Here are 4 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Alcohol use during breastfeeding linked to cognitive harms in children

To take the posttest, go to: https://bit.ly/2vJyUDc
Expires July 30, 2019

2. Cigarette smoking epidemic among HCV-infected individuals

To take the posttest, go to: https://bit.ly/2B00JwX
Expires June 26, 2019

3. Pancreatic surveillance identified resectable cancers

To take the posttest, go to: https://bit.ly/2vuSKmj
Expires July 30, 2019

4. Autoimmune connective tissue disease predicted by interferon status, family history

To take the posttest, go to: https://bit.ly/2OkZHNS
Expires July 30, 2019

Here are 4 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Alcohol use during breastfeeding linked to cognitive harms in children

To take the posttest, go to: https://bit.ly/2vJyUDc
Expires July 30, 2019

2. Cigarette smoking epidemic among HCV-infected individuals

To take the posttest, go to: https://bit.ly/2B00JwX
Expires June 26, 2019

3. Pancreatic surveillance identified resectable cancers

To take the posttest, go to: https://bit.ly/2vuSKmj
Expires July 30, 2019

4. Autoimmune connective tissue disease predicted by interferon status, family history

To take the posttest, go to: https://bit.ly/2OkZHNS
Expires July 30, 2019

CMS has released its proposed rule (see related articles and a commentary) and included changes as substantial as I have seen in the last two decades. Additionally, the Affordable Care Act has been under continued attack despite its majority support from our citizenry. Loss of the individual mandate, allowance of “skinny” health plans, a rewrite of association plan rules, elimination of cost-sharing reductions and premium support – all have contributed to a shifting away from socialized medical costs and toward a system of individual responsibility for health. Depending on one’s political philosophy (and income), that may be bad or good.

Our article list this month will be interesting to many. The AGA produced a Clinical Practice Update about tumor seeding with endoscopic procedures. This should give us pause and make us reconsider our endoscopic practices. My wife (an endoscopy nurse in Minneapolis) has been asking for years whether pulling a PEG tube past an esophageal cancer might cause tumor seeding, and physicians have reassured her that there is no cause for worry. Turns out she was right (as usual). Deaths from liver disease in the U.S. have seen a dramatic increase since 1999, driven substantially by increasing alcohol use. Fecal transplants in irritable bowel syndrome? Possibly helpful, as reported in an article from Digestive Disease Week.^®

As summer comes to an end, we head into a tumultuous fall that will be dominated by November elections.

John I. Allen, MD, MBA, AGAF
Editor in Chief

CMS has released its proposed rule (see related articles and a commentary) and included changes as substantial as I have seen in the last two decades. Additionally, the Affordable Care Act has been under continued attack despite its majority support from our citizenry. Loss of the individual mandate, allowance of “skinny” health plans, a rewrite of association plan rules, elimination of cost-sharing reductions and premium support – all have contributed to a shifting away from socialized medical costs and toward a system of individual responsibility for health. Depending on one’s political philosophy (and income), that may be bad or good.

Our article list this month will be interesting to many. The AGA produced a Clinical Practice Update about tumor seeding with endoscopic procedures. This should give us pause and make us reconsider our endoscopic practices. My wife (an endoscopy nurse in Minneapolis) has been asking for years whether pulling a PEG tube past an esophageal cancer might cause tumor seeding, and physicians have reassured her that there is no cause for worry. Turns out she was right (as usual). Deaths from liver disease in the U.S. have seen a dramatic increase since 1999, driven substantially by increasing alcohol use. Fecal transplants in irritable bowel syndrome? Possibly helpful, as reported in an article from Digestive Disease Week.^®

As summer comes to an end, we head into a tumultuous fall that will be dominated by November elections.

John I. Allen, MD, MBA, AGAF
Editor in Chief

CMS has released its proposed rule (see related articles and a commentary) and included changes as substantial as I have seen in the last two decades. Additionally, the Affordable Care Act has been under continued attack despite its majority support from our citizenry. Loss of the individual mandate, allowance of “skinny” health plans, a rewrite of association plan rules, elimination of cost-sharing reductions and premium support – all have contributed to a shifting away from socialized medical costs and toward a system of individual responsibility for health. Depending on one’s political philosophy (and income), that may be bad or good.

Our article list this month will be interesting to many. The AGA produced a Clinical Practice Update about tumor seeding with endoscopic procedures. This should give us pause and make us reconsider our endoscopic practices. My wife (an endoscopy nurse in Minneapolis) has been asking for years whether pulling a PEG tube past an esophageal cancer might cause tumor seeding, and physicians have reassured her that there is no cause for worry. Turns out she was right (as usual). Deaths from liver disease in the U.S. have seen a dramatic increase since 1999, driven substantially by increasing alcohol use. Fecal transplants in irritable bowel syndrome? Possibly helpful, as reported in an article from Digestive Disease Week.^®

As summer comes to an end, we head into a tumultuous fall that will be dominated by November elections.

John I. Allen, MD, MBA, AGAF
Editor in Chief

The term “dual diagnosis” describes the clinically challenging comorbidity of a substance use disorder (SUD) along with another major mental illness. Based on data from the Epidemiologic Catchment Area study, the lifetime prevalence of SUDs among patients with mental illness is approximately 30%, and is higher among patients with certain mental disorders, such as schizophrenia (47%), bipolar disorder (61%), and antisocial personality disorder (84%).¹ These statistics highlight that addiction is often the rule rather than the exception among those with severe mental illness.¹ Not surprisingly, the combined effects of having an SUD along with another mental illness are uniformly negative (Table 1^2-4).

Based on outcomes research, the core tenets of evidence-based dual-diagnosis treatment include the importance of integrated (rather than parallel) and simultaneous (rather than sequential) care, which means an ideal treatment program includes a unified, multidisciplinary team whose coordinated efforts focus on treating both disorders concurrently.² Evidence-based psychotherapies for addiction, including motivational interviewing, cognitive-behavioral therapy, relapse prevention, contingency management, skills training, and/or case management, are a necessity,^3,5 and must be balanced with rational and appropriate pharmacotherapy targeting both the SUD as well as the other disorder (Table 2^2,3,5-9).

3 ‘Real-world’ clinical challenges

Ideal vs real-world treatment

Treating patients with co-occurring disorders (CODs) within integrated dual-disorder treatment (IDDT) programs sounds straightforward. However, implementing evidence-based “best practice” treatment is a significant challenge in the real world for several reasons. First, individuals with CODs often struggle with poor insight, low motivation to change, and lack of access to health care. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), 52% of individuals with CODs in the U.S. received no treatment at all in 2016.¹⁰ For patients with dual disorders who do seek care, most are not given access to specialty SUD treatment¹⁰ and may instead find themselves treated by psychiatrists with limited SUD training who fail to provide evidence-based psychotherapies and underutilize pharmacotherapies for SUDs.¹¹ In the setting of CODs, the “harm reduction model” can be conflated with therapeutic nihilism, resulting in the neglect of SUD issues, with clinicians expecting patients to seek SUD treatment on their own, through self-help groups such as Alcoholics Anonymous or in other community treatment programs staffed by nonprofessionals that often are not tailored to the unique needs of patients with dual disorders. Psychiatrists working with other mental health professionals who provide psychotherapy for SUDs often do so in parallel rather than in an evidence-based, integrated fashion.

IDDT programs are not widely available. One study found that fewer than 20% of addiction treatment programs and fewer than 10% of mental health programs in the U.S. met criteria for dual diagnosis–capable services.¹² Getting treatment programs to become dual diagnosis–capable is possible, but it is a time-consuming and costly endeavor that, once achieved, requires continuous staff training and programmatic adaptations to interruptions in funding.^13-16 With myriad barriers to the establishment and maintenance of IDDTs, many patients with dual disorders are left without access to the most effective and comprehensive care; as few as 4% of individuals with CODs are treated within integrated programs.¹⁷

Diagnostic dilemmas

Establishing whether or not a patient with an active SUD has another serious mental illness (SMI) is a crucial first step for optimizing treatment, but diagnostic reliability can prove challenging and requires careful clinical assessment (Table 3). As always in psychiatry, accurate diagnosis is limited to careful clinical assessment¹⁸ and, in the case of possible dual disorders, is complicated by the fact that both SUDs as well as non-SUDs can result in the same psychiatric symptoms (eg, insomnia, anxiety, depression, manic behaviors, and psychosis). Clinicians must therefore distinguish between:

• Symptoms of substance intoxication or withdrawal vs independent symptoms of an underlying psychiatric disorder (that persist beyond a month after cessation of intoxication or withdrawal)
• Subclinical symptoms vs threshold mental illness, keeping in mind that some mood and anxiety states can be normal given social situations and stressors (eg, turmoil in relationships, employment difficulties, homelessness, etc.)
• Any mental illness (AMI) vs SMI. The latter is defined by SAMHSA as AMI that substantially interferes with or limits ≥1 major life activities.¹⁰

With these distinctions in mind, data from the 2016 National Survey on Drug Use and Health indicate that dual-diagnosis comorbidity was higher when the thres­hold for mental illness was lower—among the 19 million adults in the U.S. with SUDs, the past-year prevalence was 43% for AMI and 14% for SMI.¹⁰ Looking at substance-induced disorders vs “independent” disorders, the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions found that for individuals with SUDs, the past-year prevalence of an independent mood or anxiety disorder was 35% and 26%, respectively.¹⁹ Taken together, these findings illustrate the substantial rate of dual-diagnosis comorbidity, the diagnostic heterogeneity and range of severity of CODs,²⁰ and the potential for both false negatives (eg, diagnosing a substance-induced syndrome when in fact a patient has an underlying disorder) and false positives (diagnosing a full-blown mental illness when symptoms are subclinical or substance-induced) when performing diagnostic assessments in the setting of known SUDs.

Continue to: False positives are more likely...

False positives are more likely when patients seeking treatment for non-SUDs don’t disclose active drug use, even when asked. Both patients and their treating clinicians may also be prone to underestimating the significant potential for morbidity associated with SUDs, such that substance-induced symptoms may be misattributed to a dual disorder. Diagnostic questioning and thorough chart review that includes careful assessment of whether psychiatric symptoms preceded the onset of substance use, and whether they persisted in the setting of extended sobriety, is therefore paramount for minimizing false positives when assessing for dual diagnoses.^18,21 Likewise, random urine toxicology testing can be invaluable in verifying claims regarding sobriety.

Another factor that can complicate diagnosis is that there are often considerable secondary gains (eg, disability income, hospitalization, housing, access to prescription medications, and mitigation of the blame and stigma associated with addiction) associated with having a dual disorder as opposed to having “just” a SUD. As a result, for some patients, obtaining a non-SUD diagnosis can be highly incentivized.^22,23 Clinicians must therefore be savvy about the high potential for malingering, embellishment, and mislabeling of symptoms when conducting diagnostic interviews. For example, in assessing for psychosis, the frequent endorsement of “hearing voices” in patients with SUDs often results in a diagnosis of schizophrenia or unspecified psychotic disorder,²² despite the fact that this symptom can occur during substance intoxication and withdrawal, is well documented among people without mental illness as well as those with non-psychotic disorders,²⁴ and can resolve without medications or with non-antipsychotic pharmacotherapy.²⁵

When assessing for dual disorders, diagnostic false positives and false negatives can both contribute to inappropriate treatment and unrealistic expectations for recovery, and therefore underscore the importance of careful diagnostic assessment. Even with diligent assessment, however, diagnostic clarity can prove elusive due to inadequate sobriety, inconsistent reporting, and poor memory.²⁶ Therefore, for patients with known SUDs but diagnostic uncertainty about a dual disorder, the work-up should include a trial of prospective observation, with completion of appropriate detoxification, throughout a 1-month period of sobriety and in the absence of psychiatric medications, to determine if there are persistent symptoms that would justify a dual diagnosis. In research settings, such observations have revealed that most of depressive symptoms among alcoholics who present for substance abuse treatment resolve after a month of abstinence.²⁷ A similar time course for resolution has been noted for anxiety, distress, fatigue, and depressive symptoms among individuals with cocaine dependence.²⁸ These findings support the guideline established in DSM-IV that symptoms persisting beyond a month of sobriety “should be considered to be manifestations of an independent, non-substance-induced mental disorder,”²⁹ while symptoms occurring within that month may well be substance-induced. Unfortunately, in real-world clinical practice, and particularly in outpatient settings, it can be quite difficult to achieve the requisite period of sobriety for reliable diagnosis, and patients are often prematurely prescribed medications (eg, an antidepressant, antipsychotic, or mood stabilizer) that can confound the cause of symptomatic resolution. Such prescriptions are driven by compelling pressures from patients to relieve their acute suffering, as well as the predilection of some clinicians to give patients “the benefit of doubt” in assessing for dual diagnoses. However, whether an inappropriate diagnosis or a prescription for an unnecessary medication represents a benefit is debatable at best.

Pharmacotherapy

A third real-world challenge in managing patients with dual disorders involves optimizing pharmacotherapy. Unfortunately, because patients with SUDs often are excluded from clinical trials, evidence-based guidance for patients with dual disorders is lacking. In addition, medications for both CODs often remain inaccessible to patients with dual disorders for 3 reasons:

• SUDs negatively impact medication adherence among patients with dual disorders, who sometimes point out that “it says right here on the bottle not to take this medication with drugs or alcohol!”
• Some self-help groups still espouse blanket opposition of any “psychotropic” medications, even when clearly indicated for patients with COD. Groups that recognize the importance of pharmacotherapy, such as Dual Diagnosis Anonymous (DDA), have emerged, but are not yet widely available.³⁰
• Although there are increasing options for FDA-approved medications for SUDs, they are limited to the treatment of alcohol, opioid, and nicotine use disorders³¹; are often restricted due to hospital and health insurance formularies³²; and remain underprescribed for patients with dual disorders.¹¹

Continue to: Although underutilization of pharmacotherapy is...

Although underutilization of pharmacotherapy is a pitfall to be avoided in the treatment of patients with dual disorders, medication overutilization can be just as problematic. Patients with dual disorders are sometimes singularly focused on resolving acute anxiety, depression, or psychosis at the expense of working towards sobriety.³³ Although the “self-medication hypothesis” is frequently invoked by patients and clinicians alike to suggest that substance use occurs in the service of “treating” underlying disorders,³⁴ this theory has not been well supported in studies.^35-37 Some patients may pledge dedication to abstinence, but still pressure physicians for a pharmacologic solution to their suffering. With expanding legalization of cannabis for both recreational and medical purposes, patients are increasingly seeking doctors’ recommendations for “medical marijuana” for a wide range of complaints, despite the fact that data supporting a therapeutic role for cannabis in the treatment of mental illness is sparse,³⁸ whereas the potential harm in terms of either causing or worsening psychosis is well established.^39,40 Clinicians must be knowledgeable about the abuse potential of prescribed medications, ranging from sleep aids, analgesics, and muscle relaxants to antidepressants and antipsychotics, while also being mindful of the psychological meaningfulness of seeking, prescribing, and not prescribing medications.⁴¹

Although the simultaneous treatment of patients with dual disorders that includes pharmacotherapy for both SUDs and CODs is vital for optimizing clinical outcomes, clinicians should strive for diagnostic accuracy and use medications judiciously. In addition, although pharmacotherapy often is necessary to deliver evidence-based treatment for patients with dual disorders, it is inadequate as standalone treatment and should be administered along with psychosocial interventions within an integrated, multidisciplinary treatment setting.

The keys to optimal outcomes

The treatment of patients with dual disorders can be challenging, to say the least. Ideal, evidence-based therapy in the form of an IDDT program can be difficult for clinicians to implement and for patients to access. Best efforts to perform meticulous clinical assessment to clarify diagnoses, use pharmacotherapy judiciously, work collaboratively in a multidisciplinary setting, and optimize treatment given available resources are keys to clinical success.

Bottom Line

Ideal treatment of patients with dual disorders consists of simultaneous, integrated interventions delivered by a multidisciplinary team. However, in the real world, limited resources, diagnostic challenges, and both over- and underutilization of pharmacotherapy often hamper optimal treatment.

Related Resources

• Substance Abuse and Mental Health Services Administration. Co-occurring disorders. https://www.samhsa.gov/disorders/co-occurring.
• National Alliance on Mental Illness. Dual diagnosis. https://www.nami.org/Learn-More/Mental-Health-Conditions/Related-Conditions/Dual-Diagnosis.
• Foundations Recovery Network. Dual diagnosis support groups. http://www.dualdiagnosis.org/resource/ddrn/self-helpsupport-groups/support-groups.
• Substance Abuse and Mental Health Services Administration. Integrated treatment for co-occurring disorders evidence-based practices (EBP) KIT. https://store.samhsa.gov/product/Integrated-Treatment-for-Co-Occurring-Disorders-Evidence-Based-Practices-EBP-KIT/SMA08-4367.
• Substance Abuse and Mental Health Services Administration. Substance abuse treatment for persons with co-occurring disorders. https://store.samhsa.gov/shin/content/SMA13-3992/SMA13-3992.pdf.

The term “dual diagnosis” describes the clinically challenging comorbidity of a substance use disorder (SUD) along with another major mental illness. Based on data from the Epidemiologic Catchment Area study, the lifetime prevalence of SUDs among patients with mental illness is approximately 30%, and is higher among patients with certain mental disorders, such as schizophrenia (47%), bipolar disorder (61%), and antisocial personality disorder (84%).¹ These statistics highlight that addiction is often the rule rather than the exception among those with severe mental illness.¹ Not surprisingly, the combined effects of having an SUD along with another mental illness are uniformly negative (Table 1^2-4).

Based on outcomes research, the core tenets of evidence-based dual-diagnosis treatment include the importance of integrated (rather than parallel) and simultaneous (rather than sequential) care, which means an ideal treatment program includes a unified, multidisciplinary team whose coordinated efforts focus on treating both disorders concurrently.² Evidence-based psychotherapies for addiction, including motivational interviewing, cognitive-behavioral therapy, relapse prevention, contingency management, skills training, and/or case management, are a necessity,^3,5 and must be balanced with rational and appropriate pharmacotherapy targeting both the SUD as well as the other disorder (Table 2^2,3,5-9).

3 ‘Real-world’ clinical challenges

Ideal vs real-world treatment

Treating patients with co-occurring disorders (CODs) within integrated dual-disorder treatment (IDDT) programs sounds straightforward. However, implementing evidence-based “best practice” treatment is a significant challenge in the real world for several reasons. First, individuals with CODs often struggle with poor insight, low motivation to change, and lack of access to health care. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), 52% of individuals with CODs in the U.S. received no treatment at all in 2016.¹⁰ For patients with dual disorders who do seek care, most are not given access to specialty SUD treatment¹⁰ and may instead find themselves treated by psychiatrists with limited SUD training who fail to provide evidence-based psychotherapies and underutilize pharmacotherapies for SUDs.¹¹ In the setting of CODs, the “harm reduction model” can be conflated with therapeutic nihilism, resulting in the neglect of SUD issues, with clinicians expecting patients to seek SUD treatment on their own, through self-help groups such as Alcoholics Anonymous or in other community treatment programs staffed by nonprofessionals that often are not tailored to the unique needs of patients with dual disorders. Psychiatrists working with other mental health professionals who provide psychotherapy for SUDs often do so in parallel rather than in an evidence-based, integrated fashion.

IDDT programs are not widely available. One study found that fewer than 20% of addiction treatment programs and fewer than 10% of mental health programs in the U.S. met criteria for dual diagnosis–capable services.¹² Getting treatment programs to become dual diagnosis–capable is possible, but it is a time-consuming and costly endeavor that, once achieved, requires continuous staff training and programmatic adaptations to interruptions in funding.^13-16 With myriad barriers to the establishment and maintenance of IDDTs, many patients with dual disorders are left without access to the most effective and comprehensive care; as few as 4% of individuals with CODs are treated within integrated programs.¹⁷

Diagnostic dilemmas

Establishing whether or not a patient with an active SUD has another serious mental illness (SMI) is a crucial first step for optimizing treatment, but diagnostic reliability can prove challenging and requires careful clinical assessment (Table 3). As always in psychiatry, accurate diagnosis is limited to careful clinical assessment¹⁸ and, in the case of possible dual disorders, is complicated by the fact that both SUDs as well as non-SUDs can result in the same psychiatric symptoms (eg, insomnia, anxiety, depression, manic behaviors, and psychosis). Clinicians must therefore distinguish between:

• Symptoms of substance intoxication or withdrawal vs independent symptoms of an underlying psychiatric disorder (that persist beyond a month after cessation of intoxication or withdrawal)
• Subclinical symptoms vs threshold mental illness, keeping in mind that some mood and anxiety states can be normal given social situations and stressors (eg, turmoil in relationships, employment difficulties, homelessness, etc.)
• Any mental illness (AMI) vs SMI. The latter is defined by SAMHSA as AMI that substantially interferes with or limits ≥1 major life activities.¹⁰

With these distinctions in mind, data from the 2016 National Survey on Drug Use and Health indicate that dual-diagnosis comorbidity was higher when the thres­hold for mental illness was lower—among the 19 million adults in the U.S. with SUDs, the past-year prevalence was 43% for AMI and 14% for SMI.¹⁰ Looking at substance-induced disorders vs “independent” disorders, the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions found that for individuals with SUDs, the past-year prevalence of an independent mood or anxiety disorder was 35% and 26%, respectively.¹⁹ Taken together, these findings illustrate the substantial rate of dual-diagnosis comorbidity, the diagnostic heterogeneity and range of severity of CODs,²⁰ and the potential for both false negatives (eg, diagnosing a substance-induced syndrome when in fact a patient has an underlying disorder) and false positives (diagnosing a full-blown mental illness when symptoms are subclinical or substance-induced) when performing diagnostic assessments in the setting of known SUDs.

Continue to: False positives are more likely...

False positives are more likely when patients seeking treatment for non-SUDs don’t disclose active drug use, even when asked. Both patients and their treating clinicians may also be prone to underestimating the significant potential for morbidity associated with SUDs, such that substance-induced symptoms may be misattributed to a dual disorder. Diagnostic questioning and thorough chart review that includes careful assessment of whether psychiatric symptoms preceded the onset of substance use, and whether they persisted in the setting of extended sobriety, is therefore paramount for minimizing false positives when assessing for dual diagnoses.^18,21 Likewise, random urine toxicology testing can be invaluable in verifying claims regarding sobriety.

Another factor that can complicate diagnosis is that there are often considerable secondary gains (eg, disability income, hospitalization, housing, access to prescription medications, and mitigation of the blame and stigma associated with addiction) associated with having a dual disorder as opposed to having “just” a SUD. As a result, for some patients, obtaining a non-SUD diagnosis can be highly incentivized.^22,23 Clinicians must therefore be savvy about the high potential for malingering, embellishment, and mislabeling of symptoms when conducting diagnostic interviews. For example, in assessing for psychosis, the frequent endorsement of “hearing voices” in patients with SUDs often results in a diagnosis of schizophrenia or unspecified psychotic disorder,²² despite the fact that this symptom can occur during substance intoxication and withdrawal, is well documented among people without mental illness as well as those with non-psychotic disorders,²⁴ and can resolve without medications or with non-antipsychotic pharmacotherapy.²⁵

When assessing for dual disorders, diagnostic false positives and false negatives can both contribute to inappropriate treatment and unrealistic expectations for recovery, and therefore underscore the importance of careful diagnostic assessment. Even with diligent assessment, however, diagnostic clarity can prove elusive due to inadequate sobriety, inconsistent reporting, and poor memory.²⁶ Therefore, for patients with known SUDs but diagnostic uncertainty about a dual disorder, the work-up should include a trial of prospective observation, with completion of appropriate detoxification, throughout a 1-month period of sobriety and in the absence of psychiatric medications, to determine if there are persistent symptoms that would justify a dual diagnosis. In research settings, such observations have revealed that most of depressive symptoms among alcoholics who present for substance abuse treatment resolve after a month of abstinence.²⁷ A similar time course for resolution has been noted for anxiety, distress, fatigue, and depressive symptoms among individuals with cocaine dependence.²⁸ These findings support the guideline established in DSM-IV that symptoms persisting beyond a month of sobriety “should be considered to be manifestations of an independent, non-substance-induced mental disorder,”²⁹ while symptoms occurring within that month may well be substance-induced. Unfortunately, in real-world clinical practice, and particularly in outpatient settings, it can be quite difficult to achieve the requisite period of sobriety for reliable diagnosis, and patients are often prematurely prescribed medications (eg, an antidepressant, antipsychotic, or mood stabilizer) that can confound the cause of symptomatic resolution. Such prescriptions are driven by compelling pressures from patients to relieve their acute suffering, as well as the predilection of some clinicians to give patients “the benefit of doubt” in assessing for dual diagnoses. However, whether an inappropriate diagnosis or a prescription for an unnecessary medication represents a benefit is debatable at best.

Pharmacotherapy

A third real-world challenge in managing patients with dual disorders involves optimizing pharmacotherapy. Unfortunately, because patients with SUDs often are excluded from clinical trials, evidence-based guidance for patients with dual disorders is lacking. In addition, medications for both CODs often remain inaccessible to patients with dual disorders for 3 reasons:

• SUDs negatively impact medication adherence among patients with dual disorders, who sometimes point out that “it says right here on the bottle not to take this medication with drugs or alcohol!”
• Some self-help groups still espouse blanket opposition of any “psychotropic” medications, even when clearly indicated for patients with COD. Groups that recognize the importance of pharmacotherapy, such as Dual Diagnosis Anonymous (DDA), have emerged, but are not yet widely available.³⁰
• Although there are increasing options for FDA-approved medications for SUDs, they are limited to the treatment of alcohol, opioid, and nicotine use disorders³¹; are often restricted due to hospital and health insurance formularies³²; and remain underprescribed for patients with dual disorders.¹¹

Continue to: Although underutilization of pharmacotherapy is...

Although underutilization of pharmacotherapy is a pitfall to be avoided in the treatment of patients with dual disorders, medication overutilization can be just as problematic. Patients with dual disorders are sometimes singularly focused on resolving acute anxiety, depression, or psychosis at the expense of working towards sobriety.³³ Although the “self-medication hypothesis” is frequently invoked by patients and clinicians alike to suggest that substance use occurs in the service of “treating” underlying disorders,³⁴ this theory has not been well supported in studies.^35-37 Some patients may pledge dedication to abstinence, but still pressure physicians for a pharmacologic solution to their suffering. With expanding legalization of cannabis for both recreational and medical purposes, patients are increasingly seeking doctors’ recommendations for “medical marijuana” for a wide range of complaints, despite the fact that data supporting a therapeutic role for cannabis in the treatment of mental illness is sparse,³⁸ whereas the potential harm in terms of either causing or worsening psychosis is well established.^39,40 Clinicians must be knowledgeable about the abuse potential of prescribed medications, ranging from sleep aids, analgesics, and muscle relaxants to antidepressants and antipsychotics, while also being mindful of the psychological meaningfulness of seeking, prescribing, and not prescribing medications.⁴¹

Although the simultaneous treatment of patients with dual disorders that includes pharmacotherapy for both SUDs and CODs is vital for optimizing clinical outcomes, clinicians should strive for diagnostic accuracy and use medications judiciously. In addition, although pharmacotherapy often is necessary to deliver evidence-based treatment for patients with dual disorders, it is inadequate as standalone treatment and should be administered along with psychosocial interventions within an integrated, multidisciplinary treatment setting.

The keys to optimal outcomes

The treatment of patients with dual disorders can be challenging, to say the least. Ideal, evidence-based therapy in the form of an IDDT program can be difficult for clinicians to implement and for patients to access. Best efforts to perform meticulous clinical assessment to clarify diagnoses, use pharmacotherapy judiciously, work collaboratively in a multidisciplinary setting, and optimize treatment given available resources are keys to clinical success.

Bottom Line

Ideal treatment of patients with dual disorders consists of simultaneous, integrated interventions delivered by a multidisciplinary team. However, in the real world, limited resources, diagnostic challenges, and both over- and underutilization of pharmacotherapy often hamper optimal treatment.

Related Resources

• Substance Abuse and Mental Health Services Administration. Co-occurring disorders. https://www.samhsa.gov/disorders/co-occurring.
• National Alliance on Mental Illness. Dual diagnosis. https://www.nami.org/Learn-More/Mental-Health-Conditions/Related-Conditions/Dual-Diagnosis.
• Foundations Recovery Network. Dual diagnosis support groups. http://www.dualdiagnosis.org/resource/ddrn/self-helpsupport-groups/support-groups.
• Substance Abuse and Mental Health Services Administration. Integrated treatment for co-occurring disorders evidence-based practices (EBP) KIT. https://store.samhsa.gov/product/Integrated-Treatment-for-Co-Occurring-Disorders-Evidence-Based-Practices-EBP-KIT/SMA08-4367.
• Substance Abuse and Mental Health Services Administration. Substance abuse treatment for persons with co-occurring disorders. https://store.samhsa.gov/shin/content/SMA13-3992/SMA13-3992.pdf.

The term “dual diagnosis” describes the clinically challenging comorbidity of a substance use disorder (SUD) along with another major mental illness. Based on data from the Epidemiologic Catchment Area study, the lifetime prevalence of SUDs among patients with mental illness is approximately 30%, and is higher among patients with certain mental disorders, such as schizophrenia (47%), bipolar disorder (61%), and antisocial personality disorder (84%).¹ These statistics highlight that addiction is often the rule rather than the exception among those with severe mental illness.¹ Not surprisingly, the combined effects of having an SUD along with another mental illness are uniformly negative (Table 1^2-4).

Based on outcomes research, the core tenets of evidence-based dual-diagnosis treatment include the importance of integrated (rather than parallel) and simultaneous (rather than sequential) care, which means an ideal treatment program includes a unified, multidisciplinary team whose coordinated efforts focus on treating both disorders concurrently.² Evidence-based psychotherapies for addiction, including motivational interviewing, cognitive-behavioral therapy, relapse prevention, contingency management, skills training, and/or case management, are a necessity,^3,5 and must be balanced with rational and appropriate pharmacotherapy targeting both the SUD as well as the other disorder (Table 2^2,3,5-9).

3 ‘Real-world’ clinical challenges

Ideal vs real-world treatment

Treating patients with co-occurring disorders (CODs) within integrated dual-disorder treatment (IDDT) programs sounds straightforward. However, implementing evidence-based “best practice” treatment is a significant challenge in the real world for several reasons. First, individuals with CODs often struggle with poor insight, low motivation to change, and lack of access to health care. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), 52% of individuals with CODs in the U.S. received no treatment at all in 2016.¹⁰ For patients with dual disorders who do seek care, most are not given access to specialty SUD treatment¹⁰ and may instead find themselves treated by psychiatrists with limited SUD training who fail to provide evidence-based psychotherapies and underutilize pharmacotherapies for SUDs.¹¹ In the setting of CODs, the “harm reduction model” can be conflated with therapeutic nihilism, resulting in the neglect of SUD issues, with clinicians expecting patients to seek SUD treatment on their own, through self-help groups such as Alcoholics Anonymous or in other community treatment programs staffed by nonprofessionals that often are not tailored to the unique needs of patients with dual disorders. Psychiatrists working with other mental health professionals who provide psychotherapy for SUDs often do so in parallel rather than in an evidence-based, integrated fashion.

IDDT programs are not widely available. One study found that fewer than 20% of addiction treatment programs and fewer than 10% of mental health programs in the U.S. met criteria for dual diagnosis–capable services.¹² Getting treatment programs to become dual diagnosis–capable is possible, but it is a time-consuming and costly endeavor that, once achieved, requires continuous staff training and programmatic adaptations to interruptions in funding.^13-16 With myriad barriers to the establishment and maintenance of IDDTs, many patients with dual disorders are left without access to the most effective and comprehensive care; as few as 4% of individuals with CODs are treated within integrated programs.¹⁷

Diagnostic dilemmas

Establishing whether or not a patient with an active SUD has another serious mental illness (SMI) is a crucial first step for optimizing treatment, but diagnostic reliability can prove challenging and requires careful clinical assessment (Table 3). As always in psychiatry, accurate diagnosis is limited to careful clinical assessment¹⁸ and, in the case of possible dual disorders, is complicated by the fact that both SUDs as well as non-SUDs can result in the same psychiatric symptoms (eg, insomnia, anxiety, depression, manic behaviors, and psychosis). Clinicians must therefore distinguish between:

• Symptoms of substance intoxication or withdrawal vs independent symptoms of an underlying psychiatric disorder (that persist beyond a month after cessation of intoxication or withdrawal)
• Subclinical symptoms vs threshold mental illness, keeping in mind that some mood and anxiety states can be normal given social situations and stressors (eg, turmoil in relationships, employment difficulties, homelessness, etc.)
• Any mental illness (AMI) vs SMI. The latter is defined by SAMHSA as AMI that substantially interferes with or limits ≥1 major life activities.¹⁰

With these distinctions in mind, data from the 2016 National Survey on Drug Use and Health indicate that dual-diagnosis comorbidity was higher when the thres­hold for mental illness was lower—among the 19 million adults in the U.S. with SUDs, the past-year prevalence was 43% for AMI and 14% for SMI.¹⁰ Looking at substance-induced disorders vs “independent” disorders, the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions found that for individuals with SUDs, the past-year prevalence of an independent mood or anxiety disorder was 35% and 26%, respectively.¹⁹ Taken together, these findings illustrate the substantial rate of dual-diagnosis comorbidity, the diagnostic heterogeneity and range of severity of CODs,²⁰ and the potential for both false negatives (eg, diagnosing a substance-induced syndrome when in fact a patient has an underlying disorder) and false positives (diagnosing a full-blown mental illness when symptoms are subclinical or substance-induced) when performing diagnostic assessments in the setting of known SUDs.

Continue to: False positives are more likely...

False positives are more likely when patients seeking treatment for non-SUDs don’t disclose active drug use, even when asked. Both patients and their treating clinicians may also be prone to underestimating the significant potential for morbidity associated with SUDs, such that substance-induced symptoms may be misattributed to a dual disorder. Diagnostic questioning and thorough chart review that includes careful assessment of whether psychiatric symptoms preceded the onset of substance use, and whether they persisted in the setting of extended sobriety, is therefore paramount for minimizing false positives when assessing for dual diagnoses.^18,21 Likewise, random urine toxicology testing can be invaluable in verifying claims regarding sobriety.

Another factor that can complicate diagnosis is that there are often considerable secondary gains (eg, disability income, hospitalization, housing, access to prescription medications, and mitigation of the blame and stigma associated with addiction) associated with having a dual disorder as opposed to having “just” a SUD. As a result, for some patients, obtaining a non-SUD diagnosis can be highly incentivized.^22,23 Clinicians must therefore be savvy about the high potential for malingering, embellishment, and mislabeling of symptoms when conducting diagnostic interviews. For example, in assessing for psychosis, the frequent endorsement of “hearing voices” in patients with SUDs often results in a diagnosis of schizophrenia or unspecified psychotic disorder,²² despite the fact that this symptom can occur during substance intoxication and withdrawal, is well documented among people without mental illness as well as those with non-psychotic disorders,²⁴ and can resolve without medications or with non-antipsychotic pharmacotherapy.²⁵

When assessing for dual disorders, diagnostic false positives and false negatives can both contribute to inappropriate treatment and unrealistic expectations for recovery, and therefore underscore the importance of careful diagnostic assessment. Even with diligent assessment, however, diagnostic clarity can prove elusive due to inadequate sobriety, inconsistent reporting, and poor memory.²⁶ Therefore, for patients with known SUDs but diagnostic uncertainty about a dual disorder, the work-up should include a trial of prospective observation, with completion of appropriate detoxification, throughout a 1-month period of sobriety and in the absence of psychiatric medications, to determine if there are persistent symptoms that would justify a dual diagnosis. In research settings, such observations have revealed that most of depressive symptoms among alcoholics who present for substance abuse treatment resolve after a month of abstinence.²⁷ A similar time course for resolution has been noted for anxiety, distress, fatigue, and depressive symptoms among individuals with cocaine dependence.²⁸ These findings support the guideline established in DSM-IV that symptoms persisting beyond a month of sobriety “should be considered to be manifestations of an independent, non-substance-induced mental disorder,”²⁹ while symptoms occurring within that month may well be substance-induced. Unfortunately, in real-world clinical practice, and particularly in outpatient settings, it can be quite difficult to achieve the requisite period of sobriety for reliable diagnosis, and patients are often prematurely prescribed medications (eg, an antidepressant, antipsychotic, or mood stabilizer) that can confound the cause of symptomatic resolution. Such prescriptions are driven by compelling pressures from patients to relieve their acute suffering, as well as the predilection of some clinicians to give patients “the benefit of doubt” in assessing for dual diagnoses. However, whether an inappropriate diagnosis or a prescription for an unnecessary medication represents a benefit is debatable at best.

Pharmacotherapy

A third real-world challenge in managing patients with dual disorders involves optimizing pharmacotherapy. Unfortunately, because patients with SUDs often are excluded from clinical trials, evidence-based guidance for patients with dual disorders is lacking. In addition, medications for both CODs often remain inaccessible to patients with dual disorders for 3 reasons:

• SUDs negatively impact medication adherence among patients with dual disorders, who sometimes point out that “it says right here on the bottle not to take this medication with drugs or alcohol!”
• Some self-help groups still espouse blanket opposition of any “psychotropic” medications, even when clearly indicated for patients with COD. Groups that recognize the importance of pharmacotherapy, such as Dual Diagnosis Anonymous (DDA), have emerged, but are not yet widely available.³⁰
• Although there are increasing options for FDA-approved medications for SUDs, they are limited to the treatment of alcohol, opioid, and nicotine use disorders³¹; are often restricted due to hospital and health insurance formularies³²; and remain underprescribed for patients with dual disorders.¹¹

Continue to: Although underutilization of pharmacotherapy is...

Although underutilization of pharmacotherapy is a pitfall to be avoided in the treatment of patients with dual disorders, medication overutilization can be just as problematic. Patients with dual disorders are sometimes singularly focused on resolving acute anxiety, depression, or psychosis at the expense of working towards sobriety.³³ Although the “self-medication hypothesis” is frequently invoked by patients and clinicians alike to suggest that substance use occurs in the service of “treating” underlying disorders,³⁴ this theory has not been well supported in studies.^35-37 Some patients may pledge dedication to abstinence, but still pressure physicians for a pharmacologic solution to their suffering. With expanding legalization of cannabis for both recreational and medical purposes, patients are increasingly seeking doctors’ recommendations for “medical marijuana” for a wide range of complaints, despite the fact that data supporting a therapeutic role for cannabis in the treatment of mental illness is sparse,³⁸ whereas the potential harm in terms of either causing or worsening psychosis is well established.^39,40 Clinicians must be knowledgeable about the abuse potential of prescribed medications, ranging from sleep aids, analgesics, and muscle relaxants to antidepressants and antipsychotics, while also being mindful of the psychological meaningfulness of seeking, prescribing, and not prescribing medications.⁴¹

Although the simultaneous treatment of patients with dual disorders that includes pharmacotherapy for both SUDs and CODs is vital for optimizing clinical outcomes, clinicians should strive for diagnostic accuracy and use medications judiciously. In addition, although pharmacotherapy often is necessary to deliver evidence-based treatment for patients with dual disorders, it is inadequate as standalone treatment and should be administered along with psychosocial interventions within an integrated, multidisciplinary treatment setting.

The keys to optimal outcomes

The treatment of patients with dual disorders can be challenging, to say the least. Ideal, evidence-based therapy in the form of an IDDT program can be difficult for clinicians to implement and for patients to access. Best efforts to perform meticulous clinical assessment to clarify diagnoses, use pharmacotherapy judiciously, work collaboratively in a multidisciplinary setting, and optimize treatment given available resources are keys to clinical success.

Bottom Line

Ideal treatment of patients with dual disorders consists of simultaneous, integrated interventions delivered by a multidisciplinary team. However, in the real world, limited resources, diagnostic challenges, and both over- and underutilization of pharmacotherapy often hamper optimal treatment.

Related Resources

• Substance Abuse and Mental Health Services Administration. Co-occurring disorders. https://www.samhsa.gov/disorders/co-occurring.
• National Alliance on Mental Illness. Dual diagnosis. https://www.nami.org/Learn-More/Mental-Health-Conditions/Related-Conditions/Dual-Diagnosis.
• Foundations Recovery Network. Dual diagnosis support groups. http://www.dualdiagnosis.org/resource/ddrn/self-helpsupport-groups/support-groups.
• Substance Abuse and Mental Health Services Administration. Integrated treatment for co-occurring disorders evidence-based practices (EBP) KIT. https://store.samhsa.gov/product/Integrated-Treatment-for-Co-Occurring-Disorders-Evidence-Based-Practices-EBP-KIT/SMA08-4367.
• Substance Abuse and Mental Health Services Administration. Substance abuse treatment for persons with co-occurring disorders. https://store.samhsa.gov/shin/content/SMA13-3992/SMA13-3992.pdf.

For patients with suspected opioid-induced constipation, start by taking a careful history of defecation and dietary patterns, stool consistency, incomplete evacuation, and “alarm symptoms,” such as bloody stools or weight loss, state new guidelines from the American Gastroenterological Association in Gastroenterology.

Hemera/thinkstock

Clinicians also should rule out other causes of constipation, such as pelvic outlet dysfunction, mechanical obstruction, metabolic abnormalities, and comorbidities or concurrent medications, wrote Seth D. Crockett, MD, MPH, of the University of North Carolina at Chapel Hill, together with his associates. The guideline was published online Sept. 1.

Opioid therapy can lead to a range of gastrointestinal symptoms, such as constipation, gastroesophageal reflux, nausea and vomiting, bloating, and abdominal pain. Among these, constipation is by far the most common and debilitating, the guideline notes. In past studies, 40%-80% of patients who received opioids developed opioid-induced constipation (OIC), a more severe presentation that involves a combination of reduced stool frequency in addition to other symptoms, such as harder stools, new or worsening straining during defecation, and a sense of incomplete rectal evacuation.

Treating OIC should start with lifestyle interventions, such as drinking more fluids, toileting as soon as possible when feeling the urge to defecate, and adding regular moderate exercise whenever tolerable, the guideline advises. For patients on oral or parenteral therapy, consider switching to an equianalgesic dose of a less-constipating opioid, such as transdermal fentanyl or oxycodone-naloxone combination therapy.

Many patients with OIC require interventions beyond lifestyle changes or opioid switching. For these patients, the guideline advises starting with conventional laxative therapies based on their safety, low cost, and “established efficacy” in the OIC setting. Options include stool softeners (docusate sodium), osmotic laxatives (polyethylene glycol, magnesium hydroxide, magnesium citrate, and lactulose), lubricants (mineral oil), and stimulant laxatives (bisacodyl, sodium picosulfate, and senna). “Of note, there is little evidence that routine use of stimulant laxatives is harmful to the colon, despite widespread concern to the contrary,” the guideline states. Although randomized, controlled trials have not evaluated particular laxative combinations or titrations for OIC, the best evidence supports stimulant and osmotic laxative therapy, the authors note.

Before deeming any case of OIC laxative refractory, ensure that a patient receives an adequate trial of at least two classes of laxatives administered on a regular schedule, not just “as needed,” the guideline specifies. For example, a patient might receive a 2-week trial of a daily osmotic laxative plus a stimulant laxative two to three times weekly. The guideline authors suggest restricting the use of enemas to rescue therapy. They also note that consuming more fiber tends not to help patients with OIC because fiber does not affect colonic motility.

For truly laxative-refractory OIC, the guidelines recommend escalating treatment to peripherally acting mu-opioid receptor antagonists (PAMORAs). These drugs restore the function of the enteric nervous system by blocking mu-opioid receptors in the gut. Among the PAMORAs, the guideline strongly recommends the use of naldemedine or naloxegol over no treatment, based on robust data from randomized, double-blind, placebo-controlled trials. In the phase 3 COMPOSE 1, 2, and 3 trials, about 52% of patients who received naldemedine achieved at least three spontaneous bowel movements per week, compared with 35% of patients who received placebo. Additionally, in a 52-week safety and efficacy study (COMPOSE 3), naldemedine was associated with one more spontaneous bowel movement per week versus placebo and with a low absolute increase in adverse events.

The guideline bases its strong recommendation for naloxegol on moderate-quality data from three studies, including two phase 3, double-blind, randomized, placebo-controlled trials. Although at least five randomized, controlled trials have evaluated methylnaltrexone, the evidence was low quality and therefore the guideline only conditionally recommends prescribing this PAMORA over no treatment.

The guideline also makes no recommendation on the use of the intestinal secretagogue lubiprostone or the 5HT agonist prucalopride. Studies of lubiprostone were limited by possible reporting bias and showed no clear treatment benefit, the authors state. They describe a similar evidence gap for prucalopride, noting that at least one trial ended early without publication of the findings. They recommend further studying lubiprostone as well as prucalopride and other highly selective 5-HT4 agonists for treating OIC. Head-to-head trials would help guide treatment choice for patients with laxative-refractory OIC, they add. “Cost-effectiveness studies are also lacking in this field, which could inform prescribing strategy, particularly for newer, more expensive agents.”

For patients with suspected opioid-induced constipation, start by taking a careful history of defecation and dietary patterns, stool consistency, incomplete evacuation, and “alarm symptoms,” such as bloody stools or weight loss, state new guidelines from the American Gastroenterological Association in Gastroenterology.

Hemera/thinkstock

Clinicians also should rule out other causes of constipation, such as pelvic outlet dysfunction, mechanical obstruction, metabolic abnormalities, and comorbidities or concurrent medications, wrote Seth D. Crockett, MD, MPH, of the University of North Carolina at Chapel Hill, together with his associates. The guideline was published online Sept. 1.

Opioid therapy can lead to a range of gastrointestinal symptoms, such as constipation, gastroesophageal reflux, nausea and vomiting, bloating, and abdominal pain. Among these, constipation is by far the most common and debilitating, the guideline notes. In past studies, 40%-80% of patients who received opioids developed opioid-induced constipation (OIC), a more severe presentation that involves a combination of reduced stool frequency in addition to other symptoms, such as harder stools, new or worsening straining during defecation, and a sense of incomplete rectal evacuation.

Treating OIC should start with lifestyle interventions, such as drinking more fluids, toileting as soon as possible when feeling the urge to defecate, and adding regular moderate exercise whenever tolerable, the guideline advises. For patients on oral or parenteral therapy, consider switching to an equianalgesic dose of a less-constipating opioid, such as transdermal fentanyl or oxycodone-naloxone combination therapy.

Many patients with OIC require interventions beyond lifestyle changes or opioid switching. For these patients, the guideline advises starting with conventional laxative therapies based on their safety, low cost, and “established efficacy” in the OIC setting. Options include stool softeners (docusate sodium), osmotic laxatives (polyethylene glycol, magnesium hydroxide, magnesium citrate, and lactulose), lubricants (mineral oil), and stimulant laxatives (bisacodyl, sodium picosulfate, and senna). “Of note, there is little evidence that routine use of stimulant laxatives is harmful to the colon, despite widespread concern to the contrary,” the guideline states. Although randomized, controlled trials have not evaluated particular laxative combinations or titrations for OIC, the best evidence supports stimulant and osmotic laxative therapy, the authors note.

Before deeming any case of OIC laxative refractory, ensure that a patient receives an adequate trial of at least two classes of laxatives administered on a regular schedule, not just “as needed,” the guideline specifies. For example, a patient might receive a 2-week trial of a daily osmotic laxative plus a stimulant laxative two to three times weekly. The guideline authors suggest restricting the use of enemas to rescue therapy. They also note that consuming more fiber tends not to help patients with OIC because fiber does not affect colonic motility.

For truly laxative-refractory OIC, the guidelines recommend escalating treatment to peripherally acting mu-opioid receptor antagonists (PAMORAs). These drugs restore the function of the enteric nervous system by blocking mu-opioid receptors in the gut. Among the PAMORAs, the guideline strongly recommends the use of naldemedine or naloxegol over no treatment, based on robust data from randomized, double-blind, placebo-controlled trials. In the phase 3 COMPOSE 1, 2, and 3 trials, about 52% of patients who received naldemedine achieved at least three spontaneous bowel movements per week, compared with 35% of patients who received placebo. Additionally, in a 52-week safety and efficacy study (COMPOSE 3), naldemedine was associated with one more spontaneous bowel movement per week versus placebo and with a low absolute increase in adverse events.

The guideline bases its strong recommendation for naloxegol on moderate-quality data from three studies, including two phase 3, double-blind, randomized, placebo-controlled trials. Although at least five randomized, controlled trials have evaluated methylnaltrexone, the evidence was low quality and therefore the guideline only conditionally recommends prescribing this PAMORA over no treatment.

The guideline also makes no recommendation on the use of the intestinal secretagogue lubiprostone or the 5HT agonist prucalopride. Studies of lubiprostone were limited by possible reporting bias and showed no clear treatment benefit, the authors state. They describe a similar evidence gap for prucalopride, noting that at least one trial ended early without publication of the findings. They recommend further studying lubiprostone as well as prucalopride and other highly selective 5-HT4 agonists for treating OIC. Head-to-head trials would help guide treatment choice for patients with laxative-refractory OIC, they add. “Cost-effectiveness studies are also lacking in this field, which could inform prescribing strategy, particularly for newer, more expensive agents.”

For patients with suspected opioid-induced constipation, start by taking a careful history of defecation and dietary patterns, stool consistency, incomplete evacuation, and “alarm symptoms,” such as bloody stools or weight loss, state new guidelines from the American Gastroenterological Association in Gastroenterology.

Hemera/thinkstock

Clinicians also should rule out other causes of constipation, such as pelvic outlet dysfunction, mechanical obstruction, metabolic abnormalities, and comorbidities or concurrent medications, wrote Seth D. Crockett, MD, MPH, of the University of North Carolina at Chapel Hill, together with his associates. The guideline was published online Sept. 1.

Opioid therapy can lead to a range of gastrointestinal symptoms, such as constipation, gastroesophageal reflux, nausea and vomiting, bloating, and abdominal pain. Among these, constipation is by far the most common and debilitating, the guideline notes. In past studies, 40%-80% of patients who received opioids developed opioid-induced constipation (OIC), a more severe presentation that involves a combination of reduced stool frequency in addition to other symptoms, such as harder stools, new or worsening straining during defecation, and a sense of incomplete rectal evacuation.

Treating OIC should start with lifestyle interventions, such as drinking more fluids, toileting as soon as possible when feeling the urge to defecate, and adding regular moderate exercise whenever tolerable, the guideline advises. For patients on oral or parenteral therapy, consider switching to an equianalgesic dose of a less-constipating opioid, such as transdermal fentanyl or oxycodone-naloxone combination therapy.

Many patients with OIC require interventions beyond lifestyle changes or opioid switching. For these patients, the guideline advises starting with conventional laxative therapies based on their safety, low cost, and “established efficacy” in the OIC setting. Options include stool softeners (docusate sodium), osmotic laxatives (polyethylene glycol, magnesium hydroxide, magnesium citrate, and lactulose), lubricants (mineral oil), and stimulant laxatives (bisacodyl, sodium picosulfate, and senna). “Of note, there is little evidence that routine use of stimulant laxatives is harmful to the colon, despite widespread concern to the contrary,” the guideline states. Although randomized, controlled trials have not evaluated particular laxative combinations or titrations for OIC, the best evidence supports stimulant and osmotic laxative therapy, the authors note.

Before deeming any case of OIC laxative refractory, ensure that a patient receives an adequate trial of at least two classes of laxatives administered on a regular schedule, not just “as needed,” the guideline specifies. For example, a patient might receive a 2-week trial of a daily osmotic laxative plus a stimulant laxative two to three times weekly. The guideline authors suggest restricting the use of enemas to rescue therapy. They also note that consuming more fiber tends not to help patients with OIC because fiber does not affect colonic motility.

For truly laxative-refractory OIC, the guidelines recommend escalating treatment to peripherally acting mu-opioid receptor antagonists (PAMORAs). These drugs restore the function of the enteric nervous system by blocking mu-opioid receptors in the gut. Among the PAMORAs, the guideline strongly recommends the use of naldemedine or naloxegol over no treatment, based on robust data from randomized, double-blind, placebo-controlled trials. In the phase 3 COMPOSE 1, 2, and 3 trials, about 52% of patients who received naldemedine achieved at least three spontaneous bowel movements per week, compared with 35% of patients who received placebo. Additionally, in a 52-week safety and efficacy study (COMPOSE 3), naldemedine was associated with one more spontaneous bowel movement per week versus placebo and with a low absolute increase in adverse events.

The guideline bases its strong recommendation for naloxegol on moderate-quality data from three studies, including two phase 3, double-blind, randomized, placebo-controlled trials. Although at least five randomized, controlled trials have evaluated methylnaltrexone, the evidence was low quality and therefore the guideline only conditionally recommends prescribing this PAMORA over no treatment.

The guideline also makes no recommendation on the use of the intestinal secretagogue lubiprostone or the 5HT agonist prucalopride. Studies of lubiprostone were limited by possible reporting bias and showed no clear treatment benefit, the authors state. They describe a similar evidence gap for prucalopride, noting that at least one trial ended early without publication of the findings. They recommend further studying lubiprostone as well as prucalopride and other highly selective 5-HT4 agonists for treating OIC. Head-to-head trials would help guide treatment choice for patients with laxative-refractory OIC, they add. “Cost-effectiveness studies are also lacking in this field, which could inform prescribing strategy, particularly for newer, more expensive agents.”

Nerve growth factor (NGF) therapy in aging rats improves angiogenesis and speeds gastric ulcer healing, which suggests possible applications in human medicine, a recent study found.

Compared with young individuals, elderly people have significantly lower levels of NGF in gastric endothelial cells (GECs), a finding that is associated with impaired angiogenesis and delayed gastric ulcer healing.

“Our previous studies have shown that the gastric mucosa of aging individuals ... has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully elucidated,” wrote Amrita Ahluwalia, PhD, of Medical and Research Services at the Veterans Affairs Long Beach (Calif.) Healthcare System and her coauthors.

Mapping the drivers of angiogenesis in the gastric mucosa could lead to treatment options for elderly patients with injured or ulcerated gastric tissue. In prior trials (with rats), “treatment with VEGF [vascular endothelial growth factor] only partly reversed impaired angiogenesis in aging [GECs], indicating an essential role for other factor(s) in addition to VEGF,” the investigators wrote in the September issue of Cellular and Molecular Gastroenterology and Hepatology. They looked to NGF as another possible factor because recent studies had shown it could improve angiogenesis in the brain.

The present study measured NGF expression in rats and humans of varying ages, with NGF treatment and gene therapy performed in rats (in vitro and in vivo).

In vitro angiogenesis was 4.1-fold lower in GECs from aging rats (24 months of age) than it was in GECs from young rats (3 months of age; P less than .001). NGF protein and NGF mRNA levels were also significantly lower in aging GECs than they were with young GECs (NGF protein, 3.0-fold lower; NGF mRNA, 4.2-fold lower; P less than .001).

Treatment of aging rat GECs with exogenous NGF increased angiogenesis by 1.5-fold (P less than .001). Pretreatment with a PI3 kinase inhibitor or an mTOR inhibitor abolished this improvement, suggesting that the PI3 kinase/Akt and mTOR pathways are involved.

When NGF gene therapy was performed in aging GECs, NGF levels rose to the level of that in young GECs, with an accompanying restoration of angiogenesis (threefold increase; P less than .001). Proliferation of aging GECs also increased with gene therapy (P less than .001).

In vivo studies revealed that NGF expression and cell proliferation in aging rat gastric mucosa were lower than in younger rats. Of note, older rats treated with local NGF protein showed increased gastric mucosa angiogenesis and faster ulcer healing, compared with phosphate-buffered saline treatment.

Similar age-related NGF declines were found in humans. When gastric mucosa biopsies were collected from younger individuals (younger than 40 years old; n = 10) and compared with samples from an older population (at least 70 years old; n = 10), the investigators found that NGF expression was 5.5-fold lower in the older people (P less than .001).

“This clearly indicates human relevance of our experimental findings and also can explain impaired angiogenesis and delayed healing of injured gastric mucosa in aging individuals,” the investigators wrote.

“Aging gastropathy and its consequences are clinically critical issues,” the investigators noted, “especially because the aging U.S. population is growing rapidly and it is estimated that, by the year 2030, approximately 70 million Americans will be older than 65 years of age.” Gastric ulcers become more common with age, and individuals 70 years or older have an eightfold increased risk of associated complications, compared with people under 50 years.

The investigators noted that multiple growth factors likely play a role in stimulation of angiogenesis, including NGF, VEGF, epidermal growth factor, and basic fibroblast growth factor. “Further studies are necessary to investigate the role of other growth factors and cytokines in angiogenesis, [gastric ulcer] healing, and their impairment in aging,” the investigators concluded.

The study was funded by the Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The authors declared no conflicts of interest.
 

SOURCE: Ahluwalia A et al. CMGH. 2018 May 17. doi: 10.1016/j.jcmgh.2018.05.003

Nerve growth factor (NGF) therapy in aging rats improves angiogenesis and speeds gastric ulcer healing, which suggests possible applications in human medicine, a recent study found.

Compared with young individuals, elderly people have significantly lower levels of NGF in gastric endothelial cells (GECs), a finding that is associated with impaired angiogenesis and delayed gastric ulcer healing.

“Our previous studies have shown that the gastric mucosa of aging individuals ... has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully elucidated,” wrote Amrita Ahluwalia, PhD, of Medical and Research Services at the Veterans Affairs Long Beach (Calif.) Healthcare System and her coauthors.

Mapping the drivers of angiogenesis in the gastric mucosa could lead to treatment options for elderly patients with injured or ulcerated gastric tissue. In prior trials (with rats), “treatment with VEGF [vascular endothelial growth factor] only partly reversed impaired angiogenesis in aging [GECs], indicating an essential role for other factor(s) in addition to VEGF,” the investigators wrote in the September issue of Cellular and Molecular Gastroenterology and Hepatology. They looked to NGF as another possible factor because recent studies had shown it could improve angiogenesis in the brain.

The present study measured NGF expression in rats and humans of varying ages, with NGF treatment and gene therapy performed in rats (in vitro and in vivo).

In vitro angiogenesis was 4.1-fold lower in GECs from aging rats (24 months of age) than it was in GECs from young rats (3 months of age; P less than .001). NGF protein and NGF mRNA levels were also significantly lower in aging GECs than they were with young GECs (NGF protein, 3.0-fold lower; NGF mRNA, 4.2-fold lower; P less than .001).

Treatment of aging rat GECs with exogenous NGF increased angiogenesis by 1.5-fold (P less than .001). Pretreatment with a PI3 kinase inhibitor or an mTOR inhibitor abolished this improvement, suggesting that the PI3 kinase/Akt and mTOR pathways are involved.

When NGF gene therapy was performed in aging GECs, NGF levels rose to the level of that in young GECs, with an accompanying restoration of angiogenesis (threefold increase; P less than .001). Proliferation of aging GECs also increased with gene therapy (P less than .001).

In vivo studies revealed that NGF expression and cell proliferation in aging rat gastric mucosa were lower than in younger rats. Of note, older rats treated with local NGF protein showed increased gastric mucosa angiogenesis and faster ulcer healing, compared with phosphate-buffered saline treatment.

Similar age-related NGF declines were found in humans. When gastric mucosa biopsies were collected from younger individuals (younger than 40 years old; n = 10) and compared with samples from an older population (at least 70 years old; n = 10), the investigators found that NGF expression was 5.5-fold lower in the older people (P less than .001).

“This clearly indicates human relevance of our experimental findings and also can explain impaired angiogenesis and delayed healing of injured gastric mucosa in aging individuals,” the investigators wrote.

“Aging gastropathy and its consequences are clinically critical issues,” the investigators noted, “especially because the aging U.S. population is growing rapidly and it is estimated that, by the year 2030, approximately 70 million Americans will be older than 65 years of age.” Gastric ulcers become more common with age, and individuals 70 years or older have an eightfold increased risk of associated complications, compared with people under 50 years.

The investigators noted that multiple growth factors likely play a role in stimulation of angiogenesis, including NGF, VEGF, epidermal growth factor, and basic fibroblast growth factor. “Further studies are necessary to investigate the role of other growth factors and cytokines in angiogenesis, [gastric ulcer] healing, and their impairment in aging,” the investigators concluded.

The study was funded by the Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The authors declared no conflicts of interest.
 

SOURCE: Ahluwalia A et al. CMGH. 2018 May 17. doi: 10.1016/j.jcmgh.2018.05.003

Nerve growth factor (NGF) therapy in aging rats improves angiogenesis and speeds gastric ulcer healing, which suggests possible applications in human medicine, a recent study found.

Compared with young individuals, elderly people have significantly lower levels of NGF in gastric endothelial cells (GECs), a finding that is associated with impaired angiogenesis and delayed gastric ulcer healing.

“Our previous studies have shown that the gastric mucosa of aging individuals ... has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully elucidated,” wrote Amrita Ahluwalia, PhD, of Medical and Research Services at the Veterans Affairs Long Beach (Calif.) Healthcare System and her coauthors.

Mapping the drivers of angiogenesis in the gastric mucosa could lead to treatment options for elderly patients with injured or ulcerated gastric tissue. In prior trials (with rats), “treatment with VEGF [vascular endothelial growth factor] only partly reversed impaired angiogenesis in aging [GECs], indicating an essential role for other factor(s) in addition to VEGF,” the investigators wrote in the September issue of Cellular and Molecular Gastroenterology and Hepatology. They looked to NGF as another possible factor because recent studies had shown it could improve angiogenesis in the brain.

The present study measured NGF expression in rats and humans of varying ages, with NGF treatment and gene therapy performed in rats (in vitro and in vivo).

In vitro angiogenesis was 4.1-fold lower in GECs from aging rats (24 months of age) than it was in GECs from young rats (3 months of age; P less than .001). NGF protein and NGF mRNA levels were also significantly lower in aging GECs than they were with young GECs (NGF protein, 3.0-fold lower; NGF mRNA, 4.2-fold lower; P less than .001).

Treatment of aging rat GECs with exogenous NGF increased angiogenesis by 1.5-fold (P less than .001). Pretreatment with a PI3 kinase inhibitor or an mTOR inhibitor abolished this improvement, suggesting that the PI3 kinase/Akt and mTOR pathways are involved.

When NGF gene therapy was performed in aging GECs, NGF levels rose to the level of that in young GECs, with an accompanying restoration of angiogenesis (threefold increase; P less than .001). Proliferation of aging GECs also increased with gene therapy (P less than .001).

In vivo studies revealed that NGF expression and cell proliferation in aging rat gastric mucosa were lower than in younger rats. Of note, older rats treated with local NGF protein showed increased gastric mucosa angiogenesis and faster ulcer healing, compared with phosphate-buffered saline treatment.

Similar age-related NGF declines were found in humans. When gastric mucosa biopsies were collected from younger individuals (younger than 40 years old; n = 10) and compared with samples from an older population (at least 70 years old; n = 10), the investigators found that NGF expression was 5.5-fold lower in the older people (P less than .001).

“This clearly indicates human relevance of our experimental findings and also can explain impaired angiogenesis and delayed healing of injured gastric mucosa in aging individuals,” the investigators wrote.

“Aging gastropathy and its consequences are clinically critical issues,” the investigators noted, “especially because the aging U.S. population is growing rapidly and it is estimated that, by the year 2030, approximately 70 million Americans will be older than 65 years of age.” Gastric ulcers become more common with age, and individuals 70 years or older have an eightfold increased risk of associated complications, compared with people under 50 years.

The investigators noted that multiple growth factors likely play a role in stimulation of angiogenesis, including NGF, VEGF, epidermal growth factor, and basic fibroblast growth factor. “Further studies are necessary to investigate the role of other growth factors and cytokines in angiogenesis, [gastric ulcer] healing, and their impairment in aging,” the investigators concluded.

The study was funded by the Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The authors declared no conflicts of interest.
 

SOURCE: Ahluwalia A et al. CMGH. 2018 May 17. doi: 10.1016/j.jcmgh.2018.05.003

A proactive side-effect management strategy enabled many patients with high-risk renal cell carcinoma (RCC) to stay on adjuvant sunitinib therapy in a recent clinical trial, researchers report.

With dose interruptions, dose reductions, and supportive medical therapy, adverse events on adjuvant sunitinib were predictable, manageable, and reversible, according to their report on the S-TRAC (Sunitinib as Adjuvant Treatment for High-Risk Renal Cell Carcinoma Following Nephrectomy) trial.

Patients did report reduced health-related quality of life, but with the exception of diarrhea and loss of appetite, those changes were generally not clinically significant, the investigators wrote. The report is in Annals of Oncology.

The safety profile for sunitinib was acceptable in adjuvant RCC treatment in S-TRAC, with no safety signals observed, said Michael Staehler, MD, PhD, department of urology, Ludwig Maximilian University of Munich, and his coauthors.

“It is likely proactive management contributed to preservation of global health status and quality of life, and alleviation of treatment-related symptoms, thereby enabling patients to remain on effective adjuvant therapy,” Dr. Staehler and his coauthors said.

Sunitinib is approved by the Food and Drug Administration for adjuvant treatment of patients at high risk of recurrent RCC after nephrectomy. That was based in part on previously reported results of the phase 3 S-TRAC study, which showed a 24% reduction in risk of a disease-free survival event versus placebo.

For the 306 patients randomized to sunitinib, 71% stayed on treatment for at least 8 months, reaching cycle 6 of therapy, while 56% finished the full year of treatment, Dr. Staehler and his coauthors said in this new report on S-TRAC focused on adverse events and patient-reported outcomes.

The most common adverse events in the sunitinib arm of S-TRAC included diarrhea in 56.9%, versus 21.4% in the placebo arm, palmar-plantar erythrodysesthesia (PPE) in 50.3% versus 10.2% for placebo, and hypertension in 36.9% versus 11.8% for placebo. The frequency of serious adverse events was similar between arms, according to the investigators, at 21.9% for sunitinib and 17.1% for placebo.

Adverse events were the most common reason for dose reduction, cited in 34.6% of cases, and for dose interruption, reported in 46.4%, they said.

Treatment discontinuations due to adverse events occurred in 28.1%, usually because of PPE.

The S-TRAC study investigators used the EORTC QLQ-C30 instrument to evaluate patient experience during treatment.

That evaluation included an analysis of global health status/quality of life score that favored placebo, with a mean difference in the overall means of –4.76. Although statistically significant (P greater than or equal to .0001), the point estimate of the difference was below the commonly accepted threshold that would indicate clinically meaningful deterioration, investigators said.

Similar patterns that were statistically significant but not clinically meaningful were seen for symptoms including fatigue and pain. However, patient-reported scores for diarrhea and loss of appetite did reach the level of a clinically meaningful difference.

But only one patient permanently discontinued sunitinib because of diarrhea, and none permanently discontinued because of loss of appetite, Dr. Staehler and his coauthors noted.

The work was sponsored by Pfizer. Dr. Staehler reported honoraria, consulting fees, and research grants from Pfizer, Bayer, GSK, Roche, BMS, Novartis, Exelixis, and AVEO. Coauthors reported disclosures related to Merck, Sanofi, Astellas, Celldex, Acerta, Janssen, and others.

SOURCE: Staehler M et al. Ann Oncol. 2018 Aug 23. doi: 10.1093/annonc/mdy329.

A proactive side-effect management strategy enabled many patients with high-risk renal cell carcinoma (RCC) to stay on adjuvant sunitinib therapy in a recent clinical trial, researchers report.

With dose interruptions, dose reductions, and supportive medical therapy, adverse events on adjuvant sunitinib were predictable, manageable, and reversible, according to their report on the S-TRAC (Sunitinib as Adjuvant Treatment for High-Risk Renal Cell Carcinoma Following Nephrectomy) trial.

Patients did report reduced health-related quality of life, but with the exception of diarrhea and loss of appetite, those changes were generally not clinically significant, the investigators wrote. The report is in Annals of Oncology.

The safety profile for sunitinib was acceptable in adjuvant RCC treatment in S-TRAC, with no safety signals observed, said Michael Staehler, MD, PhD, department of urology, Ludwig Maximilian University of Munich, and his coauthors.

“It is likely proactive management contributed to preservation of global health status and quality of life, and alleviation of treatment-related symptoms, thereby enabling patients to remain on effective adjuvant therapy,” Dr. Staehler and his coauthors said.

Sunitinib is approved by the Food and Drug Administration for adjuvant treatment of patients at high risk of recurrent RCC after nephrectomy. That was based in part on previously reported results of the phase 3 S-TRAC study, which showed a 24% reduction in risk of a disease-free survival event versus placebo.

For the 306 patients randomized to sunitinib, 71% stayed on treatment for at least 8 months, reaching cycle 6 of therapy, while 56% finished the full year of treatment, Dr. Staehler and his coauthors said in this new report on S-TRAC focused on adverse events and patient-reported outcomes.

The most common adverse events in the sunitinib arm of S-TRAC included diarrhea in 56.9%, versus 21.4% in the placebo arm, palmar-plantar erythrodysesthesia (PPE) in 50.3% versus 10.2% for placebo, and hypertension in 36.9% versus 11.8% for placebo. The frequency of serious adverse events was similar between arms, according to the investigators, at 21.9% for sunitinib and 17.1% for placebo.

Adverse events were the most common reason for dose reduction, cited in 34.6% of cases, and for dose interruption, reported in 46.4%, they said.

Treatment discontinuations due to adverse events occurred in 28.1%, usually because of PPE.

The S-TRAC study investigators used the EORTC QLQ-C30 instrument to evaluate patient experience during treatment.

That evaluation included an analysis of global health status/quality of life score that favored placebo, with a mean difference in the overall means of –4.76. Although statistically significant (P greater than or equal to .0001), the point estimate of the difference was below the commonly accepted threshold that would indicate clinically meaningful deterioration, investigators said.

Similar patterns that were statistically significant but not clinically meaningful were seen for symptoms including fatigue and pain. However, patient-reported scores for diarrhea and loss of appetite did reach the level of a clinically meaningful difference.

But only one patient permanently discontinued sunitinib because of diarrhea, and none permanently discontinued because of loss of appetite, Dr. Staehler and his coauthors noted.

The work was sponsored by Pfizer. Dr. Staehler reported honoraria, consulting fees, and research grants from Pfizer, Bayer, GSK, Roche, BMS, Novartis, Exelixis, and AVEO. Coauthors reported disclosures related to Merck, Sanofi, Astellas, Celldex, Acerta, Janssen, and others.

SOURCE: Staehler M et al. Ann Oncol. 2018 Aug 23. doi: 10.1093/annonc/mdy329.

A proactive side-effect management strategy enabled many patients with high-risk renal cell carcinoma (RCC) to stay on adjuvant sunitinib therapy in a recent clinical trial, researchers report.

With dose interruptions, dose reductions, and supportive medical therapy, adverse events on adjuvant sunitinib were predictable, manageable, and reversible, according to their report on the S-TRAC (Sunitinib as Adjuvant Treatment for High-Risk Renal Cell Carcinoma Following Nephrectomy) trial.

Patients did report reduced health-related quality of life, but with the exception of diarrhea and loss of appetite, those changes were generally not clinically significant, the investigators wrote. The report is in Annals of Oncology.

The safety profile for sunitinib was acceptable in adjuvant RCC treatment in S-TRAC, with no safety signals observed, said Michael Staehler, MD, PhD, department of urology, Ludwig Maximilian University of Munich, and his coauthors.

“It is likely proactive management contributed to preservation of global health status and quality of life, and alleviation of treatment-related symptoms, thereby enabling patients to remain on effective adjuvant therapy,” Dr. Staehler and his coauthors said.

Sunitinib is approved by the Food and Drug Administration for adjuvant treatment of patients at high risk of recurrent RCC after nephrectomy. That was based in part on previously reported results of the phase 3 S-TRAC study, which showed a 24% reduction in risk of a disease-free survival event versus placebo.

For the 306 patients randomized to sunitinib, 71% stayed on treatment for at least 8 months, reaching cycle 6 of therapy, while 56% finished the full year of treatment, Dr. Staehler and his coauthors said in this new report on S-TRAC focused on adverse events and patient-reported outcomes.

The most common adverse events in the sunitinib arm of S-TRAC included diarrhea in 56.9%, versus 21.4% in the placebo arm, palmar-plantar erythrodysesthesia (PPE) in 50.3% versus 10.2% for placebo, and hypertension in 36.9% versus 11.8% for placebo. The frequency of serious adverse events was similar between arms, according to the investigators, at 21.9% for sunitinib and 17.1% for placebo.

Adverse events were the most common reason for dose reduction, cited in 34.6% of cases, and for dose interruption, reported in 46.4%, they said.

Treatment discontinuations due to adverse events occurred in 28.1%, usually because of PPE.

The S-TRAC study investigators used the EORTC QLQ-C30 instrument to evaluate patient experience during treatment.

That evaluation included an analysis of global health status/quality of life score that favored placebo, with a mean difference in the overall means of –4.76. Although statistically significant (P greater than or equal to .0001), the point estimate of the difference was below the commonly accepted threshold that would indicate clinically meaningful deterioration, investigators said.

Similar patterns that were statistically significant but not clinically meaningful were seen for symptoms including fatigue and pain. However, patient-reported scores for diarrhea and loss of appetite did reach the level of a clinically meaningful difference.

But only one patient permanently discontinued sunitinib because of diarrhea, and none permanently discontinued because of loss of appetite, Dr. Staehler and his coauthors noted.

The work was sponsored by Pfizer. Dr. Staehler reported honoraria, consulting fees, and research grants from Pfizer, Bayer, GSK, Roche, BMS, Novartis, Exelixis, and AVEO. Coauthors reported disclosures related to Merck, Sanofi, Astellas, Celldex, Acerta, Janssen, and others.

SOURCE: Staehler M et al. Ann Oncol. 2018 Aug 23. doi: 10.1093/annonc/mdy329.