Discuss this article at www.facebook.com/CurrentPsychiatry

Mr. N, age 29, presents to the emergency department at the urging of his family because of poor self-care, bizarre behavior, and disturbed sleep. He first experienced psychiatric symptoms 10 years ago after his mother died. He became dysphoric and paranoid, displaying bizarre responses and behaviors with poor self-care and a gradual functional decline. He has been taking sertraline, 100 mg/d, for 10 years.

Upon arrival at the hospital’s inpatient unit, Mr. N is unkempt, oddly related, and paranoid. His affect is constricted. Mr. N displays thought blocking and possibly is responding to internal stimuli. Sertraline is continued and haloperidol, 1 mg/d, is initiated. For the next 2 weeks, Mr. N continues to be oddly related, irritable, and paranoid, and experiences disturbed sleep and thought blocking. After an episode of impulsive aggression, the treatment team initiates aripiprazole, which is titrated to 30 mg/d for 1 week. Mr. N’s clinical status worsens; he is menacing toward other patients and his thinking is more disorganized, with loose associations and ideas of reference. He requires 4 injections of IM haloperidol, 5 mg, and several visits to the seclusion room over the next week. Haloperidol is increased to 30 mg/d over the next 10 days, then aripiprazole is discontinued because of a putative drug interaction with haloperidol. Following the medication changes Mr. N demonstrates better behavioral control, but still is grossly psychotic. While awaiting transfer to a state hospital, Mr. N receives a trial of olanzapine, 20 to 40 mg/d, for 2 weeks without significant benefit.

Several clinical trials demonstrate a significant reduction in intensity of psychotic symptoms with aripiprazole, which has a unique mechanism of action.¹ However, since its FDA approval in 2002, several case reports have described treatment-emergent psychotic symptoms associated with aripiprazole initiation. Over the past 40 years, reports of worsening psychosis associated with antipsychotics have been limited to patients with schizophrenia who were taking high dosages or who had high plasma concentrations, when anticholinergic delirium may have explained increased psychotic symptoms.^2-4

How can a drug effectively treat psychotic symptoms and occasionally worsen them? In this article, we discuss the relevant pharmacology and clinical literature on aripiprazole and try to make sense of this apparent paradox.

Unique pharmacologic profile

Antipsychotics have been reported to be either neutral antagonists or inverse agonists at the D2 receptor, based on in vitro data.⁵ Aripiprazole and its main metabolite, dehydroaripiprazole, originally were described as partial agonists at D2 dopamine receptors.^6,7 However, it appears aripiprazole’s pharmacologic action is better explained by the concept of functional selectivity. Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonistic.⁵

Researchers have hypothesized that the pathophysiology of schizophrenia may, in part, be caused by dysfunction of mesocorticolimbic dopaminergic neurons characterized by an enhanced sensitivity of postsynaptic D2 receptors and increased sensitivity to dopaminergic drugs.^8,9 In addition, chronic treatment with a D2 receptor antagonist is associated with increases in postsynaptic dopamine receptor density (ie, an increase in receptor reserve).^10,11 Upregulation of D2 receptors may explain several features seen in patients chronically treated with antipsychotics, including tardive dyskinesia¹² and rapid psychotic relapse after discontinuing an antipsychotic (supersensitivity psychosis).¹³ Because chronic antipsychotic treatment leads to high postsynaptic receptor reserve, aripiprazole initiation may produce overactivation of D2 receptors, which might worsen a patient’s condition.¹⁴ In vitro data^15-18 and clinical observations indicate that aripiprazole has intrinsic efficacy at D2 receptors, as do clinical observations, such as:

• its propensity to reduce serum prolactin¹⁹
• a decreased likelihood of producing extrapyramidal side effects despite >80% occupancy of D2 receptors⁶
• case reports documenting aripiprazole-associated mania,²⁰ improvement of risperidone-associated cognitive impairment,²¹ and pathologic gambling.²²

Emergence or worsening of psychotic symptoms or a marginal antipsychotic effect may occur if aripiprazole is indeed a postsynaptic D2 receptor agonist. An individual patient’s outcome likely would depend on his or her sensitivity to psychosis and concurrent or previous exposure to a D2 receptor antagonist. For example, stimulation of postsynaptic D2 receptors may be further augmented if the dosage of the previous antipsychotic was reduced or withdrawn before initiating aripiprazole because additional receptors would be available for interaction with aripiprazole.

Case reports

A literature review revealed 23 reports of treatment-emergent psychosis associated with aripiprazole initiation (Table). The mean age of the patients was 47 (range: 17 to 69) and 57% were men. Most patients (87%) were diagnosed with a schizophrenia-spectrum illness before aripiprazole initiation. Most (57%) had mild, stable, or no psychotic symptoms before aripiprazole initiation. Most were receiving relatively high doses of antipsychotics (average chlorpromazine equivalents [CPZE]: 648 mg/d) before aripiprazole initiation. This medication was either decreased or discontinued in 70% of patients.

Emergence or worsening of psychotic symptoms included agitation, aggressive behavior, and increased psychomotor activity. However, akathisia evaluation was described in only 2 reports: 1 author identified akathisia symptoms, but attributed them to a concomitant antipsychotic (fluphenazine)²³ and the other report specifically excluded the possibility of akathisia.²⁴ Two systematic studies have attempted to establish risk factors for aripiprazole-associated worsening psychosis (Box).^14,25

In our literature review, the mean final dose of aripiprazole was 21.5 mg/d (range: 2 to 60 mg/d). In the cases describing subsequent treatment, all but 1 patient were switched to another antipsychotic, including 2 whose psychotic symptoms stabilized with continuation of aripiprazole and addition of a second antipsychotic. Interestingly, in the case reported by Adan-Manes et al,²⁶ initial treatment with aripiprazole monotherapy was efficacious, but a subsequent trial of adjunctive aripiprazole resulted in worsening psychosis.

Table

Case reports: Treatment-emergent psychosis associated with aripiprazole

Other potential explanations

Aripiprazole’s manufacturer reported the incidence of psychosis-related adverse events in an analysis of 9 randomized schizophrenia trials.²⁷ The rates of psychosis-related adverse events ranged from 0.6% to 18%, but there was no apparent relationship to study design or method of transitioning to aripiprazole. Rates of psychosis-related adverse events were similar between aripiprazole and the control group (placebo in 3 studies, another antipsychotic in 2 studies).

Emergence or worsening of psychotic symptoms temporally associated with aripiprazole initiation does not necessarily imply causation. As in Mr. N’s case, it is not always possible to determine whether worsening psychosis is the natural disease course or a treatment effect. In addition, it is not possible to differentiate lack of efficacy from a true propensity for aripiprazole to worsen psychosis.

It also is conceivable discontinuation or dosage reduction of a previous antipsychotic would worsen psychotic symptoms or cause side effects. When significant changes in psychopathology or side effects develop during the transition from 1 antipsychotic to another, it is difficult to determine etiology. Specifically, rapid transition from a medication with significant anticholinergic and antihistaminic properties—such as quetiapine or olanzapine—to 1 without these properties—such as aripiprazole—may result in symptoms of activation, including restlessness, insomnia, and anxiety. Consequently, these symptoms could be mistaken for worsening psychosis.²⁸ Only 1 patient in this series was reported to abruptly discontinue an antipsychotic with significant anticholinergic properties (clozapine) before initiating aripiprazole.²⁴ Studies by Takeuchi et al¹⁴ and Pae et al²⁵ did not report the relative baseline use of antipsychotic medication with anticholinergic properties.

In a pooled analysis of treatment-emergent adverse events in 5 randomized clinical trials of patients receiving aripiprazole for acute relapse of schizophrenia, the incidence of akathisia was 10%, although it is not clear if this is a dose-related adverse effect.²⁹ Because akathisia may be confused for worsening psychosis,³⁰ it is possible akathisia was mistakenly identified as worsening psychotic symptoms in Mr. N’s case, as well as several reports from our literature review.

Covert akathisia is unlikely to explain worsening psychopathology observed in all patients in our literature review because confusion of akathisia and worsening psychosis is not a widespread phenomenon. In a post hoc analysis of pooled safety data from aripiprazole trials, Kane et al³¹ did not find a correlation between presence of akathisia and aripiprazole efficacy as measured by the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS negative, Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement, and percentage of responders. Pae et al²⁵ also noted there was no correlation between scores on the Barnes Akathisia Rating Scale and worsening psychopathology in patients switched to aripiprazole.

An antagonist always is an antagonist and clinicians have appreciated this concept since the days of chlorpromazine. The activity of aripiprazole, however, is on a pharmacologic continuum between a neutral antagonist and full agonist and currently there is no way to precisely determine the level of D2 receptor agonist action in a patient.

Although it is interesting to speculate that aripiprazole’s D2 receptor agonist action may contribute to worsening psychosis,^32-34 there are other plausible explanations to consider. Rapid transition from a drug with significant anticholinergic properties and aripiprazole-associated akathisia may contribute to worsening psychopathology in patients starting aripiprazole. Because covert side effects may be incorrectly identified as psychotic agitation, we cannot exclude this as a possible etiologic factor in Mr. N’s case as well as the cases in our literature review.

Related Resource

• Abilify [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Biperiden • Akineton
• Carbamazepine • Tegretol
• Chlorpromazine • Thorazine
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Divalproex • Depakote
• Duloxetine • Cymbalta
• Fluphenazine • Permitil, Prolixin
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Nortriptyline • Aventyl, Pamelor
• Methylphenidate • Concerta
• Molindone • Moban
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Propranolol • Inderal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Thyroxine • Synthroid
• Valproic acid • Depakene
• Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Mr. N, age 29, presents to the emergency department at the urging of his family because of poor self-care, bizarre behavior, and disturbed sleep. He first experienced psychiatric symptoms 10 years ago after his mother died. He became dysphoric and paranoid, displaying bizarre responses and behaviors with poor self-care and a gradual functional decline. He has been taking sertraline, 100 mg/d, for 10 years.

Upon arrival at the hospital’s inpatient unit, Mr. N is unkempt, oddly related, and paranoid. His affect is constricted. Mr. N displays thought blocking and possibly is responding to internal stimuli. Sertraline is continued and haloperidol, 1 mg/d, is initiated. For the next 2 weeks, Mr. N continues to be oddly related, irritable, and paranoid, and experiences disturbed sleep and thought blocking. After an episode of impulsive aggression, the treatment team initiates aripiprazole, which is titrated to 30 mg/d for 1 week. Mr. N’s clinical status worsens; he is menacing toward other patients and his thinking is more disorganized, with loose associations and ideas of reference. He requires 4 injections of IM haloperidol, 5 mg, and several visits to the seclusion room over the next week. Haloperidol is increased to 30 mg/d over the next 10 days, then aripiprazole is discontinued because of a putative drug interaction with haloperidol. Following the medication changes Mr. N demonstrates better behavioral control, but still is grossly psychotic. While awaiting transfer to a state hospital, Mr. N receives a trial of olanzapine, 20 to 40 mg/d, for 2 weeks without significant benefit.

Several clinical trials demonstrate a significant reduction in intensity of psychotic symptoms with aripiprazole, which has a unique mechanism of action.¹ However, since its FDA approval in 2002, several case reports have described treatment-emergent psychotic symptoms associated with aripiprazole initiation. Over the past 40 years, reports of worsening psychosis associated with antipsychotics have been limited to patients with schizophrenia who were taking high dosages or who had high plasma concentrations, when anticholinergic delirium may have explained increased psychotic symptoms.^2-4

How can a drug effectively treat psychotic symptoms and occasionally worsen them? In this article, we discuss the relevant pharmacology and clinical literature on aripiprazole and try to make sense of this apparent paradox.

Unique pharmacologic profile

Antipsychotics have been reported to be either neutral antagonists or inverse agonists at the D2 receptor, based on in vitro data.⁵ Aripiprazole and its main metabolite, dehydroaripiprazole, originally were described as partial agonists at D2 dopamine receptors.^6,7 However, it appears aripiprazole’s pharmacologic action is better explained by the concept of functional selectivity. Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonistic.⁵

Researchers have hypothesized that the pathophysiology of schizophrenia may, in part, be caused by dysfunction of mesocorticolimbic dopaminergic neurons characterized by an enhanced sensitivity of postsynaptic D2 receptors and increased sensitivity to dopaminergic drugs.^8,9 In addition, chronic treatment with a D2 receptor antagonist is associated with increases in postsynaptic dopamine receptor density (ie, an increase in receptor reserve).^10,11 Upregulation of D2 receptors may explain several features seen in patients chronically treated with antipsychotics, including tardive dyskinesia¹² and rapid psychotic relapse after discontinuing an antipsychotic (supersensitivity psychosis).¹³ Because chronic antipsychotic treatment leads to high postsynaptic receptor reserve, aripiprazole initiation may produce overactivation of D2 receptors, which might worsen a patient’s condition.¹⁴ In vitro data^15-18 and clinical observations indicate that aripiprazole has intrinsic efficacy at D2 receptors, as do clinical observations, such as:

• its propensity to reduce serum prolactin¹⁹
• a decreased likelihood of producing extrapyramidal side effects despite >80% occupancy of D2 receptors⁶
• case reports documenting aripiprazole-associated mania,²⁰ improvement of risperidone-associated cognitive impairment,²¹ and pathologic gambling.²²

Emergence or worsening of psychotic symptoms or a marginal antipsychotic effect may occur if aripiprazole is indeed a postsynaptic D2 receptor agonist. An individual patient’s outcome likely would depend on his or her sensitivity to psychosis and concurrent or previous exposure to a D2 receptor antagonist. For example, stimulation of postsynaptic D2 receptors may be further augmented if the dosage of the previous antipsychotic was reduced or withdrawn before initiating aripiprazole because additional receptors would be available for interaction with aripiprazole.

Case reports

A literature review revealed 23 reports of treatment-emergent psychosis associated with aripiprazole initiation (Table). The mean age of the patients was 47 (range: 17 to 69) and 57% were men. Most patients (87%) were diagnosed with a schizophrenia-spectrum illness before aripiprazole initiation. Most (57%) had mild, stable, or no psychotic symptoms before aripiprazole initiation. Most were receiving relatively high doses of antipsychotics (average chlorpromazine equivalents [CPZE]: 648 mg/d) before aripiprazole initiation. This medication was either decreased or discontinued in 70% of patients.

Emergence or worsening of psychotic symptoms included agitation, aggressive behavior, and increased psychomotor activity. However, akathisia evaluation was described in only 2 reports: 1 author identified akathisia symptoms, but attributed them to a concomitant antipsychotic (fluphenazine)²³ and the other report specifically excluded the possibility of akathisia.²⁴ Two systematic studies have attempted to establish risk factors for aripiprazole-associated worsening psychosis (Box).^14,25

In our literature review, the mean final dose of aripiprazole was 21.5 mg/d (range: 2 to 60 mg/d). In the cases describing subsequent treatment, all but 1 patient were switched to another antipsychotic, including 2 whose psychotic symptoms stabilized with continuation of aripiprazole and addition of a second antipsychotic. Interestingly, in the case reported by Adan-Manes et al,²⁶ initial treatment with aripiprazole monotherapy was efficacious, but a subsequent trial of adjunctive aripiprazole resulted in worsening psychosis.

Table

Case reports: Treatment-emergent psychosis associated with aripiprazole

Other potential explanations

Aripiprazole’s manufacturer reported the incidence of psychosis-related adverse events in an analysis of 9 randomized schizophrenia trials.²⁷ The rates of psychosis-related adverse events ranged from 0.6% to 18%, but there was no apparent relationship to study design or method of transitioning to aripiprazole. Rates of psychosis-related adverse events were similar between aripiprazole and the control group (placebo in 3 studies, another antipsychotic in 2 studies).

Emergence or worsening of psychotic symptoms temporally associated with aripiprazole initiation does not necessarily imply causation. As in Mr. N’s case, it is not always possible to determine whether worsening psychosis is the natural disease course or a treatment effect. In addition, it is not possible to differentiate lack of efficacy from a true propensity for aripiprazole to worsen psychosis.

It also is conceivable discontinuation or dosage reduction of a previous antipsychotic would worsen psychotic symptoms or cause side effects. When significant changes in psychopathology or side effects develop during the transition from 1 antipsychotic to another, it is difficult to determine etiology. Specifically, rapid transition from a medication with significant anticholinergic and antihistaminic properties—such as quetiapine or olanzapine—to 1 without these properties—such as aripiprazole—may result in symptoms of activation, including restlessness, insomnia, and anxiety. Consequently, these symptoms could be mistaken for worsening psychosis.²⁸ Only 1 patient in this series was reported to abruptly discontinue an antipsychotic with significant anticholinergic properties (clozapine) before initiating aripiprazole.²⁴ Studies by Takeuchi et al¹⁴ and Pae et al²⁵ did not report the relative baseline use of antipsychotic medication with anticholinergic properties.

In a pooled analysis of treatment-emergent adverse events in 5 randomized clinical trials of patients receiving aripiprazole for acute relapse of schizophrenia, the incidence of akathisia was 10%, although it is not clear if this is a dose-related adverse effect.²⁹ Because akathisia may be confused for worsening psychosis,³⁰ it is possible akathisia was mistakenly identified as worsening psychotic symptoms in Mr. N’s case, as well as several reports from our literature review.

Covert akathisia is unlikely to explain worsening psychopathology observed in all patients in our literature review because confusion of akathisia and worsening psychosis is not a widespread phenomenon. In a post hoc analysis of pooled safety data from aripiprazole trials, Kane et al³¹ did not find a correlation between presence of akathisia and aripiprazole efficacy as measured by the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS negative, Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement, and percentage of responders. Pae et al²⁵ also noted there was no correlation between scores on the Barnes Akathisia Rating Scale and worsening psychopathology in patients switched to aripiprazole.

An antagonist always is an antagonist and clinicians have appreciated this concept since the days of chlorpromazine. The activity of aripiprazole, however, is on a pharmacologic continuum between a neutral antagonist and full agonist and currently there is no way to precisely determine the level of D2 receptor agonist action in a patient.

Although it is interesting to speculate that aripiprazole’s D2 receptor agonist action may contribute to worsening psychosis,^32-34 there are other plausible explanations to consider. Rapid transition from a drug with significant anticholinergic properties and aripiprazole-associated akathisia may contribute to worsening psychopathology in patients starting aripiprazole. Because covert side effects may be incorrectly identified as psychotic agitation, we cannot exclude this as a possible etiologic factor in Mr. N’s case as well as the cases in our literature review.

Related Resource

• Abilify [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Biperiden • Akineton
• Carbamazepine • Tegretol
• Chlorpromazine • Thorazine
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Divalproex • Depakote
• Duloxetine • Cymbalta
• Fluphenazine • Permitil, Prolixin
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Nortriptyline • Aventyl, Pamelor
• Methylphenidate • Concerta
• Molindone • Moban
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Propranolol • Inderal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Thyroxine • Synthroid
• Valproic acid • Depakene
• Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Mr. N, age 29, presents to the emergency department at the urging of his family because of poor self-care, bizarre behavior, and disturbed sleep. He first experienced psychiatric symptoms 10 years ago after his mother died. He became dysphoric and paranoid, displaying bizarre responses and behaviors with poor self-care and a gradual functional decline. He has been taking sertraline, 100 mg/d, for 10 years.

Upon arrival at the hospital’s inpatient unit, Mr. N is unkempt, oddly related, and paranoid. His affect is constricted. Mr. N displays thought blocking and possibly is responding to internal stimuli. Sertraline is continued and haloperidol, 1 mg/d, is initiated. For the next 2 weeks, Mr. N continues to be oddly related, irritable, and paranoid, and experiences disturbed sleep and thought blocking. After an episode of impulsive aggression, the treatment team initiates aripiprazole, which is titrated to 30 mg/d for 1 week. Mr. N’s clinical status worsens; he is menacing toward other patients and his thinking is more disorganized, with loose associations and ideas of reference. He requires 4 injections of IM haloperidol, 5 mg, and several visits to the seclusion room over the next week. Haloperidol is increased to 30 mg/d over the next 10 days, then aripiprazole is discontinued because of a putative drug interaction with haloperidol. Following the medication changes Mr. N demonstrates better behavioral control, but still is grossly psychotic. While awaiting transfer to a state hospital, Mr. N receives a trial of olanzapine, 20 to 40 mg/d, for 2 weeks without significant benefit.

Several clinical trials demonstrate a significant reduction in intensity of psychotic symptoms with aripiprazole, which has a unique mechanism of action.¹ However, since its FDA approval in 2002, several case reports have described treatment-emergent psychotic symptoms associated with aripiprazole initiation. Over the past 40 years, reports of worsening psychosis associated with antipsychotics have been limited to patients with schizophrenia who were taking high dosages or who had high plasma concentrations, when anticholinergic delirium may have explained increased psychotic symptoms.^2-4

How can a drug effectively treat psychotic symptoms and occasionally worsen them? In this article, we discuss the relevant pharmacology and clinical literature on aripiprazole and try to make sense of this apparent paradox.

Unique pharmacologic profile

Antipsychotics have been reported to be either neutral antagonists or inverse agonists at the D2 receptor, based on in vitro data.⁵ Aripiprazole and its main metabolite, dehydroaripiprazole, originally were described as partial agonists at D2 dopamine receptors.^6,7 However, it appears aripiprazole’s pharmacologic action is better explained by the concept of functional selectivity. Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonistic.⁵

Researchers have hypothesized that the pathophysiology of schizophrenia may, in part, be caused by dysfunction of mesocorticolimbic dopaminergic neurons characterized by an enhanced sensitivity of postsynaptic D2 receptors and increased sensitivity to dopaminergic drugs.^8,9 In addition, chronic treatment with a D2 receptor antagonist is associated with increases in postsynaptic dopamine receptor density (ie, an increase in receptor reserve).^10,11 Upregulation of D2 receptors may explain several features seen in patients chronically treated with antipsychotics, including tardive dyskinesia¹² and rapid psychotic relapse after discontinuing an antipsychotic (supersensitivity psychosis).¹³ Because chronic antipsychotic treatment leads to high postsynaptic receptor reserve, aripiprazole initiation may produce overactivation of D2 receptors, which might worsen a patient’s condition.¹⁴ In vitro data^15-18 and clinical observations indicate that aripiprazole has intrinsic efficacy at D2 receptors, as do clinical observations, such as:

• its propensity to reduce serum prolactin¹⁹
• a decreased likelihood of producing extrapyramidal side effects despite >80% occupancy of D2 receptors⁶
• case reports documenting aripiprazole-associated mania,²⁰ improvement of risperidone-associated cognitive impairment,²¹ and pathologic gambling.²²

Emergence or worsening of psychotic symptoms or a marginal antipsychotic effect may occur if aripiprazole is indeed a postsynaptic D2 receptor agonist. An individual patient’s outcome likely would depend on his or her sensitivity to psychosis and concurrent or previous exposure to a D2 receptor antagonist. For example, stimulation of postsynaptic D2 receptors may be further augmented if the dosage of the previous antipsychotic was reduced or withdrawn before initiating aripiprazole because additional receptors would be available for interaction with aripiprazole.

Case reports

A literature review revealed 23 reports of treatment-emergent psychosis associated with aripiprazole initiation (Table). The mean age of the patients was 47 (range: 17 to 69) and 57% were men. Most patients (87%) were diagnosed with a schizophrenia-spectrum illness before aripiprazole initiation. Most (57%) had mild, stable, or no psychotic symptoms before aripiprazole initiation. Most were receiving relatively high doses of antipsychotics (average chlorpromazine equivalents [CPZE]: 648 mg/d) before aripiprazole initiation. This medication was either decreased or discontinued in 70% of patients.

Emergence or worsening of psychotic symptoms included agitation, aggressive behavior, and increased psychomotor activity. However, akathisia evaluation was described in only 2 reports: 1 author identified akathisia symptoms, but attributed them to a concomitant antipsychotic (fluphenazine)²³ and the other report specifically excluded the possibility of akathisia.²⁴ Two systematic studies have attempted to establish risk factors for aripiprazole-associated worsening psychosis (Box).^14,25

In our literature review, the mean final dose of aripiprazole was 21.5 mg/d (range: 2 to 60 mg/d). In the cases describing subsequent treatment, all but 1 patient were switched to another antipsychotic, including 2 whose psychotic symptoms stabilized with continuation of aripiprazole and addition of a second antipsychotic. Interestingly, in the case reported by Adan-Manes et al,²⁶ initial treatment with aripiprazole monotherapy was efficacious, but a subsequent trial of adjunctive aripiprazole resulted in worsening psychosis.

Table

Case reports: Treatment-emergent psychosis associated with aripiprazole

Other potential explanations

Aripiprazole’s manufacturer reported the incidence of psychosis-related adverse events in an analysis of 9 randomized schizophrenia trials.²⁷ The rates of psychosis-related adverse events ranged from 0.6% to 18%, but there was no apparent relationship to study design or method of transitioning to aripiprazole. Rates of psychosis-related adverse events were similar between aripiprazole and the control group (placebo in 3 studies, another antipsychotic in 2 studies).

Emergence or worsening of psychotic symptoms temporally associated with aripiprazole initiation does not necessarily imply causation. As in Mr. N’s case, it is not always possible to determine whether worsening psychosis is the natural disease course or a treatment effect. In addition, it is not possible to differentiate lack of efficacy from a true propensity for aripiprazole to worsen psychosis.

It also is conceivable discontinuation or dosage reduction of a previous antipsychotic would worsen psychotic symptoms or cause side effects. When significant changes in psychopathology or side effects develop during the transition from 1 antipsychotic to another, it is difficult to determine etiology. Specifically, rapid transition from a medication with significant anticholinergic and antihistaminic properties—such as quetiapine or olanzapine—to 1 without these properties—such as aripiprazole—may result in symptoms of activation, including restlessness, insomnia, and anxiety. Consequently, these symptoms could be mistaken for worsening psychosis.²⁸ Only 1 patient in this series was reported to abruptly discontinue an antipsychotic with significant anticholinergic properties (clozapine) before initiating aripiprazole.²⁴ Studies by Takeuchi et al¹⁴ and Pae et al²⁵ did not report the relative baseline use of antipsychotic medication with anticholinergic properties.

In a pooled analysis of treatment-emergent adverse events in 5 randomized clinical trials of patients receiving aripiprazole for acute relapse of schizophrenia, the incidence of akathisia was 10%, although it is not clear if this is a dose-related adverse effect.²⁹ Because akathisia may be confused for worsening psychosis,³⁰ it is possible akathisia was mistakenly identified as worsening psychotic symptoms in Mr. N’s case, as well as several reports from our literature review.

Covert akathisia is unlikely to explain worsening psychopathology observed in all patients in our literature review because confusion of akathisia and worsening psychosis is not a widespread phenomenon. In a post hoc analysis of pooled safety data from aripiprazole trials, Kane et al³¹ did not find a correlation between presence of akathisia and aripiprazole efficacy as measured by the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS negative, Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement, and percentage of responders. Pae et al²⁵ also noted there was no correlation between scores on the Barnes Akathisia Rating Scale and worsening psychopathology in patients switched to aripiprazole.

An antagonist always is an antagonist and clinicians have appreciated this concept since the days of chlorpromazine. The activity of aripiprazole, however, is on a pharmacologic continuum between a neutral antagonist and full agonist and currently there is no way to precisely determine the level of D2 receptor agonist action in a patient.

Although it is interesting to speculate that aripiprazole’s D2 receptor agonist action may contribute to worsening psychosis,^32-34 there are other plausible explanations to consider. Rapid transition from a drug with significant anticholinergic properties and aripiprazole-associated akathisia may contribute to worsening psychopathology in patients starting aripiprazole. Because covert side effects may be incorrectly identified as psychotic agitation, we cannot exclude this as a possible etiologic factor in Mr. N’s case as well as the cases in our literature review.

Related Resource

• Abilify [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Biperiden • Akineton
• Carbamazepine • Tegretol
• Chlorpromazine • Thorazine
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Divalproex • Depakote
• Duloxetine • Cymbalta
• Fluphenazine • Permitil, Prolixin
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Nortriptyline • Aventyl, Pamelor
• Methylphenidate • Concerta
• Molindone • Moban
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Propranolol • Inderal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Thyroxine • Synthroid
• Valproic acid • Depakene
• Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Vague symptoms. Unexpected flares. Inconsistent manifestations. These characteristics can make diagnosis and treatment of chronic pelvic pain frustrating for both patient and physician. Most patients undergo myriad tests and studies to uncover the source of their pain—but a targeted pelvic exam may be all that is necessary to identify a prevalent but commonly overlooked cause of pelvic pain. Levator myalgia, myofascial pelvic pain syndrome, and pelvic floor spasm are all terms that describe a condition that may affect as many as 78% of women who are given a diagnosis of chronic pelvic pain.¹ This syndrome may be represented by an array of symptoms, including pelvic pressure, dyspareunia, rectal discomfort, and irritative urinary symptoms such as spasms, frequency, and urgency. It is characterized by the presence of tight, band-like pelvic muscles that reproduce the patient’s pain when palpated.²

Diagnosis of this syndrome often surprises the patient. Although the concept of a muscle spasm is not foreign, the location is unexpected. Patients and physicians alike may forget that there is a large complex of muscles that completely lines the pelvic girdle. To complicate matters, the patient often associates the onset of her symptoms with an acute event such as a “bad” urinary tract infection or pelvic or vaginal surgery, which may divert attention from the musculature. Although a muscle spasm may be the cause of the patient’s pain, it’s important to realize that an underlying process may have triggered the original spasm. To provide effective treatment of pain, therefore, you must identify the fundamental cause, assuming that it is reversible, rather than focus exclusively on symptoms.

Although there are many therapeutic options for levator myalgia, an appraisal of the extensive literature on these medications is beyond the scope of this article. Rather, we will review alternative treatment modalities and summarize the results of five trials that explored physical therapy, trigger-point or chemodenervation injection, and neuromodulation (TABLE).

Weighing the nonpharmaceutical options for treatment
of myofascial pelvic pain

Pelvic myofascial therapy offers relief—but qualified therapists may be scarce

FitzGerald MP, Anderson RU, Potts J, et al; Urological Pelvic Pain Collaborative Research Network. Randomized multicenter feasibility trial of myofascial physical therapy for the treatment of urological chronic pelvic pain syndromes. J Urology. 2009;182(2):570–580.

Physical therapy of the pelvic floor—otherwise known as pelvic myofascial therapy—requires a therapist who is highly trained and specialized in this technique. It is more invasive than other forms of rehabilitative therapy because of the need to perform transvaginal maneuvers (FIGURE 1).

This pilot study by the Urological Pelvic Pain Collaborative Research Network evaluated the ability of patients to adhere to pelvic myofascial therapy, the response of their pain to therapy, and adverse events associated with manual therapy. It found that patients were willing to undergo the therapy, despite the invasive nature of the maneuvers, because it was significantly effective.

Details of the study

Patients (both men and women) were randomized to myofascial physical therapy or global therapeutic massage. Myofascial therapy consisted of internal or vaginal manipulation of the trigger-point muscle bundles and tissues of the pelvic floor. It also focused on muscles of the hip girdle and abdomen. The comparison group underwent traditional Western full-body massage. In both groups, treatment lasted 1 hour every week, and participants agreed to 10 full treatments.

Patients were eligible for the study if they experienced pelvic pain, urinary frequency, or bladder discomfort in the previous 6 months. In addition, an examiner must have been able to elicit tenderness upon palpation of the pelvic floor during examination. Patients were excluded if they showed signs of urinary tract infection or dysmenorrhea.

A total of 47 patients were randomized—24 to global massage and 23 to myofascial physical therapy. Overall, the myofascial group experienced a significantly higher rate of improvement in the global response at 12 weeks than did patients in the global-massage group (57% vs 21%; P=.03). Patients were willing to engage in myofascial pelvic therapy, and adverse events were minor.

FIGURE 1 Transvaginal myofascial therapy
Physical therapy of the pelvic floor is more invasive than other forms of rehabilitative therapy because of the need to perform transvaginal maneuvers.

Need for specialized training may limit number of therapists

The randomized controlled study design renders these findings fairly reliable. Therapists were unmasked and aware of the treatment arms but were trained to make the different therapy sessions appear as similar as possible.

Although investigators were enthusiastic about their initial findings, additional studies are needed to validate the results. Moreover, these findings may be difficult to generalize because women who volunteer to participate in such a study may differ from the general population.

Nevertheless, patients who suffer from chronic pelvic pain may take heart that there is a nonpharmaceutical alternative to manage their symptoms, although availability is likely limited in many areas. Given the nature of the physical therapy required for this particular location of myofascial pain, specialized training is necessary for therapists. Despite motivated patients and well-informed providers, it may be difficult to find specialized therapists within local vicinities. Referrals to centers where this type of therapy is offered may be necessary.

The ideal agent for trigger-point injections remains a mystery

Langford CF, Udvari Nagy S, Ghoniem G M. Levator ani trigger point injections: An underutilized treatment for chronic pelvic pain. Neurourol Urodyn. 2007;26(1):59–62.

Abbott JA, Jarvis SK, Lyons SD, Thomson A, Vancaille TG. Botulinum toxin type A for chronic pain and pelvic floor spasm in women: a randomized controlled trial. Obstet Gynecol. 2006;108(4):915–923.

Trigger points are discrete, tender areas within a ridge of contracted muscle. These points may cause focal pain or referred pain upon irritation of the muscle.² Trigger-point injection therapy aims to anesthetize or relax these points by infiltrating the muscle with medications.

These two studies evaluated the value of trigger-point injections in the treatment of pelvic myofascial pain; they found that the injections provide relief, although the mechanism of action and the ideal agent remain to be determined.

Langford et al: Details of the study

In this prospective study, 18 women who had pelvic pain of at least 6 months’ duration and confirmed trigger points on examination underwent transvaginal injection of a solution of bupivacaine, lidocaine, and triamcinolone. They were assessed by questionnaire at baseline and 3 months after injection. Assessment included a visual analog scale for pain severity. Investigators defined success as a decrease in pain of 50% or more and global-satisfaction and global-cure visual scores of 60% or higher.

Thirteen of the 18 women (72.2%) improved after their first injection, with six women reporting a complete absence of pain. Overall, women reported significant decreases in pain and increases in the rates of satisfaction and cure, meeting the definition of success at 3 months after the injection.

Among the theories proposed to explain the mechanism of action of trigger-point injections are:

• disruption of reflex arcs within skeletal muscle
• release of endorphins
• mechanical changes in abnormally contracted muscle fibers.

This last theory highlights one of the limitations of this study—lack of a placebo arm. Could it be possible that the injection of any fluid produces the same effect?

This study was not designed to investigate the causal relationship between the injection of a particular solution and pain relief, but it does highlight the need for studies to clarify the mechanism of action, including use of a placebo. It also prompts questions about the duration of effect after a single injection.

Goal of chemodenervation is blocking of muscle activity

Botulinum toxin type A (Botox) blocks the release of acetylcholine from presynaptic neurons. The release of acetylcholine stimulates muscle contractions; therefore, blockage of its release reduces muscle activity. This type of chemodenervation has found widespread use, and botulinum toxin A now has approval from the Food and Drug Administration (FDA) for treatment of chronic migraine, limb spasticity, cervical dystonia, strabismus, hyperhidrosis, and facial cosmesis.³ Although it is not approved for pelvic floor levator spasm, its success in treating other myotonic disorders suggests that its application may be relevant.

Abbott et al: Details of the study

Abbott and colleagues performed a double-blind, randomized, controlled trial to compare injection of botulinum toxin A with injection of saline. They measured changes in the pain scale, quality of life, and vaginal pressure.

Women were eligible for the study if they had subjectively reported pelvic pain of more than 2 years’ duration and objective evidence of trigger points (on examination) and elevated vaginal resting pressure (by vaginal manometry). Neither the clinical research staff nor the patient knew the contents of the injections, but all women received a total of four—two at sites in the puborectalis muscle and two in the pubococcygeus muscle.

After periodic assessment by questionnaire and examination through 6 months after injection, no differences were found in the pain score or resting vaginal pressure between the group of women who received botulinum toxin A and the group who received placebo. However, each group experienced a significant reduction in pain and vaginal pressure, compared with baseline. And both groups reported improved quality of life, compared with baseline. Neither group reported voiding dysfunction.

Neuromodulation shows promise as treatment for pelvic myofascial pain

van Balken MR, Vandoninck V, Messelink, BJ, et al. Percutaneous tibial nerve stimulation as neuromodulative treatment of chronic pelvic pain. Eur Urol. 2003;43(2):158–163.

Zabihi N, Mourtzinos A, Maher MG, Raz S, Rodriguez LV. Short-term results of bilateral S2-S4 sacral neuromodulation for the treatment of refractory interstitial cystitis, painful bladder syndrome, and chronic pelvic pain. Int Urogynecol J Pelvic Floor Dysfunct. 2008;19(4):553–557.

Neuromodulation is the science of using electrical impulses to alter neuronal activities. The exact mechanisms of action are unclear, but the technology has been utilized to control symptoms of overactive bladder and urinary retention caused by poor relaxation of the urethral and pelvic floor muscles. While studying the effects of sacral nerve root neuromodulation on the bladder, investigators noted improvements in other symptoms, such as pelvic pain.

Neuromodulation of the sacral nerve roots may be achieved by direct conduction of electrical impulses from a lead implanted in the sacrum (sacral neuromodulation) or by the retrograde conduction of these impulses through the posterior tibial nerve (percutaneous tibial nerve stimulation, or PTNS) (FIGURE 2). The tibial nerve arises from sacral nerves L5 to S3 and is one of the larger branches of the sciatic nerve.

FIGURE 2 InterStim therapy
Stimulation of the sacral nerve has been used successfully to manage overactive bladder and urinary retention and may prove useful in the treatment of pelvic myofascial pain.

Van Balken et al: Details of the study

In this prospective observational study, 33 patients (both male and female) who had chronic pelvic pain by history and examination were treated with weekly, 30-minute outpatient sessions of PTNS for 12 weeks. Participants were asked to provide baseline pain scores and keep a diary of their pain. Quality-of-life questionnaires were also administered at baseline and at 12 weeks.

Investigators considered both subjective and objective success in their outcomes. If a patient elected to continue therapy, he or she was classified as a subjective success. Objective success required a decrease of at least 50% in the pain score. At the end of 12 weeks, although 33 patients (42%) wanted to continue therapy, only seven (21%) met the definition for objective success. Of those seven, six elected to continue therapy.

This study sheds light on a treatment modality that has not been studied adequately for the indication of pelvic pain but that may be promising in patients who have levator myalgia. Limitations of this study include the lack of a placebo arm, short-term outcome, and lack of localization of pain. Furthermore, although PTNS has FDA approval for treatment of urinary urgency, frequency, and urge incontinence, it is not approved for the treatment of pelvic pain. These preliminary findings demonstrate potential but, as with any new indication, long-term comparative studies are needed.

Zabihi et al: Details of the study

Patients in this retrospective study had a diagnosis of interstitial cystitis or chronic pelvic pain. Pelvic myofascial pain and trigger points were not required for eligibility. Thirty patients (21 women and nine men) had temporary placement of a lead containing four small electrodes along the S2 to S4 sacral nerve roots on both sides of the sacrum. They were then followed for a trial period of 2 to 4 weeks. To qualify for the final stage of the study, in which the leads were connected internally to a generator implanted in the buttocks, patients had to report improvement of at least 50% in their symptoms. If their improvement did not meet that threshold, the leads were removed.

Twenty-three patients (77%) met the criteria for permanent implantation. Of these patients, 42% reported improvement of more than 50% at 6 postoperative months. Quality-of-life scores also improved significantly.

Sacral neuromodulation is not FDA-approved for the treatment of chronic pelvic pain; further studies are needed before it can be recommended for this indication.

We want to hear from you! Tell us what you think.

Vague symptoms. Unexpected flares. Inconsistent manifestations. These characteristics can make diagnosis and treatment of chronic pelvic pain frustrating for both patient and physician. Most patients undergo myriad tests and studies to uncover the source of their pain—but a targeted pelvic exam may be all that is necessary to identify a prevalent but commonly overlooked cause of pelvic pain. Levator myalgia, myofascial pelvic pain syndrome, and pelvic floor spasm are all terms that describe a condition that may affect as many as 78% of women who are given a diagnosis of chronic pelvic pain.¹ This syndrome may be represented by an array of symptoms, including pelvic pressure, dyspareunia, rectal discomfort, and irritative urinary symptoms such as spasms, frequency, and urgency. It is characterized by the presence of tight, band-like pelvic muscles that reproduce the patient’s pain when palpated.²

Diagnosis of this syndrome often surprises the patient. Although the concept of a muscle spasm is not foreign, the location is unexpected. Patients and physicians alike may forget that there is a large complex of muscles that completely lines the pelvic girdle. To complicate matters, the patient often associates the onset of her symptoms with an acute event such as a “bad” urinary tract infection or pelvic or vaginal surgery, which may divert attention from the musculature. Although a muscle spasm may be the cause of the patient’s pain, it’s important to realize that an underlying process may have triggered the original spasm. To provide effective treatment of pain, therefore, you must identify the fundamental cause, assuming that it is reversible, rather than focus exclusively on symptoms.

Although there are many therapeutic options for levator myalgia, an appraisal of the extensive literature on these medications is beyond the scope of this article. Rather, we will review alternative treatment modalities and summarize the results of five trials that explored physical therapy, trigger-point or chemodenervation injection, and neuromodulation (TABLE).

Weighing the nonpharmaceutical options for treatment
of myofascial pelvic pain

Pelvic myofascial therapy offers relief—but qualified therapists may be scarce

FitzGerald MP, Anderson RU, Potts J, et al; Urological Pelvic Pain Collaborative Research Network. Randomized multicenter feasibility trial of myofascial physical therapy for the treatment of urological chronic pelvic pain syndromes. J Urology. 2009;182(2):570–580.

Physical therapy of the pelvic floor—otherwise known as pelvic myofascial therapy—requires a therapist who is highly trained and specialized in this technique. It is more invasive than other forms of rehabilitative therapy because of the need to perform transvaginal maneuvers (FIGURE 1).

This pilot study by the Urological Pelvic Pain Collaborative Research Network evaluated the ability of patients to adhere to pelvic myofascial therapy, the response of their pain to therapy, and adverse events associated with manual therapy. It found that patients were willing to undergo the therapy, despite the invasive nature of the maneuvers, because it was significantly effective.

Details of the study

Patients (both men and women) were randomized to myofascial physical therapy or global therapeutic massage. Myofascial therapy consisted of internal or vaginal manipulation of the trigger-point muscle bundles and tissues of the pelvic floor. It also focused on muscles of the hip girdle and abdomen. The comparison group underwent traditional Western full-body massage. In both groups, treatment lasted 1 hour every week, and participants agreed to 10 full treatments.

Patients were eligible for the study if they experienced pelvic pain, urinary frequency, or bladder discomfort in the previous 6 months. In addition, an examiner must have been able to elicit tenderness upon palpation of the pelvic floor during examination. Patients were excluded if they showed signs of urinary tract infection or dysmenorrhea.

A total of 47 patients were randomized—24 to global massage and 23 to myofascial physical therapy. Overall, the myofascial group experienced a significantly higher rate of improvement in the global response at 12 weeks than did patients in the global-massage group (57% vs 21%; P=.03). Patients were willing to engage in myofascial pelvic therapy, and adverse events were minor.

FIGURE 1 Transvaginal myofascial therapy
Physical therapy of the pelvic floor is more invasive than other forms of rehabilitative therapy because of the need to perform transvaginal maneuvers.

Need for specialized training may limit number of therapists

The randomized controlled study design renders these findings fairly reliable. Therapists were unmasked and aware of the treatment arms but were trained to make the different therapy sessions appear as similar as possible.

Although investigators were enthusiastic about their initial findings, additional studies are needed to validate the results. Moreover, these findings may be difficult to generalize because women who volunteer to participate in such a study may differ from the general population.

Nevertheless, patients who suffer from chronic pelvic pain may take heart that there is a nonpharmaceutical alternative to manage their symptoms, although availability is likely limited in many areas. Given the nature of the physical therapy required for this particular location of myofascial pain, specialized training is necessary for therapists. Despite motivated patients and well-informed providers, it may be difficult to find specialized therapists within local vicinities. Referrals to centers where this type of therapy is offered may be necessary.

The ideal agent for trigger-point injections remains a mystery

Langford CF, Udvari Nagy S, Ghoniem G M. Levator ani trigger point injections: An underutilized treatment for chronic pelvic pain. Neurourol Urodyn. 2007;26(1):59–62.

Abbott JA, Jarvis SK, Lyons SD, Thomson A, Vancaille TG. Botulinum toxin type A for chronic pain and pelvic floor spasm in women: a randomized controlled trial. Obstet Gynecol. 2006;108(4):915–923.

Trigger points are discrete, tender areas within a ridge of contracted muscle. These points may cause focal pain or referred pain upon irritation of the muscle.² Trigger-point injection therapy aims to anesthetize or relax these points by infiltrating the muscle with medications.

These two studies evaluated the value of trigger-point injections in the treatment of pelvic myofascial pain; they found that the injections provide relief, although the mechanism of action and the ideal agent remain to be determined.

Langford et al: Details of the study

In this prospective study, 18 women who had pelvic pain of at least 6 months’ duration and confirmed trigger points on examination underwent transvaginal injection of a solution of bupivacaine, lidocaine, and triamcinolone. They were assessed by questionnaire at baseline and 3 months after injection. Assessment included a visual analog scale for pain severity. Investigators defined success as a decrease in pain of 50% or more and global-satisfaction and global-cure visual scores of 60% or higher.

Thirteen of the 18 women (72.2%) improved after their first injection, with six women reporting a complete absence of pain. Overall, women reported significant decreases in pain and increases in the rates of satisfaction and cure, meeting the definition of success at 3 months after the injection.

Among the theories proposed to explain the mechanism of action of trigger-point injections are:

• disruption of reflex arcs within skeletal muscle
• release of endorphins
• mechanical changes in abnormally contracted muscle fibers.

This last theory highlights one of the limitations of this study—lack of a placebo arm. Could it be possible that the injection of any fluid produces the same effect?

This study was not designed to investigate the causal relationship between the injection of a particular solution and pain relief, but it does highlight the need for studies to clarify the mechanism of action, including use of a placebo. It also prompts questions about the duration of effect after a single injection.

Goal of chemodenervation is blocking of muscle activity

Botulinum toxin type A (Botox) blocks the release of acetylcholine from presynaptic neurons. The release of acetylcholine stimulates muscle contractions; therefore, blockage of its release reduces muscle activity. This type of chemodenervation has found widespread use, and botulinum toxin A now has approval from the Food and Drug Administration (FDA) for treatment of chronic migraine, limb spasticity, cervical dystonia, strabismus, hyperhidrosis, and facial cosmesis.³ Although it is not approved for pelvic floor levator spasm, its success in treating other myotonic disorders suggests that its application may be relevant.

Abbott et al: Details of the study

Abbott and colleagues performed a double-blind, randomized, controlled trial to compare injection of botulinum toxin A with injection of saline. They measured changes in the pain scale, quality of life, and vaginal pressure.

Women were eligible for the study if they had subjectively reported pelvic pain of more than 2 years’ duration and objective evidence of trigger points (on examination) and elevated vaginal resting pressure (by vaginal manometry). Neither the clinical research staff nor the patient knew the contents of the injections, but all women received a total of four—two at sites in the puborectalis muscle and two in the pubococcygeus muscle.

After periodic assessment by questionnaire and examination through 6 months after injection, no differences were found in the pain score or resting vaginal pressure between the group of women who received botulinum toxin A and the group who received placebo. However, each group experienced a significant reduction in pain and vaginal pressure, compared with baseline. And both groups reported improved quality of life, compared with baseline. Neither group reported voiding dysfunction.

Neuromodulation shows promise as treatment for pelvic myofascial pain

van Balken MR, Vandoninck V, Messelink, BJ, et al. Percutaneous tibial nerve stimulation as neuromodulative treatment of chronic pelvic pain. Eur Urol. 2003;43(2):158–163.

Zabihi N, Mourtzinos A, Maher MG, Raz S, Rodriguez LV. Short-term results of bilateral S2-S4 sacral neuromodulation for the treatment of refractory interstitial cystitis, painful bladder syndrome, and chronic pelvic pain. Int Urogynecol J Pelvic Floor Dysfunct. 2008;19(4):553–557.

Neuromodulation is the science of using electrical impulses to alter neuronal activities. The exact mechanisms of action are unclear, but the technology has been utilized to control symptoms of overactive bladder and urinary retention caused by poor relaxation of the urethral and pelvic floor muscles. While studying the effects of sacral nerve root neuromodulation on the bladder, investigators noted improvements in other symptoms, such as pelvic pain.

Neuromodulation of the sacral nerve roots may be achieved by direct conduction of electrical impulses from a lead implanted in the sacrum (sacral neuromodulation) or by the retrograde conduction of these impulses through the posterior tibial nerve (percutaneous tibial nerve stimulation, or PTNS) (FIGURE 2). The tibial nerve arises from sacral nerves L5 to S3 and is one of the larger branches of the sciatic nerve.

FIGURE 2 InterStim therapy
Stimulation of the sacral nerve has been used successfully to manage overactive bladder and urinary retention and may prove useful in the treatment of pelvic myofascial pain.

Van Balken et al: Details of the study

In this prospective observational study, 33 patients (both male and female) who had chronic pelvic pain by history and examination were treated with weekly, 30-minute outpatient sessions of PTNS for 12 weeks. Participants were asked to provide baseline pain scores and keep a diary of their pain. Quality-of-life questionnaires were also administered at baseline and at 12 weeks.

Investigators considered both subjective and objective success in their outcomes. If a patient elected to continue therapy, he or she was classified as a subjective success. Objective success required a decrease of at least 50% in the pain score. At the end of 12 weeks, although 33 patients (42%) wanted to continue therapy, only seven (21%) met the definition for objective success. Of those seven, six elected to continue therapy.

This study sheds light on a treatment modality that has not been studied adequately for the indication of pelvic pain but that may be promising in patients who have levator myalgia. Limitations of this study include the lack of a placebo arm, short-term outcome, and lack of localization of pain. Furthermore, although PTNS has FDA approval for treatment of urinary urgency, frequency, and urge incontinence, it is not approved for the treatment of pelvic pain. These preliminary findings demonstrate potential but, as with any new indication, long-term comparative studies are needed.

Zabihi et al: Details of the study

Patients in this retrospective study had a diagnosis of interstitial cystitis or chronic pelvic pain. Pelvic myofascial pain and trigger points were not required for eligibility. Thirty patients (21 women and nine men) had temporary placement of a lead containing four small electrodes along the S2 to S4 sacral nerve roots on both sides of the sacrum. They were then followed for a trial period of 2 to 4 weeks. To qualify for the final stage of the study, in which the leads were connected internally to a generator implanted in the buttocks, patients had to report improvement of at least 50% in their symptoms. If their improvement did not meet that threshold, the leads were removed.

Twenty-three patients (77%) met the criteria for permanent implantation. Of these patients, 42% reported improvement of more than 50% at 6 postoperative months. Quality-of-life scores also improved significantly.

Sacral neuromodulation is not FDA-approved for the treatment of chronic pelvic pain; further studies are needed before it can be recommended for this indication.

We want to hear from you! Tell us what you think.

Vague symptoms. Unexpected flares. Inconsistent manifestations. These characteristics can make diagnosis and treatment of chronic pelvic pain frustrating for both patient and physician. Most patients undergo myriad tests and studies to uncover the source of their pain—but a targeted pelvic exam may be all that is necessary to identify a prevalent but commonly overlooked cause of pelvic pain. Levator myalgia, myofascial pelvic pain syndrome, and pelvic floor spasm are all terms that describe a condition that may affect as many as 78% of women who are given a diagnosis of chronic pelvic pain.¹ This syndrome may be represented by an array of symptoms, including pelvic pressure, dyspareunia, rectal discomfort, and irritative urinary symptoms such as spasms, frequency, and urgency. It is characterized by the presence of tight, band-like pelvic muscles that reproduce the patient’s pain when palpated.²

Diagnosis of this syndrome often surprises the patient. Although the concept of a muscle spasm is not foreign, the location is unexpected. Patients and physicians alike may forget that there is a large complex of muscles that completely lines the pelvic girdle. To complicate matters, the patient often associates the onset of her symptoms with an acute event such as a “bad” urinary tract infection or pelvic or vaginal surgery, which may divert attention from the musculature. Although a muscle spasm may be the cause of the patient’s pain, it’s important to realize that an underlying process may have triggered the original spasm. To provide effective treatment of pain, therefore, you must identify the fundamental cause, assuming that it is reversible, rather than focus exclusively on symptoms.

Although there are many therapeutic options for levator myalgia, an appraisal of the extensive literature on these medications is beyond the scope of this article. Rather, we will review alternative treatment modalities and summarize the results of five trials that explored physical therapy, trigger-point or chemodenervation injection, and neuromodulation (TABLE).

Weighing the nonpharmaceutical options for treatment
of myofascial pelvic pain

Pelvic myofascial therapy offers relief—but qualified therapists may be scarce

FitzGerald MP, Anderson RU, Potts J, et al; Urological Pelvic Pain Collaborative Research Network. Randomized multicenter feasibility trial of myofascial physical therapy for the treatment of urological chronic pelvic pain syndromes. J Urology. 2009;182(2):570–580.

Physical therapy of the pelvic floor—otherwise known as pelvic myofascial therapy—requires a therapist who is highly trained and specialized in this technique. It is more invasive than other forms of rehabilitative therapy because of the need to perform transvaginal maneuvers (FIGURE 1).

This pilot study by the Urological Pelvic Pain Collaborative Research Network evaluated the ability of patients to adhere to pelvic myofascial therapy, the response of their pain to therapy, and adverse events associated with manual therapy. It found that patients were willing to undergo the therapy, despite the invasive nature of the maneuvers, because it was significantly effective.

Details of the study

Patients (both men and women) were randomized to myofascial physical therapy or global therapeutic massage. Myofascial therapy consisted of internal or vaginal manipulation of the trigger-point muscle bundles and tissues of the pelvic floor. It also focused on muscles of the hip girdle and abdomen. The comparison group underwent traditional Western full-body massage. In both groups, treatment lasted 1 hour every week, and participants agreed to 10 full treatments.

Patients were eligible for the study if they experienced pelvic pain, urinary frequency, or bladder discomfort in the previous 6 months. In addition, an examiner must have been able to elicit tenderness upon palpation of the pelvic floor during examination. Patients were excluded if they showed signs of urinary tract infection or dysmenorrhea.

A total of 47 patients were randomized—24 to global massage and 23 to myofascial physical therapy. Overall, the myofascial group experienced a significantly higher rate of improvement in the global response at 12 weeks than did patients in the global-massage group (57% vs 21%; P=.03). Patients were willing to engage in myofascial pelvic therapy, and adverse events were minor.

FIGURE 1 Transvaginal myofascial therapy
Physical therapy of the pelvic floor is more invasive than other forms of rehabilitative therapy because of the need to perform transvaginal maneuvers.

Need for specialized training may limit number of therapists

The randomized controlled study design renders these findings fairly reliable. Therapists were unmasked and aware of the treatment arms but were trained to make the different therapy sessions appear as similar as possible.

Although investigators were enthusiastic about their initial findings, additional studies are needed to validate the results. Moreover, these findings may be difficult to generalize because women who volunteer to participate in such a study may differ from the general population.

Nevertheless, patients who suffer from chronic pelvic pain may take heart that there is a nonpharmaceutical alternative to manage their symptoms, although availability is likely limited in many areas. Given the nature of the physical therapy required for this particular location of myofascial pain, specialized training is necessary for therapists. Despite motivated patients and well-informed providers, it may be difficult to find specialized therapists within local vicinities. Referrals to centers where this type of therapy is offered may be necessary.

The ideal agent for trigger-point injections remains a mystery

Langford CF, Udvari Nagy S, Ghoniem G M. Levator ani trigger point injections: An underutilized treatment for chronic pelvic pain. Neurourol Urodyn. 2007;26(1):59–62.

Abbott JA, Jarvis SK, Lyons SD, Thomson A, Vancaille TG. Botulinum toxin type A for chronic pain and pelvic floor spasm in women: a randomized controlled trial. Obstet Gynecol. 2006;108(4):915–923.

Trigger points are discrete, tender areas within a ridge of contracted muscle. These points may cause focal pain or referred pain upon irritation of the muscle.² Trigger-point injection therapy aims to anesthetize or relax these points by infiltrating the muscle with medications.

These two studies evaluated the value of trigger-point injections in the treatment of pelvic myofascial pain; they found that the injections provide relief, although the mechanism of action and the ideal agent remain to be determined.

Langford et al: Details of the study

In this prospective study, 18 women who had pelvic pain of at least 6 months’ duration and confirmed trigger points on examination underwent transvaginal injection of a solution of bupivacaine, lidocaine, and triamcinolone. They were assessed by questionnaire at baseline and 3 months after injection. Assessment included a visual analog scale for pain severity. Investigators defined success as a decrease in pain of 50% or more and global-satisfaction and global-cure visual scores of 60% or higher.

Thirteen of the 18 women (72.2%) improved after their first injection, with six women reporting a complete absence of pain. Overall, women reported significant decreases in pain and increases in the rates of satisfaction and cure, meeting the definition of success at 3 months after the injection.

Among the theories proposed to explain the mechanism of action of trigger-point injections are:

• disruption of reflex arcs within skeletal muscle
• release of endorphins
• mechanical changes in abnormally contracted muscle fibers.

This last theory highlights one of the limitations of this study—lack of a placebo arm. Could it be possible that the injection of any fluid produces the same effect?

This study was not designed to investigate the causal relationship between the injection of a particular solution and pain relief, but it does highlight the need for studies to clarify the mechanism of action, including use of a placebo. It also prompts questions about the duration of effect after a single injection.

Goal of chemodenervation is blocking of muscle activity

Botulinum toxin type A (Botox) blocks the release of acetylcholine from presynaptic neurons. The release of acetylcholine stimulates muscle contractions; therefore, blockage of its release reduces muscle activity. This type of chemodenervation has found widespread use, and botulinum toxin A now has approval from the Food and Drug Administration (FDA) for treatment of chronic migraine, limb spasticity, cervical dystonia, strabismus, hyperhidrosis, and facial cosmesis.³ Although it is not approved for pelvic floor levator spasm, its success in treating other myotonic disorders suggests that its application may be relevant.

Abbott et al: Details of the study

Abbott and colleagues performed a double-blind, randomized, controlled trial to compare injection of botulinum toxin A with injection of saline. They measured changes in the pain scale, quality of life, and vaginal pressure.

Women were eligible for the study if they had subjectively reported pelvic pain of more than 2 years’ duration and objective evidence of trigger points (on examination) and elevated vaginal resting pressure (by vaginal manometry). Neither the clinical research staff nor the patient knew the contents of the injections, but all women received a total of four—two at sites in the puborectalis muscle and two in the pubococcygeus muscle.

After periodic assessment by questionnaire and examination through 6 months after injection, no differences were found in the pain score or resting vaginal pressure between the group of women who received botulinum toxin A and the group who received placebo. However, each group experienced a significant reduction in pain and vaginal pressure, compared with baseline. And both groups reported improved quality of life, compared with baseline. Neither group reported voiding dysfunction.

Neuromodulation shows promise as treatment for pelvic myofascial pain

van Balken MR, Vandoninck V, Messelink, BJ, et al. Percutaneous tibial nerve stimulation as neuromodulative treatment of chronic pelvic pain. Eur Urol. 2003;43(2):158–163.

Zabihi N, Mourtzinos A, Maher MG, Raz S, Rodriguez LV. Short-term results of bilateral S2-S4 sacral neuromodulation for the treatment of refractory interstitial cystitis, painful bladder syndrome, and chronic pelvic pain. Int Urogynecol J Pelvic Floor Dysfunct. 2008;19(4):553–557.

Neuromodulation is the science of using electrical impulses to alter neuronal activities. The exact mechanisms of action are unclear, but the technology has been utilized to control symptoms of overactive bladder and urinary retention caused by poor relaxation of the urethral and pelvic floor muscles. While studying the effects of sacral nerve root neuromodulation on the bladder, investigators noted improvements in other symptoms, such as pelvic pain.

Neuromodulation of the sacral nerve roots may be achieved by direct conduction of electrical impulses from a lead implanted in the sacrum (sacral neuromodulation) or by the retrograde conduction of these impulses through the posterior tibial nerve (percutaneous tibial nerve stimulation, or PTNS) (FIGURE 2). The tibial nerve arises from sacral nerves L5 to S3 and is one of the larger branches of the sciatic nerve.

FIGURE 2 InterStim therapy
Stimulation of the sacral nerve has been used successfully to manage overactive bladder and urinary retention and may prove useful in the treatment of pelvic myofascial pain.

Van Balken et al: Details of the study

In this prospective observational study, 33 patients (both male and female) who had chronic pelvic pain by history and examination were treated with weekly, 30-minute outpatient sessions of PTNS for 12 weeks. Participants were asked to provide baseline pain scores and keep a diary of their pain. Quality-of-life questionnaires were also administered at baseline and at 12 weeks.

Investigators considered both subjective and objective success in their outcomes. If a patient elected to continue therapy, he or she was classified as a subjective success. Objective success required a decrease of at least 50% in the pain score. At the end of 12 weeks, although 33 patients (42%) wanted to continue therapy, only seven (21%) met the definition for objective success. Of those seven, six elected to continue therapy.

This study sheds light on a treatment modality that has not been studied adequately for the indication of pelvic pain but that may be promising in patients who have levator myalgia. Limitations of this study include the lack of a placebo arm, short-term outcome, and lack of localization of pain. Furthermore, although PTNS has FDA approval for treatment of urinary urgency, frequency, and urge incontinence, it is not approved for the treatment of pelvic pain. These preliminary findings demonstrate potential but, as with any new indication, long-term comparative studies are needed.

Zabihi et al: Details of the study

Patients in this retrospective study had a diagnosis of interstitial cystitis or chronic pelvic pain. Pelvic myofascial pain and trigger points were not required for eligibility. Thirty patients (21 women and nine men) had temporary placement of a lead containing four small electrodes along the S2 to S4 sacral nerve roots on both sides of the sacrum. They were then followed for a trial period of 2 to 4 weeks. To qualify for the final stage of the study, in which the leads were connected internally to a generator implanted in the buttocks, patients had to report improvement of at least 50% in their symptoms. If their improvement did not meet that threshold, the leads were removed.

Twenty-three patients (77%) met the criteria for permanent implantation. Of these patients, 42% reported improvement of more than 50% at 6 postoperative months. Quality-of-life scores also improved significantly.

Sacral neuromodulation is not FDA-approved for the treatment of chronic pelvic pain; further studies are needed before it can be recommended for this indication.

We want to hear from you! Tell us what you think.

As a scientist and certified colon therapist with a colon hydrotherapy practice, I was concerned by the lack of objectivity in your recent article, “The dangers of colon cleansing” (J Fam Pract. 2011;60:454-457). The authors cited literature describing adverse effects associated with common laxative preparations used prior to colonoscopy exams, such as oral sodium phosphate or polyethylene glycol, but neither one is generally used by patients looking to colon cleanse to “enhance their well-being.” Ironically, the use of colon hydrotherapy is growing in popularity as an alternative to these laxatives for colonoscopy prep,¹ yet the authors made no mention of this.

The article also contained jumps in logic that misrepresent colon cleansing in general, and colon hydrotherapy in particular. For example, the first case study involved a 31-year-old with Crohn’s disease—a specific contraindication for colon therapy. Therapists certified by the Global Professional Association for Colon Therapy (http://GPACT.org) are taught to give extensive health background questionnaires before administering colon hydrotherapy, so it is difficult to determine whether the therapist or the patient was at fault for failure to disclose her health status. Other case reports the authors cited described isolated events that either involved people who already had severe health problems or could not be attributed to colon hydrotherapy with certainty.

While there is no denying the paucity of studies on the potential benefits of colonic irrigation, it is unfortunate that the authors chose to omit the few studies that have been conducted. One study found that daily water irrigations in patients who underwent sigmoidostomies for rectal cancer were not associated with alterations in the colonic mucosa structure.² Others determined that colonic irrigation was an effective alternative for the treatment of persistent fecal incontinence after dynamic graciloplasty³ and low anterior resection for a rectal carcinoma.⁴ In addition, the potential benefits of colonic irrigation have been shown in rats following the induction of pancreatitis by intraduodenal injection of sodium taurocholate.⁵

There are inherent risks to most, if not all, medical treatments, whether given by an allopathic doctor or alternative health practitioner. However, the huge number of colon hydrotherapy sessions performed worldwide has resulted in a vast database of testimonials to the positive effects of this therapy.

Melisa Bunderson-Schelvan, PhD
Missoula, Mont

As a scientist and certified colon therapist with a colon hydrotherapy practice, I was concerned by the lack of objectivity in your recent article, “The dangers of colon cleansing” (J Fam Pract. 2011;60:454-457). The authors cited literature describing adverse effects associated with common laxative preparations used prior to colonoscopy exams, such as oral sodium phosphate or polyethylene glycol, but neither one is generally used by patients looking to colon cleanse to “enhance their well-being.” Ironically, the use of colon hydrotherapy is growing in popularity as an alternative to these laxatives for colonoscopy prep,¹ yet the authors made no mention of this.

The article also contained jumps in logic that misrepresent colon cleansing in general, and colon hydrotherapy in particular. For example, the first case study involved a 31-year-old with Crohn’s disease—a specific contraindication for colon therapy. Therapists certified by the Global Professional Association for Colon Therapy (http://GPACT.org) are taught to give extensive health background questionnaires before administering colon hydrotherapy, so it is difficult to determine whether the therapist or the patient was at fault for failure to disclose her health status. Other case reports the authors cited described isolated events that either involved people who already had severe health problems or could not be attributed to colon hydrotherapy with certainty.

While there is no denying the paucity of studies on the potential benefits of colonic irrigation, it is unfortunate that the authors chose to omit the few studies that have been conducted. One study found that daily water irrigations in patients who underwent sigmoidostomies for rectal cancer were not associated with alterations in the colonic mucosa structure.² Others determined that colonic irrigation was an effective alternative for the treatment of persistent fecal incontinence after dynamic graciloplasty³ and low anterior resection for a rectal carcinoma.⁴ In addition, the potential benefits of colonic irrigation have been shown in rats following the induction of pancreatitis by intraduodenal injection of sodium taurocholate.⁵

There are inherent risks to most, if not all, medical treatments, whether given by an allopathic doctor or alternative health practitioner. However, the huge number of colon hydrotherapy sessions performed worldwide has resulted in a vast database of testimonials to the positive effects of this therapy.

Melisa Bunderson-Schelvan, PhD
Missoula, Mont

As a scientist and certified colon therapist with a colon hydrotherapy practice, I was concerned by the lack of objectivity in your recent article, “The dangers of colon cleansing” (J Fam Pract. 2011;60:454-457). The authors cited literature describing adverse effects associated with common laxative preparations used prior to colonoscopy exams, such as oral sodium phosphate or polyethylene glycol, but neither one is generally used by patients looking to colon cleanse to “enhance their well-being.” Ironically, the use of colon hydrotherapy is growing in popularity as an alternative to these laxatives for colonoscopy prep,¹ yet the authors made no mention of this.

The article also contained jumps in logic that misrepresent colon cleansing in general, and colon hydrotherapy in particular. For example, the first case study involved a 31-year-old with Crohn’s disease—a specific contraindication for colon therapy. Therapists certified by the Global Professional Association for Colon Therapy (http://GPACT.org) are taught to give extensive health background questionnaires before administering colon hydrotherapy, so it is difficult to determine whether the therapist or the patient was at fault for failure to disclose her health status. Other case reports the authors cited described isolated events that either involved people who already had severe health problems or could not be attributed to colon hydrotherapy with certainty.

While there is no denying the paucity of studies on the potential benefits of colonic irrigation, it is unfortunate that the authors chose to omit the few studies that have been conducted. One study found that daily water irrigations in patients who underwent sigmoidostomies for rectal cancer were not associated with alterations in the colonic mucosa structure.² Others determined that colonic irrigation was an effective alternative for the treatment of persistent fecal incontinence after dynamic graciloplasty³ and low anterior resection for a rectal carcinoma.⁴ In addition, the potential benefits of colonic irrigation have been shown in rats following the induction of pancreatitis by intraduodenal injection of sodium taurocholate.⁵

There are inherent risks to most, if not all, medical treatments, whether given by an allopathic doctor or alternative health practitioner. However, the huge number of colon hydrotherapy sessions performed worldwide has resulted in a vast database of testimonials to the positive effects of this therapy.

Melisa Bunderson-Schelvan, PhD
Missoula, Mont

ILLUSTRATIVE CASE

A 64-year-old woman with osteoarthritis (OA) of both knees reports that acetaminophen does not relieve the pain, and both ibuprofen and naproxen give her an upset stomach. She wonders if glucosamine and chondroitin would help relieve the pain. How should you respond?

Degenerative joint disease is a common and frustrating problem for patients and clinicians. Symptomatic knee OA has a prevalence of 16% among adults older than 45 years, and is one of the top 5 reasons for disability in noninstitutionalized adults.² With no highly effective treatment for OA of the hip or knee other than joint replacement surgery, patients often turn to unproven over-the-counter remedies. Individuals with OA spend about $2600 per year out-of-pocket on disease-related expenses.²

Trials of these supplements have had mixed results
Glucosamine and chondroitin have been touted as beneficial, and sales have grown rapidly over the last decade, reaching nearly $900 million in the United States in 2008 alone.³ There have been many randomized trials of these supplements, with inconsistent results.

Larger and higher quality studies have found little or no effect, while smaller studies reported that glucosamine and chondroitin helped to relieve joint pain. A meta-analysis published in 2000 found 15 studies and reported moderate to large effect sizes, but the authors noted that quality issues and publication bias probably exaggerated the benefit.⁴ An updated Cochrane meta-analysis of 25 randomized controlled trials (RCTs), published in 2009, found little benefit from glucosamine. A subgroup analysis found that one company’s preparation appeared to be beneficial, but all 14 studies of that particular formulation had some connection with the manufacturer.⁵

STUDY SUMMARY: Effects of glucosamine and chondroitin, alone or together, were small

The meta-analysis we review in this PURL only included RCTs with an average of ≥100 patients with hip or knee OA in each group.¹ This was based on the minimum sample size needed to detect a small or moderate difference between the 2 groups (roughly 1 cm on a 10-cm visual analogue scale [VAS]). The authors found 10 eligible RCTs with a total of 3803 patients; the average age of participants ranged from 58 to 66 years. Most of the trials studied knee arthritis, and most were sponsored by pharmaceutical firms.

Included studies had to compare glucosamine sulphate, glucosamine hydrochloride, chondroitin sulphate, or a combination, either with a placebo or head-to-head. Minimum daily doses were 800 mg chondroitin and 1500 mg glucosamine. The primary outcome was absolute pain intensity over the duration of the study. The authors summarized pain scores every 3 months for up to 2 years; they also analyzed changes in joint space narrowing in the studies reporting that measure.

The authors used a sophisticated framework that adjusted for comparisons over time and between studies, allowing them to increase the power, and likely the accuracy, of their comparisons. They reported outcomes as effect sizes, then translated the findings to a real-world outcome by converting results to a 10-cm VAS. Typically, an effect size of 0.2 standard deviation (SD) units is considered small, 0.5 SD units is a moderate difference, and 0.8 SD units is large. The authors set their threshold for a clinically important difference at 0.37 SD units, which translated to a 0.9 cm change on a 10-cm VAS—a generally accepted minimal clinically significant difference in pain.

They found that all 3 interventions (glucosamine alone, chondroitin alone, and a combination) were statistically better than placebo, with very little difference in outcomes over time. Compared with placebo, VAS improvements were 0.4 cm for glucosamine (95% confidence interval [CI], 0.1-0.7), 0.3 cm for chondroitin (95% CI, 0-0.7) and 0.5 cm for the combination (95% CI, 0-0.9). All of these improvements in pain were less than the authors’ defined minimum clinically significant improvement of 0.9 cm on a 10-cm scale.

Among the 6 trials that reported on joint space narrowing, the changes were minute and not statistically significant. There was a net difference between treatment and placebo groups of less than 0.2 mm (an effect size ≤0.16 SD units). There was no evidence of increased risk of adverse effects or increased dropout rates with any of the substances.

WHAT’S NEW: Study results leave little room for doubt

This meta-analysis used more sophisticated comparison techniques and used only larger (and probably better quality) studies than previous meta-analyses. However, inclusion and exclusion were not based on any study quality criteria.

The authors found that glucosamine and chondroitin, used alone or in combination, provide little benefit in terms of pain relief of OA of the knee or hip compared with placebo, and contend that we should recommend against patients buying them. This meta-analysis is consistent with the American Academy of Orthopedic Surgeons 2008 guideline for knee OA, which recommends not using glucosamine and/or chondroitin based on good evidence.⁶

CAVEATS: Rate of joint replacement was not considered

This meta-analysis did not study the effect of these supplements on joint replacement. In a 5-year follow-up study after completion of 2 of the RCTs included in this meta-analysis, the relative risk of total joint replacement was 0.43 (95% CI, 0.2-0.92) for those in the glucosamine group (who had taken 1500 mg glucosamine sulphate for 12-36 months) compared with placebo (NNT=12).⁷ However, the authors were only able to follow up with 81% of the original participants. In the meta-analysis reported here, the difference in joint space narrowing was unlikely to be clinically significant or to lead to a difference in joint replacement rates.

Among the studies included in the meta-analysis, commercially funded trials had a greater decrease in pain with glucosamine or chondroitin compared with independent trials. This did not change the overall outcome of the meta-analysis, thereby supporting the validity of the results.

CHALLENGES TO IMPLEMENTATION: These supplements are available OTC

There are few barriers to advising patients not to use these products. Since glucosamine and chondroitin are available over-the-counter, however, patients have ready access to them, even if their doctors don’t recommend them. Several meta-analyses have not found an increased risk of harm from these products (other than the expense).^1,5

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 64-year-old woman with osteoarthritis (OA) of both knees reports that acetaminophen does not relieve the pain, and both ibuprofen and naproxen give her an upset stomach. She wonders if glucosamine and chondroitin would help relieve the pain. How should you respond?

Degenerative joint disease is a common and frustrating problem for patients and clinicians. Symptomatic knee OA has a prevalence of 16% among adults older than 45 years, and is one of the top 5 reasons for disability in noninstitutionalized adults.² With no highly effective treatment for OA of the hip or knee other than joint replacement surgery, patients often turn to unproven over-the-counter remedies. Individuals with OA spend about $2600 per year out-of-pocket on disease-related expenses.²

Trials of these supplements have had mixed results
Glucosamine and chondroitin have been touted as beneficial, and sales have grown rapidly over the last decade, reaching nearly $900 million in the United States in 2008 alone.³ There have been many randomized trials of these supplements, with inconsistent results.

Larger and higher quality studies have found little or no effect, while smaller studies reported that glucosamine and chondroitin helped to relieve joint pain. A meta-analysis published in 2000 found 15 studies and reported moderate to large effect sizes, but the authors noted that quality issues and publication bias probably exaggerated the benefit.⁴ An updated Cochrane meta-analysis of 25 randomized controlled trials (RCTs), published in 2009, found little benefit from glucosamine. A subgroup analysis found that one company’s preparation appeared to be beneficial, but all 14 studies of that particular formulation had some connection with the manufacturer.⁵

STUDY SUMMARY: Effects of glucosamine and chondroitin, alone or together, were small

The meta-analysis we review in this PURL only included RCTs with an average of ≥100 patients with hip or knee OA in each group.¹ This was based on the minimum sample size needed to detect a small or moderate difference between the 2 groups (roughly 1 cm on a 10-cm visual analogue scale [VAS]). The authors found 10 eligible RCTs with a total of 3803 patients; the average age of participants ranged from 58 to 66 years. Most of the trials studied knee arthritis, and most were sponsored by pharmaceutical firms.

Included studies had to compare glucosamine sulphate, glucosamine hydrochloride, chondroitin sulphate, or a combination, either with a placebo or head-to-head. Minimum daily doses were 800 mg chondroitin and 1500 mg glucosamine. The primary outcome was absolute pain intensity over the duration of the study. The authors summarized pain scores every 3 months for up to 2 years; they also analyzed changes in joint space narrowing in the studies reporting that measure.

The authors used a sophisticated framework that adjusted for comparisons over time and between studies, allowing them to increase the power, and likely the accuracy, of their comparisons. They reported outcomes as effect sizes, then translated the findings to a real-world outcome by converting results to a 10-cm VAS. Typically, an effect size of 0.2 standard deviation (SD) units is considered small, 0.5 SD units is a moderate difference, and 0.8 SD units is large. The authors set their threshold for a clinically important difference at 0.37 SD units, which translated to a 0.9 cm change on a 10-cm VAS—a generally accepted minimal clinically significant difference in pain.

They found that all 3 interventions (glucosamine alone, chondroitin alone, and a combination) were statistically better than placebo, with very little difference in outcomes over time. Compared with placebo, VAS improvements were 0.4 cm for glucosamine (95% confidence interval [CI], 0.1-0.7), 0.3 cm for chondroitin (95% CI, 0-0.7) and 0.5 cm for the combination (95% CI, 0-0.9). All of these improvements in pain were less than the authors’ defined minimum clinically significant improvement of 0.9 cm on a 10-cm scale.

Among the 6 trials that reported on joint space narrowing, the changes were minute and not statistically significant. There was a net difference between treatment and placebo groups of less than 0.2 mm (an effect size ≤0.16 SD units). There was no evidence of increased risk of adverse effects or increased dropout rates with any of the substances.

WHAT’S NEW: Study results leave little room for doubt

This meta-analysis used more sophisticated comparison techniques and used only larger (and probably better quality) studies than previous meta-analyses. However, inclusion and exclusion were not based on any study quality criteria.

The authors found that glucosamine and chondroitin, used alone or in combination, provide little benefit in terms of pain relief of OA of the knee or hip compared with placebo, and contend that we should recommend against patients buying them. This meta-analysis is consistent with the American Academy of Orthopedic Surgeons 2008 guideline for knee OA, which recommends not using glucosamine and/or chondroitin based on good evidence.⁶

CAVEATS: Rate of joint replacement was not considered

This meta-analysis did not study the effect of these supplements on joint replacement. In a 5-year follow-up study after completion of 2 of the RCTs included in this meta-analysis, the relative risk of total joint replacement was 0.43 (95% CI, 0.2-0.92) for those in the glucosamine group (who had taken 1500 mg glucosamine sulphate for 12-36 months) compared with placebo (NNT=12).⁷ However, the authors were only able to follow up with 81% of the original participants. In the meta-analysis reported here, the difference in joint space narrowing was unlikely to be clinically significant or to lead to a difference in joint replacement rates.

Among the studies included in the meta-analysis, commercially funded trials had a greater decrease in pain with glucosamine or chondroitin compared with independent trials. This did not change the overall outcome of the meta-analysis, thereby supporting the validity of the results.

CHALLENGES TO IMPLEMENTATION: These supplements are available OTC

There are few barriers to advising patients not to use these products. Since glucosamine and chondroitin are available over-the-counter, however, patients have ready access to them, even if their doctors don’t recommend them. Several meta-analyses have not found an increased risk of harm from these products (other than the expense).^1,5

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 64-year-old woman with osteoarthritis (OA) of both knees reports that acetaminophen does not relieve the pain, and both ibuprofen and naproxen give her an upset stomach. She wonders if glucosamine and chondroitin would help relieve the pain. How should you respond?

Degenerative joint disease is a common and frustrating problem for patients and clinicians. Symptomatic knee OA has a prevalence of 16% among adults older than 45 years, and is one of the top 5 reasons for disability in noninstitutionalized adults.² With no highly effective treatment for OA of the hip or knee other than joint replacement surgery, patients often turn to unproven over-the-counter remedies. Individuals with OA spend about $2600 per year out-of-pocket on disease-related expenses.²

Trials of these supplements have had mixed results
Glucosamine and chondroitin have been touted as beneficial, and sales have grown rapidly over the last decade, reaching nearly $900 million in the United States in 2008 alone.³ There have been many randomized trials of these supplements, with inconsistent results.

Larger and higher quality studies have found little or no effect, while smaller studies reported that glucosamine and chondroitin helped to relieve joint pain. A meta-analysis published in 2000 found 15 studies and reported moderate to large effect sizes, but the authors noted that quality issues and publication bias probably exaggerated the benefit.⁴ An updated Cochrane meta-analysis of 25 randomized controlled trials (RCTs), published in 2009, found little benefit from glucosamine. A subgroup analysis found that one company’s preparation appeared to be beneficial, but all 14 studies of that particular formulation had some connection with the manufacturer.⁵

STUDY SUMMARY: Effects of glucosamine and chondroitin, alone or together, were small

The meta-analysis we review in this PURL only included RCTs with an average of ≥100 patients with hip or knee OA in each group.¹ This was based on the minimum sample size needed to detect a small or moderate difference between the 2 groups (roughly 1 cm on a 10-cm visual analogue scale [VAS]). The authors found 10 eligible RCTs with a total of 3803 patients; the average age of participants ranged from 58 to 66 years. Most of the trials studied knee arthritis, and most were sponsored by pharmaceutical firms.

Included studies had to compare glucosamine sulphate, glucosamine hydrochloride, chondroitin sulphate, or a combination, either with a placebo or head-to-head. Minimum daily doses were 800 mg chondroitin and 1500 mg glucosamine. The primary outcome was absolute pain intensity over the duration of the study. The authors summarized pain scores every 3 months for up to 2 years; they also analyzed changes in joint space narrowing in the studies reporting that measure.

The authors used a sophisticated framework that adjusted for comparisons over time and between studies, allowing them to increase the power, and likely the accuracy, of their comparisons. They reported outcomes as effect sizes, then translated the findings to a real-world outcome by converting results to a 10-cm VAS. Typically, an effect size of 0.2 standard deviation (SD) units is considered small, 0.5 SD units is a moderate difference, and 0.8 SD units is large. The authors set their threshold for a clinically important difference at 0.37 SD units, which translated to a 0.9 cm change on a 10-cm VAS—a generally accepted minimal clinically significant difference in pain.

They found that all 3 interventions (glucosamine alone, chondroitin alone, and a combination) were statistically better than placebo, with very little difference in outcomes over time. Compared with placebo, VAS improvements were 0.4 cm for glucosamine (95% confidence interval [CI], 0.1-0.7), 0.3 cm for chondroitin (95% CI, 0-0.7) and 0.5 cm for the combination (95% CI, 0-0.9). All of these improvements in pain were less than the authors’ defined minimum clinically significant improvement of 0.9 cm on a 10-cm scale.

Among the 6 trials that reported on joint space narrowing, the changes were minute and not statistically significant. There was a net difference between treatment and placebo groups of less than 0.2 mm (an effect size ≤0.16 SD units). There was no evidence of increased risk of adverse effects or increased dropout rates with any of the substances.

WHAT’S NEW: Study results leave little room for doubt

This meta-analysis used more sophisticated comparison techniques and used only larger (and probably better quality) studies than previous meta-analyses. However, inclusion and exclusion were not based on any study quality criteria.

The authors found that glucosamine and chondroitin, used alone or in combination, provide little benefit in terms of pain relief of OA of the knee or hip compared with placebo, and contend that we should recommend against patients buying them. This meta-analysis is consistent with the American Academy of Orthopedic Surgeons 2008 guideline for knee OA, which recommends not using glucosamine and/or chondroitin based on good evidence.⁶

CAVEATS: Rate of joint replacement was not considered

This meta-analysis did not study the effect of these supplements on joint replacement. In a 5-year follow-up study after completion of 2 of the RCTs included in this meta-analysis, the relative risk of total joint replacement was 0.43 (95% CI, 0.2-0.92) for those in the glucosamine group (who had taken 1500 mg glucosamine sulphate for 12-36 months) compared with placebo (NNT=12).⁷ However, the authors were only able to follow up with 81% of the original participants. In the meta-analysis reported here, the difference in joint space narrowing was unlikely to be clinically significant or to lead to a difference in joint replacement rates.

Among the studies included in the meta-analysis, commercially funded trials had a greater decrease in pain with glucosamine or chondroitin compared with independent trials. This did not change the overall outcome of the meta-analysis, thereby supporting the validity of the results.

CHALLENGES TO IMPLEMENTATION: These supplements are available OTC

There are few barriers to advising patients not to use these products. Since glucosamine and chondroitin are available over-the-counter, however, patients have ready access to them, even if their doctors don’t recommend them. Several meta-analyses have not found an increased risk of harm from these products (other than the expense).^1,5

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

Evidence summary

A prospective study compared the bowel function of 106 adults (85 women) who underwent laparoscopic cholecystectomy with bowel function of 37 women who had laparoscopic sterilization (and served as controls).¹ The investigators gave bowel function questionnaires to both groups before surgery and 2 to 6 months afterward. They found no significant differences in bowel function between the groups.

Of the 6 women in the cholecystectomy group who reported diarrhea, only one had new-onset diarrhea, and it was “mild.” No men reported bowel function changes.¹

Case studies suggest benefit from bile acid binders
When postcholecystectomy diarrhea does occur, the best treatment is unclear in the absence of randomized controlled trials. Case reports and case series support using bile acid binders based on the hypothesis that bile acid malabsorption causes the diarrhea.

The largest case series followed 26 postcholecystectomy patients with chronic diarrhea, defined as more than 3 liquid stools in 24 hours for an average of 3.9 years (range, 3 months to 13 years). Twenty-five of the 26 (96%) had severe bile acid malabsorption.

Cholestyramine, in doses of 2 to 12 g/d “normalized bowel movements” in 23 of the 25 patients with malabsorption (92%). When treatment was suspended, diarrhea recurred in 9 of the 23 (39%); bowel habits remained regular in 14 (61%).²

A smaller case series studied 8 patients who had postcholecystectomy diarrhea, defined as more than 4 loose stools in a 24-hour period for 1 to 20 years. Six of the 8 had elevated stool bile acids and stool weight greater than 200 g/24 hours. All 6 had less frequent bowel movements within 72 hours of starting oral cholestyramine at 4 to 16 g/d (adjusting the dose to maintain 1 bowel movement daily). Diarrhea recurred in all of the patients after they stopped cholestyramine.³

A single case report of a 71-year-old man who had 4 to 6 loose stools a day for 4 years after cholecystectomy noted improvement to 2 to 3 stools daily when he was treated with either colestipol or psyllium hydrophilic mucilloid.⁴

Recommendations

We found no consensus statements regarding treatment of postcholecystectomy diarrhea. A gastroenterology textbook notes that diarrhea occurs in as many as 20% of patients.⁵ The authors recommend nightly bile acid binders and, in refractory cases, opiate antidiarrheals.

An internal medicine textbook states that postcholecystectomy diarrhea—defined as 3 or more watery bowel movements per day—occurs in 5% to 10% of patients.⁶ The authors recommend treatment with cholestyramine or colestipol.

Evidence summary

A prospective study compared the bowel function of 106 adults (85 women) who underwent laparoscopic cholecystectomy with bowel function of 37 women who had laparoscopic sterilization (and served as controls).¹ The investigators gave bowel function questionnaires to both groups before surgery and 2 to 6 months afterward. They found no significant differences in bowel function between the groups.

Of the 6 women in the cholecystectomy group who reported diarrhea, only one had new-onset diarrhea, and it was “mild.” No men reported bowel function changes.¹

Case studies suggest benefit from bile acid binders
When postcholecystectomy diarrhea does occur, the best treatment is unclear in the absence of randomized controlled trials. Case reports and case series support using bile acid binders based on the hypothesis that bile acid malabsorption causes the diarrhea.

The largest case series followed 26 postcholecystectomy patients with chronic diarrhea, defined as more than 3 liquid stools in 24 hours for an average of 3.9 years (range, 3 months to 13 years). Twenty-five of the 26 (96%) had severe bile acid malabsorption.

Cholestyramine, in doses of 2 to 12 g/d “normalized bowel movements” in 23 of the 25 patients with malabsorption (92%). When treatment was suspended, diarrhea recurred in 9 of the 23 (39%); bowel habits remained regular in 14 (61%).²

A smaller case series studied 8 patients who had postcholecystectomy diarrhea, defined as more than 4 loose stools in a 24-hour period for 1 to 20 years. Six of the 8 had elevated stool bile acids and stool weight greater than 200 g/24 hours. All 6 had less frequent bowel movements within 72 hours of starting oral cholestyramine at 4 to 16 g/d (adjusting the dose to maintain 1 bowel movement daily). Diarrhea recurred in all of the patients after they stopped cholestyramine.³

A single case report of a 71-year-old man who had 4 to 6 loose stools a day for 4 years after cholecystectomy noted improvement to 2 to 3 stools daily when he was treated with either colestipol or psyllium hydrophilic mucilloid.⁴

Recommendations

We found no consensus statements regarding treatment of postcholecystectomy diarrhea. A gastroenterology textbook notes that diarrhea occurs in as many as 20% of patients.⁵ The authors recommend nightly bile acid binders and, in refractory cases, opiate antidiarrheals.

An internal medicine textbook states that postcholecystectomy diarrhea—defined as 3 or more watery bowel movements per day—occurs in 5% to 10% of patients.⁶ The authors recommend treatment with cholestyramine or colestipol.

Evidence summary

A prospective study compared the bowel function of 106 adults (85 women) who underwent laparoscopic cholecystectomy with bowel function of 37 women who had laparoscopic sterilization (and served as controls).¹ The investigators gave bowel function questionnaires to both groups before surgery and 2 to 6 months afterward. They found no significant differences in bowel function between the groups.

Of the 6 women in the cholecystectomy group who reported diarrhea, only one had new-onset diarrhea, and it was “mild.” No men reported bowel function changes.¹

Case studies suggest benefit from bile acid binders
When postcholecystectomy diarrhea does occur, the best treatment is unclear in the absence of randomized controlled trials. Case reports and case series support using bile acid binders based on the hypothesis that bile acid malabsorption causes the diarrhea.

The largest case series followed 26 postcholecystectomy patients with chronic diarrhea, defined as more than 3 liquid stools in 24 hours for an average of 3.9 years (range, 3 months to 13 years). Twenty-five of the 26 (96%) had severe bile acid malabsorption.

Cholestyramine, in doses of 2 to 12 g/d “normalized bowel movements” in 23 of the 25 patients with malabsorption (92%). When treatment was suspended, diarrhea recurred in 9 of the 23 (39%); bowel habits remained regular in 14 (61%).²

A smaller case series studied 8 patients who had postcholecystectomy diarrhea, defined as more than 4 loose stools in a 24-hour period for 1 to 20 years. Six of the 8 had elevated stool bile acids and stool weight greater than 200 g/24 hours. All 6 had less frequent bowel movements within 72 hours of starting oral cholestyramine at 4 to 16 g/d (adjusting the dose to maintain 1 bowel movement daily). Diarrhea recurred in all of the patients after they stopped cholestyramine.³

A single case report of a 71-year-old man who had 4 to 6 loose stools a day for 4 years after cholecystectomy noted improvement to 2 to 3 stools daily when he was treated with either colestipol or psyllium hydrophilic mucilloid.⁴

Recommendations

We found no consensus statements regarding treatment of postcholecystectomy diarrhea. A gastroenterology textbook notes that diarrhea occurs in as many as 20% of patients.⁵ The authors recommend nightly bile acid binders and, in refractory cases, opiate antidiarrheals.

An internal medicine textbook states that postcholecystectomy diarrhea—defined as 3 or more watery bowel movements per day—occurs in 5% to 10% of patients.⁶ The authors recommend treatment with cholestyramine or colestipol.

The growing popularity of club teams and year-round participation in sports has spawned an epidemic of elbow injuries in primary and secondary school students and young adults alike. The incidence of elbow pain in children engaged in sports that require overhead throwing, such as baseball, football, volleyball, tennis, and javelin, ranges from 45% to 78%.¹

Fortunately, acute traumatic elbow injury, with pain severe enough to force the athlete to cease participation entirely, is relatively rare, accounting for only 1% to 5% of cases.^1,2 Far more often, elbow pain is associated with overuse, resulting in a gradual onset of medial elbow soreness that does not prevent the athlete from playing.

When an athlete seeks care for elbow pain, there are a number of things to consider, including the patient’s age, skeletal maturity, and type and frequency of throwing. Younger “throwers” typically incur injuries related to the physes, while adolescents and adults are more likely to sustain injuries to the ligaments and tendons.³ In both cases, repetitive valgus stress is the mechanism of injury. This review—of elbow anatomy (see the box),^4-6 injury, differential diagnosis, and treatment—will make it easier for you to get injured athletes back in the game.

Is it Little League elbow? Start with a targeted history

In skeletally immature athletes, open physes result in the epicondylar apophysis being the weakest structure on the medial aspect of the elbow. Thus, repetitive valgus stress and tension overload often lead to “Little League elbow”—an umbrella term with a differential diagnosis that encompasses medial epicondylar fragmentation, delayed or accelerated growth of the medial epicondyle, and delayed closure of its growth plate, among other conditions (TABLE 1).^3,7,8

In more mature athletes, repetitive microtrauma to the ulnar collateral ligament (UCL) leads to its gradual attenuation or complete failure.⁷ This increases the stress on the radiocapitellar joint and olecranon, and can lead to edema, scarring, calcification, osteophyte formation, medial epicondylitis, ulnar nerve neurapraxia, or radiocapitellar chondral damage.⁹ Extended practices and tournaments, with no substantial rest period throughout the year, put adolescents at increased risk for UCL injuries.¹⁰

Regardless of age, the medical history of an athlete with elbow pain should elicit information about the mechanism of injury; the location, duration, and quality of the pain; factors that alleviate or exacerbate the pain; the presence of weakness or paresthesias; and the extent to which the pain has affected the patient’s ability to throw. Patients with chronic UCL injuries, for example, often report a loss of arm control and decrease in throwing speed. It is also important to address hand dominance, level of participation, the position played, changes in technique or training regimen, prior injuries, and the effects of any previous treatment.¹¹

TABLE 1
Differential diagnosis of elbow injuries

Compare the affected and uninjured extremities
Inspect, palpate, and assess the active and passive range of motion, strength, and neurovascular status of both arms, with the uninjured side serving as a comparison. The scapula, shoulder, and wrist are also involved in throwing, so these joints should be examined along with the elbow.

Measure range of motion. Normal ranges for the flexion-extension arc are 0 to 140°, with 75° of pronation and 82° of supination.¹² Use a goniometer, if available, to ensure accuracy and reproducibility,¹ and pay close attention to the position that elicits pain.

In medial epicondylitis, the full range of motion should be preserved. Patients experience pain at the medial epicondyle and overlying flexor-pronator mass proximately, and pain or weakness with resisted wrist flexion, and resisted pronation, at full extension.^4,11 Flexor-pronator strain will produce similar findings, but edema or ecchymosis may be present and there may be pain immediately distal to the medial epicondyle.¹¹

Pain associated with injury to the UCL—which courses distal and slightly posterior to the medial epicondyle—typically occurs 2 cm distal to the medial epicondyle over the anterior bundle. Tenderness over the UCL has a sensitivity of 81% to 94% for UCL tears, but a specificity of only 22%.¹³

Physical maneuvers can help identify source of elbow pain

A complete UCL tear can cause valgus gapping as small as 3 mm, which makes it difficult to detect on physical exam alone.⁴ Orthopedic and sports medicine literature recommend that 3 maneuvers be used to identify UCL pathology:^4,14,15

The valgus stress test (FIGURE 1) assesses the effects of valgus stress on the UCL. Gapping >3 mm signifies UCL instability. The test has a sensitivity of 66% and a specificity of 60% for detecting a UCL strain or tear.^13,16

The milking maneuver (FIGURE 2), performed by the patient (or by a clinician if the patient lacks flexibility), reproduces a common pitching exercise. Medial elbow pain or apprehension indicates UCL injury.^13,16

The moving valgus stress test (FIGURE 3A-C) is done in an effort to recreate the flexion angles of the elbow during the late cocking and early acceleration phases of throwing. Pain anywhere in the arc of motion suggests a UCL injury; pain elicited at 45° of flexion suggests osteochondrosis of the humeral capitellum, while pain closer to full extension suggests osteochondrosis of the trochlea.^13,16

FIGURE 1
Valgus stress test

FIGURE 2
Milking maneuver

FIGURE 3
Moving valgus stress test

Does your patient have 2 positive valgus tests and posterior pain?
Valgus extension overload syndrome, which is caused by repetitive stress and results in osteophytes, chondromalacia of the medial olecranon fossa, tension in the UCL, and compression of the radiocapitellar joint, will also produce positive valgus stress and positive moving valgus stress tests. Keep in mind, however, that patients with valgus extension overload often have loss of full extension and posterior elbow pain with forced elbow hyperextension.¹⁷

Look for ulnar nerve injury
The physical examination should also be used to test for ulnar nerve injury. The elbow flexion test—a provocative maneuver in which the patient flexes the elbow as far as possible and reports any tingling or numbness of the hand—should be included in the work-up. Symptoms that develop in <60 seconds indicate a positive test for ulnar nerve compression, with the pinky and ulnar half of the ring finger most likely to have loss of vibration and light touch perception. A positive Tinel’s sign over the cubital tunnel is an indication of ulnar neuritis.¹⁸

If the ulnar nerve moves out of the ulnar groove when the groove is palpated as the elbow is flexed and extended, subluxating ulnar nerve is the likely diagnosis. If 2 structures displace over the medial epicondyle with elbow flexion, the first will be the ulnar nerve and the second will be the medial head of the triceps—an indication of a snapping medial head of triceps.¹⁸

Imaging studies may require a second look

Imaging studies are sometimes used to further aid in diagnosis of elbow injury. However, standard elbow x-rays, including an anteroposterior view in full extension, an oblique view, and a lateral view at 90° flexion, can be deceiving, as they often appear normal in conditions causing medial elbow pain associated with overhead throwing.

Careful review of the images may be needed to rule out fracture and other conditions, keeping the following factors in mind:

• A supracondylar fracture is likely if the anterior humeral line that is drawn along the anterior surface of the humeral cortex (on a lateral view) does not transect the middle third of the midcapitellum.^3,11,18
• Dislocation of the radial head is suggested if the radiocapitellar line (drawn through the center of the radial head and neck) does not transect the midcapitellum on a lateral view.^3,11,18
• Intra-articular injury with a joint effusion is indicated when an enlarged anterior fat pad, which is slightly anterior to the distal humeral diaphysis, is visible (the “sail sign”) on a normal elbow radiograph.^3,11,18
• A fracture is likely if a posterior fat pad (which lies in the olecranon fossa and is not usually visible unless an effusion elevates the fat pad away from the cortex) is visible on an elbow x-ray. ^3,11,18
• A chronic UCL tear is suggested by heterotropic calcification of the UCL.¹⁹

It is useful to x-ray both the injured and the unaffected elbows in skeletally immature athletes to compare secondary ossification centers. Little League elbow demonstrates a widening of the medial epicondyle physis, for example, when the x-rays are compared.³ Secondary ossification centers of the elbow appear first at the capitellum (age 2), followed by the radial head (age 5), medial epicondyle (age 7), trochlea (age 9), and lateral epicondyle (age 11). Most ossification centers fuse between 14 and 17 years of age.³

Computed tomography arthrograms, magnetic resonance imaging (MRI), and ultrasonography are also used to identify UCL tears. MRI, which can reveal injuries to cartilage and tendons as well, is the most commonly used imaging technique for musculoskeletal diagnosis of the elbow.^16,20

Treatment gets most athletes back on track

Most medial elbow injuries respond to conservative treatment—typically, with some combination of activity modification, nonsteroidal anti-inflammatory drugs (NSAIDs), icing, physical therapy aimed at flexor-pronator strengthening, and counterforce bracing.¹¹ Medial epicondylosis and flexor-pronator strain injuries have an excellent prognosis, with more than 90% of patients back to their previous level of activity at 1 year. Initial treatment consists of a 2- to 3-week rest period, followed by a 6- to 12-week rehabilitation protocol.¹¹

Randomized controlled trials have found limited evidence of short-term improvement in symptoms with corticosteroid injections compared with placebo or no treatment, local anesthetic, orthosis, physical therapy, and NSAIDs. However, corticosteroids were less effective than physiotherapy or oral NSAIDs in improving long-term outcomes.²¹ Despite a paucity of well-designed studies to prove their use, autologous blood, platelet-rich plasma, and botulinum toxin are sometimes used for refractory elbow pain.²¹

Treatment of Little League elbow consists of cessation of throwing for at least 4 to 6 weeks, with a gradual return to throwing and emphasis on proper throwing mechanics after the pain resolves. Most throwers are out of competition for 2 to 3 months, but fully recover with nonoperative management.²¹

UCL injuries, too, are initially treated with rest, NSAIDs, icing, bracing, and physical therapy, typically with 2 to 3 months of no throwing. Some patients also use a splint at 90° flexion at night and as needed for pain during the day. Patients whose symptoms last more than a year despite treatment may be candidates for arthroscopic debridement.¹¹

Consider reconstruction when nonsurgical management fails
UCL reconstruction was introduced in 1974, when reconstruction was performed on professional pitcher Tommy John, who went on to win 164 games.^4,9 The procedure has since undergone numerous modifications. Surgery is indicated for acute rupture, significant chronic instability, insufficient UCL tissue after debridement, or recurrent pain and valgus instability with throwing after rehabilitation.^2,4,6,9

Reconstruction generally entails fixing a tendon graft through bone tunnels in the medial epicondyle of the humerus and sublime tubercle of the ulna to reestablish valgus stability. A recent systematic review of reconstruction methods found a 76% to 95% rate of excellent results, with patients returned to their prior level of activity at a mean follow-up of 1 year.²² Rehabilitation typically begins 7 days postop; throwing (without windup) may begin in 4 to 5 months, with a gradual increase in speed and force and a return to the game at 12 months.

A stepped-up focus on prevention

The increase in UCL injuries in adolescents highlights the need for greater emphasis on prevention.¹⁰ Several governing bodies, including USA Baseball and the American Academy of Pediatrics, have developed research-based guidelines for young athletes (TABLE 2).^1,10,23-25

One of the easiest to follow is to limit an athlete’s weekly pitch count to 10 times his age. Thus, a 10 year old should pitch no more than 100 pitches in a given 7-day period. Another important measure—in addition to ensuring that young athletes receive instruction in proper pitching mechanics (see http://www.littleleague.org/Little_League_Online.htm)—is to urge coaches and parents to require players to get at least 3 months of rest after each season and to stop throwing if they have pain or fatigue.²⁴

TABLE 2
Keeping young pitchers injury-free^1,10,23-25

CORRESPONDENCE
Jennifer A. Southard, MD, MSc, Saint Alphonsus Medical Group, 6533 Emerald Street, Boise, ID 83704; [email protected]

The growing popularity of club teams and year-round participation in sports has spawned an epidemic of elbow injuries in primary and secondary school students and young adults alike. The incidence of elbow pain in children engaged in sports that require overhead throwing, such as baseball, football, volleyball, tennis, and javelin, ranges from 45% to 78%.¹

Fortunately, acute traumatic elbow injury, with pain severe enough to force the athlete to cease participation entirely, is relatively rare, accounting for only 1% to 5% of cases.^1,2 Far more often, elbow pain is associated with overuse, resulting in a gradual onset of medial elbow soreness that does not prevent the athlete from playing.

When an athlete seeks care for elbow pain, there are a number of things to consider, including the patient’s age, skeletal maturity, and type and frequency of throwing. Younger “throwers” typically incur injuries related to the physes, while adolescents and adults are more likely to sustain injuries to the ligaments and tendons.³ In both cases, repetitive valgus stress is the mechanism of injury. This review—of elbow anatomy (see the box),^4-6 injury, differential diagnosis, and treatment—will make it easier for you to get injured athletes back in the game.

Is it Little League elbow? Start with a targeted history

In skeletally immature athletes, open physes result in the epicondylar apophysis being the weakest structure on the medial aspect of the elbow. Thus, repetitive valgus stress and tension overload often lead to “Little League elbow”—an umbrella term with a differential diagnosis that encompasses medial epicondylar fragmentation, delayed or accelerated growth of the medial epicondyle, and delayed closure of its growth plate, among other conditions (TABLE 1).^3,7,8

In more mature athletes, repetitive microtrauma to the ulnar collateral ligament (UCL) leads to its gradual attenuation or complete failure.⁷ This increases the stress on the radiocapitellar joint and olecranon, and can lead to edema, scarring, calcification, osteophyte formation, medial epicondylitis, ulnar nerve neurapraxia, or radiocapitellar chondral damage.⁹ Extended practices and tournaments, with no substantial rest period throughout the year, put adolescents at increased risk for UCL injuries.¹⁰

Regardless of age, the medical history of an athlete with elbow pain should elicit information about the mechanism of injury; the location, duration, and quality of the pain; factors that alleviate or exacerbate the pain; the presence of weakness or paresthesias; and the extent to which the pain has affected the patient’s ability to throw. Patients with chronic UCL injuries, for example, often report a loss of arm control and decrease in throwing speed. It is also important to address hand dominance, level of participation, the position played, changes in technique or training regimen, prior injuries, and the effects of any previous treatment.¹¹

TABLE 1
Differential diagnosis of elbow injuries

Compare the affected and uninjured extremities
Inspect, palpate, and assess the active and passive range of motion, strength, and neurovascular status of both arms, with the uninjured side serving as a comparison. The scapula, shoulder, and wrist are also involved in throwing, so these joints should be examined along with the elbow.

Measure range of motion. Normal ranges for the flexion-extension arc are 0 to 140°, with 75° of pronation and 82° of supination.¹² Use a goniometer, if available, to ensure accuracy and reproducibility,¹ and pay close attention to the position that elicits pain.

In medial epicondylitis, the full range of motion should be preserved. Patients experience pain at the medial epicondyle and overlying flexor-pronator mass proximately, and pain or weakness with resisted wrist flexion, and resisted pronation, at full extension.^4,11 Flexor-pronator strain will produce similar findings, but edema or ecchymosis may be present and there may be pain immediately distal to the medial epicondyle.¹¹

Pain associated with injury to the UCL—which courses distal and slightly posterior to the medial epicondyle—typically occurs 2 cm distal to the medial epicondyle over the anterior bundle. Tenderness over the UCL has a sensitivity of 81% to 94% for UCL tears, but a specificity of only 22%.¹³

Physical maneuvers can help identify source of elbow pain

A complete UCL tear can cause valgus gapping as small as 3 mm, which makes it difficult to detect on physical exam alone.⁴ Orthopedic and sports medicine literature recommend that 3 maneuvers be used to identify UCL pathology:^4,14,15

The valgus stress test (FIGURE 1) assesses the effects of valgus stress on the UCL. Gapping >3 mm signifies UCL instability. The test has a sensitivity of 66% and a specificity of 60% for detecting a UCL strain or tear.^13,16

The milking maneuver (FIGURE 2), performed by the patient (or by a clinician if the patient lacks flexibility), reproduces a common pitching exercise. Medial elbow pain or apprehension indicates UCL injury.^13,16

The moving valgus stress test (FIGURE 3A-C) is done in an effort to recreate the flexion angles of the elbow during the late cocking and early acceleration phases of throwing. Pain anywhere in the arc of motion suggests a UCL injury; pain elicited at 45° of flexion suggests osteochondrosis of the humeral capitellum, while pain closer to full extension suggests osteochondrosis of the trochlea.^13,16

FIGURE 1
Valgus stress test

FIGURE 2
Milking maneuver

FIGURE 3
Moving valgus stress test

Does your patient have 2 positive valgus tests and posterior pain?
Valgus extension overload syndrome, which is caused by repetitive stress and results in osteophytes, chondromalacia of the medial olecranon fossa, tension in the UCL, and compression of the radiocapitellar joint, will also produce positive valgus stress and positive moving valgus stress tests. Keep in mind, however, that patients with valgus extension overload often have loss of full extension and posterior elbow pain with forced elbow hyperextension.¹⁷

Look for ulnar nerve injury
The physical examination should also be used to test for ulnar nerve injury. The elbow flexion test—a provocative maneuver in which the patient flexes the elbow as far as possible and reports any tingling or numbness of the hand—should be included in the work-up. Symptoms that develop in <60 seconds indicate a positive test for ulnar nerve compression, with the pinky and ulnar half of the ring finger most likely to have loss of vibration and light touch perception. A positive Tinel’s sign over the cubital tunnel is an indication of ulnar neuritis.¹⁸

If the ulnar nerve moves out of the ulnar groove when the groove is palpated as the elbow is flexed and extended, subluxating ulnar nerve is the likely diagnosis. If 2 structures displace over the medial epicondyle with elbow flexion, the first will be the ulnar nerve and the second will be the medial head of the triceps—an indication of a snapping medial head of triceps.¹⁸

Imaging studies may require a second look

Imaging studies are sometimes used to further aid in diagnosis of elbow injury. However, standard elbow x-rays, including an anteroposterior view in full extension, an oblique view, and a lateral view at 90° flexion, can be deceiving, as they often appear normal in conditions causing medial elbow pain associated with overhead throwing.

Careful review of the images may be needed to rule out fracture and other conditions, keeping the following factors in mind:

• A supracondylar fracture is likely if the anterior humeral line that is drawn along the anterior surface of the humeral cortex (on a lateral view) does not transect the middle third of the midcapitellum.^3,11,18
• Dislocation of the radial head is suggested if the radiocapitellar line (drawn through the center of the radial head and neck) does not transect the midcapitellum on a lateral view.^3,11,18
• Intra-articular injury with a joint effusion is indicated when an enlarged anterior fat pad, which is slightly anterior to the distal humeral diaphysis, is visible (the “sail sign”) on a normal elbow radiograph.^3,11,18
• A fracture is likely if a posterior fat pad (which lies in the olecranon fossa and is not usually visible unless an effusion elevates the fat pad away from the cortex) is visible on an elbow x-ray. ^3,11,18
• A chronic UCL tear is suggested by heterotropic calcification of the UCL.¹⁹

It is useful to x-ray both the injured and the unaffected elbows in skeletally immature athletes to compare secondary ossification centers. Little League elbow demonstrates a widening of the medial epicondyle physis, for example, when the x-rays are compared.³ Secondary ossification centers of the elbow appear first at the capitellum (age 2), followed by the radial head (age 5), medial epicondyle (age 7), trochlea (age 9), and lateral epicondyle (age 11). Most ossification centers fuse between 14 and 17 years of age.³

Computed tomography arthrograms, magnetic resonance imaging (MRI), and ultrasonography are also used to identify UCL tears. MRI, which can reveal injuries to cartilage and tendons as well, is the most commonly used imaging technique for musculoskeletal diagnosis of the elbow.^16,20

Treatment gets most athletes back on track

Most medial elbow injuries respond to conservative treatment—typically, with some combination of activity modification, nonsteroidal anti-inflammatory drugs (NSAIDs), icing, physical therapy aimed at flexor-pronator strengthening, and counterforce bracing.¹¹ Medial epicondylosis and flexor-pronator strain injuries have an excellent prognosis, with more than 90% of patients back to their previous level of activity at 1 year. Initial treatment consists of a 2- to 3-week rest period, followed by a 6- to 12-week rehabilitation protocol.¹¹

Randomized controlled trials have found limited evidence of short-term improvement in symptoms with corticosteroid injections compared with placebo or no treatment, local anesthetic, orthosis, physical therapy, and NSAIDs. However, corticosteroids were less effective than physiotherapy or oral NSAIDs in improving long-term outcomes.²¹ Despite a paucity of well-designed studies to prove their use, autologous blood, platelet-rich plasma, and botulinum toxin are sometimes used for refractory elbow pain.²¹

Treatment of Little League elbow consists of cessation of throwing for at least 4 to 6 weeks, with a gradual return to throwing and emphasis on proper throwing mechanics after the pain resolves. Most throwers are out of competition for 2 to 3 months, but fully recover with nonoperative management.²¹

UCL injuries, too, are initially treated with rest, NSAIDs, icing, bracing, and physical therapy, typically with 2 to 3 months of no throwing. Some patients also use a splint at 90° flexion at night and as needed for pain during the day. Patients whose symptoms last more than a year despite treatment may be candidates for arthroscopic debridement.¹¹

Consider reconstruction when nonsurgical management fails
UCL reconstruction was introduced in 1974, when reconstruction was performed on professional pitcher Tommy John, who went on to win 164 games.^4,9 The procedure has since undergone numerous modifications. Surgery is indicated for acute rupture, significant chronic instability, insufficient UCL tissue after debridement, or recurrent pain and valgus instability with throwing after rehabilitation.^2,4,6,9

Reconstruction generally entails fixing a tendon graft through bone tunnels in the medial epicondyle of the humerus and sublime tubercle of the ulna to reestablish valgus stability. A recent systematic review of reconstruction methods found a 76% to 95% rate of excellent results, with patients returned to their prior level of activity at a mean follow-up of 1 year.²² Rehabilitation typically begins 7 days postop; throwing (without windup) may begin in 4 to 5 months, with a gradual increase in speed and force and a return to the game at 12 months.

A stepped-up focus on prevention

The increase in UCL injuries in adolescents highlights the need for greater emphasis on prevention.¹⁰ Several governing bodies, including USA Baseball and the American Academy of Pediatrics, have developed research-based guidelines for young athletes (TABLE 2).^1,10,23-25

One of the easiest to follow is to limit an athlete’s weekly pitch count to 10 times his age. Thus, a 10 year old should pitch no more than 100 pitches in a given 7-day period. Another important measure—in addition to ensuring that young athletes receive instruction in proper pitching mechanics (see http://www.littleleague.org/Little_League_Online.htm)—is to urge coaches and parents to require players to get at least 3 months of rest after each season and to stop throwing if they have pain or fatigue.²⁴

TABLE 2
Keeping young pitchers injury-free^1,10,23-25

CORRESPONDENCE
Jennifer A. Southard, MD, MSc, Saint Alphonsus Medical Group, 6533 Emerald Street, Boise, ID 83704; [email protected]

The growing popularity of club teams and year-round participation in sports has spawned an epidemic of elbow injuries in primary and secondary school students and young adults alike. The incidence of elbow pain in children engaged in sports that require overhead throwing, such as baseball, football, volleyball, tennis, and javelin, ranges from 45% to 78%.¹

Fortunately, acute traumatic elbow injury, with pain severe enough to force the athlete to cease participation entirely, is relatively rare, accounting for only 1% to 5% of cases.^1,2 Far more often, elbow pain is associated with overuse, resulting in a gradual onset of medial elbow soreness that does not prevent the athlete from playing.

When an athlete seeks care for elbow pain, there are a number of things to consider, including the patient’s age, skeletal maturity, and type and frequency of throwing. Younger “throwers” typically incur injuries related to the physes, while adolescents and adults are more likely to sustain injuries to the ligaments and tendons.³ In both cases, repetitive valgus stress is the mechanism of injury. This review—of elbow anatomy (see the box),^4-6 injury, differential diagnosis, and treatment—will make it easier for you to get injured athletes back in the game.

Is it Little League elbow? Start with a targeted history

In skeletally immature athletes, open physes result in the epicondylar apophysis being the weakest structure on the medial aspect of the elbow. Thus, repetitive valgus stress and tension overload often lead to “Little League elbow”—an umbrella term with a differential diagnosis that encompasses medial epicondylar fragmentation, delayed or accelerated growth of the medial epicondyle, and delayed closure of its growth plate, among other conditions (TABLE 1).^3,7,8

In more mature athletes, repetitive microtrauma to the ulnar collateral ligament (UCL) leads to its gradual attenuation or complete failure.⁷ This increases the stress on the radiocapitellar joint and olecranon, and can lead to edema, scarring, calcification, osteophyte formation, medial epicondylitis, ulnar nerve neurapraxia, or radiocapitellar chondral damage.⁹ Extended practices and tournaments, with no substantial rest period throughout the year, put adolescents at increased risk for UCL injuries.¹⁰

Regardless of age, the medical history of an athlete with elbow pain should elicit information about the mechanism of injury; the location, duration, and quality of the pain; factors that alleviate or exacerbate the pain; the presence of weakness or paresthesias; and the extent to which the pain has affected the patient’s ability to throw. Patients with chronic UCL injuries, for example, often report a loss of arm control and decrease in throwing speed. It is also important to address hand dominance, level of participation, the position played, changes in technique or training regimen, prior injuries, and the effects of any previous treatment.¹¹

TABLE 1
Differential diagnosis of elbow injuries

Compare the affected and uninjured extremities
Inspect, palpate, and assess the active and passive range of motion, strength, and neurovascular status of both arms, with the uninjured side serving as a comparison. The scapula, shoulder, and wrist are also involved in throwing, so these joints should be examined along with the elbow.

Measure range of motion. Normal ranges for the flexion-extension arc are 0 to 140°, with 75° of pronation and 82° of supination.¹² Use a goniometer, if available, to ensure accuracy and reproducibility,¹ and pay close attention to the position that elicits pain.

In medial epicondylitis, the full range of motion should be preserved. Patients experience pain at the medial epicondyle and overlying flexor-pronator mass proximately, and pain or weakness with resisted wrist flexion, and resisted pronation, at full extension.^4,11 Flexor-pronator strain will produce similar findings, but edema or ecchymosis may be present and there may be pain immediately distal to the medial epicondyle.¹¹

Pain associated with injury to the UCL—which courses distal and slightly posterior to the medial epicondyle—typically occurs 2 cm distal to the medial epicondyle over the anterior bundle. Tenderness over the UCL has a sensitivity of 81% to 94% for UCL tears, but a specificity of only 22%.¹³

Physical maneuvers can help identify source of elbow pain

A complete UCL tear can cause valgus gapping as small as 3 mm, which makes it difficult to detect on physical exam alone.⁴ Orthopedic and sports medicine literature recommend that 3 maneuvers be used to identify UCL pathology:^4,14,15

The valgus stress test (FIGURE 1) assesses the effects of valgus stress on the UCL. Gapping >3 mm signifies UCL instability. The test has a sensitivity of 66% and a specificity of 60% for detecting a UCL strain or tear.^13,16

The milking maneuver (FIGURE 2), performed by the patient (or by a clinician if the patient lacks flexibility), reproduces a common pitching exercise. Medial elbow pain or apprehension indicates UCL injury.^13,16

The moving valgus stress test (FIGURE 3A-C) is done in an effort to recreate the flexion angles of the elbow during the late cocking and early acceleration phases of throwing. Pain anywhere in the arc of motion suggests a UCL injury; pain elicited at 45° of flexion suggests osteochondrosis of the humeral capitellum, while pain closer to full extension suggests osteochondrosis of the trochlea.^13,16

FIGURE 1
Valgus stress test

FIGURE 2
Milking maneuver

FIGURE 3
Moving valgus stress test

Does your patient have 2 positive valgus tests and posterior pain?
Valgus extension overload syndrome, which is caused by repetitive stress and results in osteophytes, chondromalacia of the medial olecranon fossa, tension in the UCL, and compression of the radiocapitellar joint, will also produce positive valgus stress and positive moving valgus stress tests. Keep in mind, however, that patients with valgus extension overload often have loss of full extension and posterior elbow pain with forced elbow hyperextension.¹⁷

Look for ulnar nerve injury
The physical examination should also be used to test for ulnar nerve injury. The elbow flexion test—a provocative maneuver in which the patient flexes the elbow as far as possible and reports any tingling or numbness of the hand—should be included in the work-up. Symptoms that develop in <60 seconds indicate a positive test for ulnar nerve compression, with the pinky and ulnar half of the ring finger most likely to have loss of vibration and light touch perception. A positive Tinel’s sign over the cubital tunnel is an indication of ulnar neuritis.¹⁸

If the ulnar nerve moves out of the ulnar groove when the groove is palpated as the elbow is flexed and extended, subluxating ulnar nerve is the likely diagnosis. If 2 structures displace over the medial epicondyle with elbow flexion, the first will be the ulnar nerve and the second will be the medial head of the triceps—an indication of a snapping medial head of triceps.¹⁸

Imaging studies may require a second look

Imaging studies are sometimes used to further aid in diagnosis of elbow injury. However, standard elbow x-rays, including an anteroposterior view in full extension, an oblique view, and a lateral view at 90° flexion, can be deceiving, as they often appear normal in conditions causing medial elbow pain associated with overhead throwing.

Careful review of the images may be needed to rule out fracture and other conditions, keeping the following factors in mind:

• A supracondylar fracture is likely if the anterior humeral line that is drawn along the anterior surface of the humeral cortex (on a lateral view) does not transect the middle third of the midcapitellum.^3,11,18
• Dislocation of the radial head is suggested if the radiocapitellar line (drawn through the center of the radial head and neck) does not transect the midcapitellum on a lateral view.^3,11,18
• Intra-articular injury with a joint effusion is indicated when an enlarged anterior fat pad, which is slightly anterior to the distal humeral diaphysis, is visible (the “sail sign”) on a normal elbow radiograph.^3,11,18
• A fracture is likely if a posterior fat pad (which lies in the olecranon fossa and is not usually visible unless an effusion elevates the fat pad away from the cortex) is visible on an elbow x-ray. ^3,11,18
• A chronic UCL tear is suggested by heterotropic calcification of the UCL.¹⁹

It is useful to x-ray both the injured and the unaffected elbows in skeletally immature athletes to compare secondary ossification centers. Little League elbow demonstrates a widening of the medial epicondyle physis, for example, when the x-rays are compared.³ Secondary ossification centers of the elbow appear first at the capitellum (age 2), followed by the radial head (age 5), medial epicondyle (age 7), trochlea (age 9), and lateral epicondyle (age 11). Most ossification centers fuse between 14 and 17 years of age.³

Computed tomography arthrograms, magnetic resonance imaging (MRI), and ultrasonography are also used to identify UCL tears. MRI, which can reveal injuries to cartilage and tendons as well, is the most commonly used imaging technique for musculoskeletal diagnosis of the elbow.^16,20

Treatment gets most athletes back on track

Most medial elbow injuries respond to conservative treatment—typically, with some combination of activity modification, nonsteroidal anti-inflammatory drugs (NSAIDs), icing, physical therapy aimed at flexor-pronator strengthening, and counterforce bracing.¹¹ Medial epicondylosis and flexor-pronator strain injuries have an excellent prognosis, with more than 90% of patients back to their previous level of activity at 1 year. Initial treatment consists of a 2- to 3-week rest period, followed by a 6- to 12-week rehabilitation protocol.¹¹

Randomized controlled trials have found limited evidence of short-term improvement in symptoms with corticosteroid injections compared with placebo or no treatment, local anesthetic, orthosis, physical therapy, and NSAIDs. However, corticosteroids were less effective than physiotherapy or oral NSAIDs in improving long-term outcomes.²¹ Despite a paucity of well-designed studies to prove their use, autologous blood, platelet-rich plasma, and botulinum toxin are sometimes used for refractory elbow pain.²¹

Treatment of Little League elbow consists of cessation of throwing for at least 4 to 6 weeks, with a gradual return to throwing and emphasis on proper throwing mechanics after the pain resolves. Most throwers are out of competition for 2 to 3 months, but fully recover with nonoperative management.²¹

UCL injuries, too, are initially treated with rest, NSAIDs, icing, bracing, and physical therapy, typically with 2 to 3 months of no throwing. Some patients also use a splint at 90° flexion at night and as needed for pain during the day. Patients whose symptoms last more than a year despite treatment may be candidates for arthroscopic debridement.¹¹

Consider reconstruction when nonsurgical management fails
UCL reconstruction was introduced in 1974, when reconstruction was performed on professional pitcher Tommy John, who went on to win 164 games.^4,9 The procedure has since undergone numerous modifications. Surgery is indicated for acute rupture, significant chronic instability, insufficient UCL tissue after debridement, or recurrent pain and valgus instability with throwing after rehabilitation.^2,4,6,9

Reconstruction generally entails fixing a tendon graft through bone tunnels in the medial epicondyle of the humerus and sublime tubercle of the ulna to reestablish valgus stability. A recent systematic review of reconstruction methods found a 76% to 95% rate of excellent results, with patients returned to their prior level of activity at a mean follow-up of 1 year.²² Rehabilitation typically begins 7 days postop; throwing (without windup) may begin in 4 to 5 months, with a gradual increase in speed and force and a return to the game at 12 months.

A stepped-up focus on prevention

The increase in UCL injuries in adolescents highlights the need for greater emphasis on prevention.¹⁰ Several governing bodies, including USA Baseball and the American Academy of Pediatrics, have developed research-based guidelines for young athletes (TABLE 2).^1,10,23-25

One of the easiest to follow is to limit an athlete’s weekly pitch count to 10 times his age. Thus, a 10 year old should pitch no more than 100 pitches in a given 7-day period. Another important measure—in addition to ensuring that young athletes receive instruction in proper pitching mechanics (see http://www.littleleague.org/Little_League_Online.htm)—is to urge coaches and parents to require players to get at least 3 months of rest after each season and to stop throwing if they have pain or fatigue.²⁴

TABLE 2
Keeping young pitchers injury-free^1,10,23-25

CORRESPONDENCE
Jennifer A. Southard, MD, MSc, Saint Alphonsus Medical Group, 6533 Emerald Street, Boise, ID 83704; [email protected]

The prevention of postsurgical adhesions is one of the greatest unmet needs in medicine today. Surgical series have shown that adhesions are present after 80%-90% of abdominal and pelvic surgeries, and that these abnormal fibrous connections have a tremendous propensity to reform after adhesiolysis. (We will define adhesions here as “attachments between surfaces at nonanatomical locations.”)

In gynecologic surgery, postoperative adhesions are a frequent cause of infertility, pain, bowel obstruction, and difficulty in later procedures. Adhesions can occur after minimally invasive procedures, which have the potential for trocar injury to structures adherent to the anterior abdominal wall. Other intraoperative injuries can occur due to obscured normal anatomy or restricted access. A significant number of patients also undergo second surgeries to treat sequelae that are directly related to adhesions.

The literature is replete with studies of adhesion development and reports of its incidence and its consequences. Still, the problem of postoperative adhesion development often goes underestimated or unrecognized. This is because we don't routinely perform early second-look operations to assess adhesion development, and because there are no serum markers or sensitive imaging techniques to allow their identification. In addition, we do not follow our patients who seek care from other providers as insurance coverage changes or as other health problems arise, such as bowel obstruction being treated by a general surgeon.

As gynecologic surgeons, we must appreciate that while infections, endometriosis, and other peritoneal insults may contribute to adhesion development, surgery is the most common cause. We also must appreciate how tissue injury leads to the development of adhesions, and why adhesion reformation so commonly occurs.

This understanding is critical to our consideration and use of the “barrier” products currently available for reducing postsurgical adhesions — and critical to our efforts to employ the tenets of gynecologic microsurgery and to achieve as optimal a surgical outcome as possible. At this point in time, use of approved surgical adjuvants in combination with good surgical technique offers the best chance at adhesion reduction and prevention.

Incidence of Adhesions

A series of reports published in the early to mid-1980s documented how commonly adhesions develop after various types of reproductive pelvic surgery. Through early second-look laparoscopy, postoperative adhesions were found to occur, in these studies, in 55%–100% of patients after their primary gynecologic surgery.

In a multicenter study published in 1987, my colleagues and I also showed that gynecologic surgeries performed at the time of laparotomy are frequently complicated by both adhesion reformation and de novo adhesion formation. More than half of the 161 women (51%) who had a second-look laparoscopy 1–12 weeks after reproductive pelvic surgery were found to have de novo adhesion formation (adhesions in at least one new location). Adhesion reformation was also widespread: At the initial laparotomy, 121 of the patients (all of whom were treated for infertility) were noted to have some form of adhesion, and adhesion reformation subsequently occurred at the site of adhesiolysis in 85% of these women, with no differences with respect to adhesion type (Fertil. Steril. 1987;47;864–6).

It was hoped, and largely expected, that the growth of laparoscopy and minimally invasive surgery approaches in more recent years would reduce postoperative adhesion development — that minimally invasive techniques would prove to be less adhesiogenic than laparotomy. Questions remain, but thus far, such hopes have diminished and our expectations for significant improvement have gone unsubstantiated.

One multicenter study on adhesion development after initial laparoscopic procedures found that the incidence of adhesions at an early second-look procedure was 97% — no lower than in prior reports of second-look laparoscopy after laparotomy.

In this study, 68 women underwent operative laparoscopic procedures, including adhesiolysis, and had second-look procedures within 90 days. The good news was that de novo adhesion formation between the two laparoscopic procedures occurred in only 8 of the women (12%) and at 11 of 47 possible sites — much less frequently than after laparotomy. Adhesion scores also decreased at the second look compared with the status of the pelvis at the initial procedure. Still, with the high rate of adhesion reformation, almost all of the women developed postoperative adhesions.

Thus, even when the initial procedure was performed laparoscopically, adhesion development was an all-too-common occurrence, and appeared to be independent of the character of the initial adhesion (Fertil. Steril. 1991;55:700–4).

More recently, data from randomized studies of various adhesion barriers and potential anti-adhesion adjuvants have further dashed hopes that laparoscopy per se can reduce adhesion development.

For instance, in a recent small pilot study of a fibrin-based product called Adhexil, “control” ovaries that were not treated had a 27% increase in the mean adhesion score between an initial laparoscopic procedure and second-look laparoscopy. The women in the study had undergone bilateral ovarian surgery, with ovaries randomized for application of the product or no treatment (Fertil. Steril. 2011;95:1086–90). Clearly, a laparoscopic approach to their procedures did not prevent the development of adhesions.

Many of the initial studies on adhesion development were comprised of patients with infertility, but more recent observations have been extended to women without infertility and to men. Studies have covered patients undergoing colectomies, for instance, as well as neonates undergoing cardiothoracic procedures.

In a recent review article on adhesion prevention and reduction, members of an interdisciplinary consensus conference stated that adhesions develop after “nearly all” abdominal and pelvic procedures performed through either standard laparotomy or laparoscopic approaches. With respect to gynecologic surgery, they point out, research has shown that the most common site for postsurgical adhesion development is the ovary (Surg. Innov. 2010;17:183–8).

Consequences

Pelvic adhesions are a well-recognized cause of infertility, contributing to up to an estimated 40% of the cases of infertility in women. Adhesions are also a leading cause of bowel obstruction and a significant cause of chronic or recurrent pelvic pain.

The contribution of pelvic adhesions to chronic pelvic pain is not completely understood. Adhesions may be the cause of pain in some women, and in other women, an incidental finding that is not contributing to pain. In patients who have endometriosis as well, the question remains as to the contribution of endometriosis per se, or adhesions, to the pain. Endometriosis can cause adhesions and chronic pelvic pain, presumably through the cyclic generation of inflammatory molecules.

The relationship between chronic pain and adhesions is further complicated by ensuing questions about the efficacy of adhesiolysis. The two randomized trials that have thus far examined the role of adhesiolysis in the reduction of chronic pelvic pain failed to demonstrate a significant improvement in pain after adhesiolysis; however, the high failure rates after follow-up may be due to adhesion reformation and de novo adhesion formation (Fertil. Steril. 2004;82:1483–91). Performance of more randomized comparisons in the future may yield improved outcomes when adhesiolysis is paired with postprocedure use of anti-adhesion adjuvants.

Despite the uncertainties, multiple studies support the current estimation that adhesions cause or significantly contribute to chronic pelvic pain in up to 30% of women with the problem. As the Ovarian Adhesion Study Group noted in one of its reports, adhesions have been reported as a primary cause of chronic pelvic pain in 13%-36% of women, depending on the study (Obstet. Gynecol. 1995;86:335–40). Economic analyses also have quantified the impact of adhesion-related hospital readmissions. A study done in the United Kingdom, for instance, concluded that 6% of all hospital readmissions in patients who had undergone abdominal or pelvic surgery were directly related to adhesions (Lancet 1999;353:1476–80).httother report on hospitalizations for lower abdominal adhesiolysis in the United States estimated that in 1988, the cost of adhesions stemming from gynecologic procedures alone was almost $1.2 billion. This estimate did not include outpatient and indirect costs (Surg. Gynecol. Obstet. 1993;176:271–6).

Why, How Adhesions Develop

Our current understanding is that adhesions develop as a result of injury to and devascularization of the peritoneum, and the subsequent inflammatory response and peritoneal wound healing process. Tissue hypoxia triggers a cascade of intracellular responses that, in combination with the fibrinous collection of blood and serosanguinous fluid at the tissue surface, may result in adhesion development.

In the initial postsurgical period, either overt bleeding or oozing may occur at the site(s) of tissue injury, forming clots. In combination with serosanguinous fluid, which may leak from damaged peritoneal surfaces, a fibrinous mass thus develops at the surgical sites and sites of tissue injury. This represents an initial step in peritoneal repair.

When surrounding tissue is normal and there is a sufficient amount of plasminogen activator present in the peritoneum — and when numerous other events and conditions are optimal — the resulting fibrinous mass can be degraded. As that occurs, and tissue healing continues, fibroblasts are recruited to the surface of the injury site from underlying tissues.

If the fibrinous mass is no longer present, fibroblasts “stop” at the tissue surfaces, and become covered by mesothelial cells which line the peritoneal surface as the process of remesothelialization occurs. This process appears to be initiated within hours after surgery and is generally believed to be completed in 3–5 days. (In such instances, healing would have occurred without adhesions, although subperitoneal fibrosis may have occurred.)

Various hypoxia-driven responses, however, such as a reduction in plasminogen activator activity, can cause the fibrinous mass to persist during the healing process, before remesothelialization occurs. In this case, fibroblasts migrate not only to, but through, the injury site, and into the persisting fibrinous mass. This is subsequently followed by deposition of collagen, fibronectin, and other extracellular matrix materials — creating the beginnings of a true adhesion.

In such cases, remesothelialization still occurs, but the mesothelial cells cover the adhesion as well as the normal tissue surfaces, forming adhesive bands and other types of connections between opposing serosal tissue surfaces. Angiogenesis then occurs as the hypoxic tissue in the adhesion sends signals (such as vascular endothelial growth factor) in an attempt to reestablish a supply of oxygen and nutrients to the injured and devascularized tissues. Subsequently, as the tissue remodels, there is a propensity for the adhesion to become more vascular and denser.

Understanding this process is important because the products currently available for reducing adhesions act as barriers during this critical period of remesothelialization, keeping peritoneal surfaces apart and minimizing the potential development of a fibrinous mass that bridges tissue surfaces. If an adhesion does not form during the 3–5-day period of remesothelialization, it is theorized that there will not be any adhesion development — unless there's new injury to the tissue surfaces.

Once an adhesion forms, however, it has acquired a particular “adhesion phenotype” — different from that of normal peritoneum — that appears to be irreversible. This is likely why it is so difficult to prevent adhesion reformation after adhesiolysis. Rates of adhesion reformation — even in the best of surgical hands — run between 80% and 90%, compared with a 50% chance of de novo adhesion development after surgery (at new sites of injury).

The identification of an adhesion phenotype came originally from comparisons of normal peritoneal and adhesion tissues harvested from the same patient, and were later confirmed in cell culture studies in which normal peritoneal fibroblasts were subjected to hypoxia (2% O₂ conditions). Fibroblasts cultured under hypoxic conditions were subsequently found to have developed particular molecular biologic characterizations that are different from those of normal peritoneal fibroblasts.

When exposed to normal amounts of oxygen again, the fibroblasts did not go back to being normal fibroblasts — they continued to manifest the adhesion phenotype (J. Am Assoc. Gynecol. Laparosc. 2004;11:307–14). These findings have been confirmed in animal and human studies, and such relationships have also been identified in other peritoneal tissue types such as mesothelial cells and macrophages.

Further research on the pathogenesis of adhesions and the molecular biologic differences between normal peritoneum and adhesions may allow identification of which patients, and which sites within a patient, are most at risk for adhesion development, as well as the discovery of new ways to reduce the development of postoperative adhesions and their clinical sequelae.

It is possible that a future generation of barrier products not only will work as a barrier separating surfaces prior to remesothelialization, but will also have local biologic effects — delivering adhesion-reducing drugs or biologics, for instance, to specific localized tissue sites. A personalized approach to adhesion prevention also might be possible, with particular factors deemed to increase adhesion risk in individual patients (a deficiency of plasminogen activator, for instance) being corrected.

In the meantime, as we've learned more about the pathophysiological state under which adhesions develop, we have found that adhesion development may occur faster than we had thought. In one recent rodent study, we identified postoperative tissue attachments as early as 2 hours after cecal abrasion. We noted considerable local edema and vessel dilatation within 2 hours of injury, angiogenesis and fibrin deposition at 8 hours, and cell proliferation at 24 hours (Fertil. Steril. 2010;93:2734–7). And interestingly, recent studies in mice have shown that laparoscopic insufflation per se can induce peritoneal adhesions, with the adhesions increasing proportionally with both increasing duration of insufflation and an increase in intraperitoneal pressure.

Prevention in Practice

During the past decade a variety of surgical adjuvants — from procoagulants and fibrinolytic agents to anti-inflammatory drugs and antibiotics — have been investigated for use in reducing the occurrence, extent, and severity of adhesions. Unfortunately, most approaches seemingly have been futile. Some products have shown trends toward efficacy in animal or early human studies and need further investigation.

The three synthetic products that are approved by the Food and Drug Administration—Gynecare Interceed, Seprafilm, and Adept — can help reduce postoperative adhesions after gynecologic procedures, and should be considered as potentially useful surgical adjuvants. A meta-analysis of studies of Gynecare Interceed, for instance, found that approximately twice as many operative sites were adhesion free after use of the barrier than after surgery alone (J. Reprod. Med. 1999;44:325–31).

Gynecare Interceed (Johnson & Johnson) and Seprafilm (Genzyme) are approved for use only at laparotomy, while Adept (Baxter International), an icodextrin solution that disperses throughout the abdominopelvic cavity, is approved for use only in laparoscopic surgery.

The key consideration to make when using Interceed — a biodegradable woven fabric composed of oxidized, regenerated cellulose — is the importance of achieving meticulous hemostasis. Its efficacy is reduced, or can even be lost, in the presence of blood. Care also must be taken not to stretch the material or alter its shape and the spacing between the weaves. Otherwise, the material, once gelated, will have a greater potential for spaces in which the tissue surfaces would not be separated and thus a greater potential for blood coagulation and fibroblast in-growth. Multiple pieces of the material may be overlapped, but there have been no benefits demonstrated (at least in animal studies) to using double layers.

Care in application also is critically important for Seprafilm, a film composed of modified hyaluronic acid and carboxymethylcellulose. Seprafilm is brittle and is difficult to apply through small incisions. While it's not impossible to deliver the product laparoscopically, many surgeons have found this very difficult. And in the United States, it is approved for use with laparotomy only.

In applying Seprafilm, it is critical to first get good exposure of the field and then position the film very carefully. Attempts to reposition the product will often result in tears or breaks. Of course, just as with Interceed, this device is believed to work primarily by separating tissue surfaces, and thus it has little to no chance of success if it does not completely separate the surgically injured tissue from other tissue surfaces in the initial postoperative period while remesothelialization is occurring.

The use of adjuvants, moreover, is no substitute for good surgical technique that aims to minimize tissue injury, tissue devascularization, and inflammation. This is easier to achieve, of course, during a microsurgical procedure such as a tubal anastomosis than in a patient with severe endometriosis or many large fibroids. Still, to the extent possible for the procedure being conducted, the tenets of gynecologic microsurgery should always be considered:

▸ Handle as little tissue as possible, as minimally as possible. To the extent possible, handle only those portions that will subsequently be excised.

▸ Keep tissues moist. Tissue drying leads to injury and loss of mesothelial cells. Raw surfaces are more prone to develop adhesions.

▸ Take special care in the use of suture. Consider whether clinical situations will allow use of less reactive and smaller-caliber suture. When using suture to tie off blood vessels, skeletonize the vessels so as to minimize the amount of tissue distal to the suture that will become hypoxic and serve as a nidus to adhesion development.

▸ Target the use of electrosurgery and other energy sources. Use it in specific localized sites where it's needed, such as to stop bleeding, but avoid widely dispersed use, when possible, again to minimize the amount of residual devitalized tissue remaining in the pelvis at the conclusion of the surgical procedure.

Pelvic Adhesions — An Update

www.isge.org

www.aagl.org

“A number of human interventional trials and animal studies have evaluated techniques and materials designed to prevent and reduce postsurgical adhesions. The results have been inconclusive and sometimes contradictory. Thus, preventing postsurgical adhesions remains an art, rather than a science.” So I began my introduction to the program on adhesion prevention at the 2010 Congress of the Society of Laparoscopic Surgeons in New York City.

Patients with adhesions can present with small bowel obstruction or with complaints of infertility, chronic pain, or dyspareunia. Unfortunately, adhesive disease is problematic. Four percent of the patients undergoing abdominal and pelvic surgery will be readmitted due to adhesion-related complications. In excess of 400,000 surgical procedures are performed annually in the United States for lysis of adhesions. In a Scottish National Health Service Study of nearly 9,000 women who previously underwent open gynecologic surgery, just less than 3% were readmitted secondary to adhesions; the highest readmit rate was ovarian surgery (BJOG 2000;107:855–62).

While one would expect a reduction in the number of patients undergoing laparoscopic surgery, in reality, the verdict is not yet clear. A 1998 meta-analysis showed a decrease in both reformed (26.6% vs. 14.3%) and de novo adhesions (45.2% vs. 37.2%) in the laparoscopic group, compared with laparotomy (Fertil. Steril. 1998;70:702–11).

Despite this, other authors cite pneumoperitoneum, prolonged surgery, high insufflation pressure, and overzealous use of energy to cut and coagulate as reasons why laparoscopic surgery increases risk of adhesions.

The economic impact of adhesions is staggering, in excess of $1.3 billion in the United States per year.

For this current excerpt of the Master Class in Gynecologic Surgery, I have solicited the wisdom of Dr. Michael Diamond. He is the Kamran S. Moghissi Professor of Obstetrics and Gynecology and associate chairman of the department of obstetrics and gynecology at Wayne State University, Detroit. Dr. Diamond also is director of the division of reproductive endocrinology and infertility and assistant dean for clinical and translational research at the university. Dr. Diamond has spent much of his academic career involved in the pathogenesis, prevention, and treatment of pelvic adhesions. He is truly considered the world's leader in this area, and we are honored to have Dr. Diamond as guest author of this important area of our surgical arena.

The prevention of postsurgical adhesions is one of the greatest unmet needs in medicine today. Surgical series have shown that adhesions are present after 80%-90% of abdominal and pelvic surgeries, and that these abnormal fibrous connections have a tremendous propensity to reform after adhesiolysis. (We will define adhesions here as “attachments between surfaces at nonanatomical locations.”)

In gynecologic surgery, postoperative adhesions are a frequent cause of infertility, pain, bowel obstruction, and difficulty in later procedures. Adhesions can occur after minimally invasive procedures, which have the potential for trocar injury to structures adherent to the anterior abdominal wall. Other intraoperative injuries can occur due to obscured normal anatomy or restricted access. A significant number of patients also undergo second surgeries to treat sequelae that are directly related to adhesions.

The literature is replete with studies of adhesion development and reports of its incidence and its consequences. Still, the problem of postoperative adhesion development often goes underestimated or unrecognized. This is because we don't routinely perform early second-look operations to assess adhesion development, and because there are no serum markers or sensitive imaging techniques to allow their identification. In addition, we do not follow our patients who seek care from other providers as insurance coverage changes or as other health problems arise, such as bowel obstruction being treated by a general surgeon.

As gynecologic surgeons, we must appreciate that while infections, endometriosis, and other peritoneal insults may contribute to adhesion development, surgery is the most common cause. We also must appreciate how tissue injury leads to the development of adhesions, and why adhesion reformation so commonly occurs.

This understanding is critical to our consideration and use of the “barrier” products currently available for reducing postsurgical adhesions — and critical to our efforts to employ the tenets of gynecologic microsurgery and to achieve as optimal a surgical outcome as possible. At this point in time, use of approved surgical adjuvants in combination with good surgical technique offers the best chance at adhesion reduction and prevention.

Incidence of Adhesions

A series of reports published in the early to mid-1980s documented how commonly adhesions develop after various types of reproductive pelvic surgery. Through early second-look laparoscopy, postoperative adhesions were found to occur, in these studies, in 55%–100% of patients after their primary gynecologic surgery.

In a multicenter study published in 1987, my colleagues and I also showed that gynecologic surgeries performed at the time of laparotomy are frequently complicated by both adhesion reformation and de novo adhesion formation. More than half of the 161 women (51%) who had a second-look laparoscopy 1–12 weeks after reproductive pelvic surgery were found to have de novo adhesion formation (adhesions in at least one new location). Adhesion reformation was also widespread: At the initial laparotomy, 121 of the patients (all of whom were treated for infertility) were noted to have some form of adhesion, and adhesion reformation subsequently occurred at the site of adhesiolysis in 85% of these women, with no differences with respect to adhesion type (Fertil. Steril. 1987;47;864–6).

It was hoped, and largely expected, that the growth of laparoscopy and minimally invasive surgery approaches in more recent years would reduce postoperative adhesion development — that minimally invasive techniques would prove to be less adhesiogenic than laparotomy. Questions remain, but thus far, such hopes have diminished and our expectations for significant improvement have gone unsubstantiated.

One multicenter study on adhesion development after initial laparoscopic procedures found that the incidence of adhesions at an early second-look procedure was 97% — no lower than in prior reports of second-look laparoscopy after laparotomy.

In this study, 68 women underwent operative laparoscopic procedures, including adhesiolysis, and had second-look procedures within 90 days. The good news was that de novo adhesion formation between the two laparoscopic procedures occurred in only 8 of the women (12%) and at 11 of 47 possible sites — much less frequently than after laparotomy. Adhesion scores also decreased at the second look compared with the status of the pelvis at the initial procedure. Still, with the high rate of adhesion reformation, almost all of the women developed postoperative adhesions.

Thus, even when the initial procedure was performed laparoscopically, adhesion development was an all-too-common occurrence, and appeared to be independent of the character of the initial adhesion (Fertil. Steril. 1991;55:700–4).

More recently, data from randomized studies of various adhesion barriers and potential anti-adhesion adjuvants have further dashed hopes that laparoscopy per se can reduce adhesion development.

For instance, in a recent small pilot study of a fibrin-based product called Adhexil, “control” ovaries that were not treated had a 27% increase in the mean adhesion score between an initial laparoscopic procedure and second-look laparoscopy. The women in the study had undergone bilateral ovarian surgery, with ovaries randomized for application of the product or no treatment (Fertil. Steril. 2011;95:1086–90). Clearly, a laparoscopic approach to their procedures did not prevent the development of adhesions.

Many of the initial studies on adhesion development were comprised of patients with infertility, but more recent observations have been extended to women without infertility and to men. Studies have covered patients undergoing colectomies, for instance, as well as neonates undergoing cardiothoracic procedures.

In a recent review article on adhesion prevention and reduction, members of an interdisciplinary consensus conference stated that adhesions develop after “nearly all” abdominal and pelvic procedures performed through either standard laparotomy or laparoscopic approaches. With respect to gynecologic surgery, they point out, research has shown that the most common site for postsurgical adhesion development is the ovary (Surg. Innov. 2010;17:183–8).

Consequences

Pelvic adhesions are a well-recognized cause of infertility, contributing to up to an estimated 40% of the cases of infertility in women. Adhesions are also a leading cause of bowel obstruction and a significant cause of chronic or recurrent pelvic pain.

The contribution of pelvic adhesions to chronic pelvic pain is not completely understood. Adhesions may be the cause of pain in some women, and in other women, an incidental finding that is not contributing to pain. In patients who have endometriosis as well, the question remains as to the contribution of endometriosis per se, or adhesions, to the pain. Endometriosis can cause adhesions and chronic pelvic pain, presumably through the cyclic generation of inflammatory molecules.

The relationship between chronic pain and adhesions is further complicated by ensuing questions about the efficacy of adhesiolysis. The two randomized trials that have thus far examined the role of adhesiolysis in the reduction of chronic pelvic pain failed to demonstrate a significant improvement in pain after adhesiolysis; however, the high failure rates after follow-up may be due to adhesion reformation and de novo adhesion formation (Fertil. Steril. 2004;82:1483–91). Performance of more randomized comparisons in the future may yield improved outcomes when adhesiolysis is paired with postprocedure use of anti-adhesion adjuvants.

Despite the uncertainties, multiple studies support the current estimation that adhesions cause or significantly contribute to chronic pelvic pain in up to 30% of women with the problem. As the Ovarian Adhesion Study Group noted in one of its reports, adhesions have been reported as a primary cause of chronic pelvic pain in 13%-36% of women, depending on the study (Obstet. Gynecol. 1995;86:335–40). Economic analyses also have quantified the impact of adhesion-related hospital readmissions. A study done in the United Kingdom, for instance, concluded that 6% of all hospital readmissions in patients who had undergone abdominal or pelvic surgery were directly related to adhesions (Lancet 1999;353:1476–80).httother report on hospitalizations for lower abdominal adhesiolysis in the United States estimated that in 1988, the cost of adhesions stemming from gynecologic procedures alone was almost $1.2 billion. This estimate did not include outpatient and indirect costs (Surg. Gynecol. Obstet. 1993;176:271–6).

Why, How Adhesions Develop

Our current understanding is that adhesions develop as a result of injury to and devascularization of the peritoneum, and the subsequent inflammatory response and peritoneal wound healing process. Tissue hypoxia triggers a cascade of intracellular responses that, in combination with the fibrinous collection of blood and serosanguinous fluid at the tissue surface, may result in adhesion development.

In the initial postsurgical period, either overt bleeding or oozing may occur at the site(s) of tissue injury, forming clots. In combination with serosanguinous fluid, which may leak from damaged peritoneal surfaces, a fibrinous mass thus develops at the surgical sites and sites of tissue injury. This represents an initial step in peritoneal repair.

When surrounding tissue is normal and there is a sufficient amount of plasminogen activator present in the peritoneum — and when numerous other events and conditions are optimal — the resulting fibrinous mass can be degraded. As that occurs, and tissue healing continues, fibroblasts are recruited to the surface of the injury site from underlying tissues.

If the fibrinous mass is no longer present, fibroblasts “stop” at the tissue surfaces, and become covered by mesothelial cells which line the peritoneal surface as the process of remesothelialization occurs. This process appears to be initiated within hours after surgery and is generally believed to be completed in 3–5 days. (In such instances, healing would have occurred without adhesions, although subperitoneal fibrosis may have occurred.)

Various hypoxia-driven responses, however, such as a reduction in plasminogen activator activity, can cause the fibrinous mass to persist during the healing process, before remesothelialization occurs. In this case, fibroblasts migrate not only to, but through, the injury site, and into the persisting fibrinous mass. This is subsequently followed by deposition of collagen, fibronectin, and other extracellular matrix materials — creating the beginnings of a true adhesion.

In such cases, remesothelialization still occurs, but the mesothelial cells cover the adhesion as well as the normal tissue surfaces, forming adhesive bands and other types of connections between opposing serosal tissue surfaces. Angiogenesis then occurs as the hypoxic tissue in the adhesion sends signals (such as vascular endothelial growth factor) in an attempt to reestablish a supply of oxygen and nutrients to the injured and devascularized tissues. Subsequently, as the tissue remodels, there is a propensity for the adhesion to become more vascular and denser.

Understanding this process is important because the products currently available for reducing adhesions act as barriers during this critical period of remesothelialization, keeping peritoneal surfaces apart and minimizing the potential development of a fibrinous mass that bridges tissue surfaces. If an adhesion does not form during the 3–5-day period of remesothelialization, it is theorized that there will not be any adhesion development — unless there's new injury to the tissue surfaces.

Once an adhesion forms, however, it has acquired a particular “adhesion phenotype” — different from that of normal peritoneum — that appears to be irreversible. This is likely why it is so difficult to prevent adhesion reformation after adhesiolysis. Rates of adhesion reformation — even in the best of surgical hands — run between 80% and 90%, compared with a 50% chance of de novo adhesion development after surgery (at new sites of injury).

The identification of an adhesion phenotype came originally from comparisons of normal peritoneal and adhesion tissues harvested from the same patient, and were later confirmed in cell culture studies in which normal peritoneal fibroblasts were subjected to hypoxia (2% O₂ conditions). Fibroblasts cultured under hypoxic conditions were subsequently found to have developed particular molecular biologic characterizations that are different from those of normal peritoneal fibroblasts.

When exposed to normal amounts of oxygen again, the fibroblasts did not go back to being normal fibroblasts — they continued to manifest the adhesion phenotype (J. Am Assoc. Gynecol. Laparosc. 2004;11:307–14). These findings have been confirmed in animal and human studies, and such relationships have also been identified in other peritoneal tissue types such as mesothelial cells and macrophages.

Further research on the pathogenesis of adhesions and the molecular biologic differences between normal peritoneum and adhesions may allow identification of which patients, and which sites within a patient, are most at risk for adhesion development, as well as the discovery of new ways to reduce the development of postoperative adhesions and their clinical sequelae.

It is possible that a future generation of barrier products not only will work as a barrier separating surfaces prior to remesothelialization, but will also have local biologic effects — delivering adhesion-reducing drugs or biologics, for instance, to specific localized tissue sites. A personalized approach to adhesion prevention also might be possible, with particular factors deemed to increase adhesion risk in individual patients (a deficiency of plasminogen activator, for instance) being corrected.

In the meantime, as we've learned more about the pathophysiological state under which adhesions develop, we have found that adhesion development may occur faster than we had thought. In one recent rodent study, we identified postoperative tissue attachments as early as 2 hours after cecal abrasion. We noted considerable local edema and vessel dilatation within 2 hours of injury, angiogenesis and fibrin deposition at 8 hours, and cell proliferation at 24 hours (Fertil. Steril. 2010;93:2734–7). And interestingly, recent studies in mice have shown that laparoscopic insufflation per se can induce peritoneal adhesions, with the adhesions increasing proportionally with both increasing duration of insufflation and an increase in intraperitoneal pressure.

Prevention in Practice

During the past decade a variety of surgical adjuvants — from procoagulants and fibrinolytic agents to anti-inflammatory drugs and antibiotics — have been investigated for use in reducing the occurrence, extent, and severity of adhesions. Unfortunately, most approaches seemingly have been futile. Some products have shown trends toward efficacy in animal or early human studies and need further investigation.

The three synthetic products that are approved by the Food and Drug Administration—Gynecare Interceed, Seprafilm, and Adept — can help reduce postoperative adhesions after gynecologic procedures, and should be considered as potentially useful surgical adjuvants. A meta-analysis of studies of Gynecare Interceed, for instance, found that approximately twice as many operative sites were adhesion free after use of the barrier than after surgery alone (J. Reprod. Med. 1999;44:325–31).

Gynecare Interceed (Johnson & Johnson) and Seprafilm (Genzyme) are approved for use only at laparotomy, while Adept (Baxter International), an icodextrin solution that disperses throughout the abdominopelvic cavity, is approved for use only in laparoscopic surgery.

The key consideration to make when using Interceed — a biodegradable woven fabric composed of oxidized, regenerated cellulose — is the importance of achieving meticulous hemostasis. Its efficacy is reduced, or can even be lost, in the presence of blood. Care also must be taken not to stretch the material or alter its shape and the spacing between the weaves. Otherwise, the material, once gelated, will have a greater potential for spaces in which the tissue surfaces would not be separated and thus a greater potential for blood coagulation and fibroblast in-growth. Multiple pieces of the material may be overlapped, but there have been no benefits demonstrated (at least in animal studies) to using double layers.

Care in application also is critically important for Seprafilm, a film composed of modified hyaluronic acid and carboxymethylcellulose. Seprafilm is brittle and is difficult to apply through small incisions. While it's not impossible to deliver the product laparoscopically, many surgeons have found this very difficult. And in the United States, it is approved for use with laparotomy only.

In applying Seprafilm, it is critical to first get good exposure of the field and then position the film very carefully. Attempts to reposition the product will often result in tears or breaks. Of course, just as with Interceed, this device is believed to work primarily by separating tissue surfaces, and thus it has little to no chance of success if it does not completely separate the surgically injured tissue from other tissue surfaces in the initial postoperative period while remesothelialization is occurring.

The use of adjuvants, moreover, is no substitute for good surgical technique that aims to minimize tissue injury, tissue devascularization, and inflammation. This is easier to achieve, of course, during a microsurgical procedure such as a tubal anastomosis than in a patient with severe endometriosis or many large fibroids. Still, to the extent possible for the procedure being conducted, the tenets of gynecologic microsurgery should always be considered:

▸ Handle as little tissue as possible, as minimally as possible. To the extent possible, handle only those portions that will subsequently be excised.

▸ Keep tissues moist. Tissue drying leads to injury and loss of mesothelial cells. Raw surfaces are more prone to develop adhesions.

▸ Take special care in the use of suture. Consider whether clinical situations will allow use of less reactive and smaller-caliber suture. When using suture to tie off blood vessels, skeletonize the vessels so as to minimize the amount of tissue distal to the suture that will become hypoxic and serve as a nidus to adhesion development.

▸ Target the use of electrosurgery and other energy sources. Use it in specific localized sites where it's needed, such as to stop bleeding, but avoid widely dispersed use, when possible, again to minimize the amount of residual devitalized tissue remaining in the pelvis at the conclusion of the surgical procedure.

Pelvic Adhesions — An Update

www.isge.org

www.aagl.org

“A number of human interventional trials and animal studies have evaluated techniques and materials designed to prevent and reduce postsurgical adhesions. The results have been inconclusive and sometimes contradictory. Thus, preventing postsurgical adhesions remains an art, rather than a science.” So I began my introduction to the program on adhesion prevention at the 2010 Congress of the Society of Laparoscopic Surgeons in New York City.

Patients with adhesions can present with small bowel obstruction or with complaints of infertility, chronic pain, or dyspareunia. Unfortunately, adhesive disease is problematic. Four percent of the patients undergoing abdominal and pelvic surgery will be readmitted due to adhesion-related complications. In excess of 400,000 surgical procedures are performed annually in the United States for lysis of adhesions. In a Scottish National Health Service Study of nearly 9,000 women who previously underwent open gynecologic surgery, just less than 3% were readmitted secondary to adhesions; the highest readmit rate was ovarian surgery (BJOG 2000;107:855–62).

While one would expect a reduction in the number of patients undergoing laparoscopic surgery, in reality, the verdict is not yet clear. A 1998 meta-analysis showed a decrease in both reformed (26.6% vs. 14.3%) and de novo adhesions (45.2% vs. 37.2%) in the laparoscopic group, compared with laparotomy (Fertil. Steril. 1998;70:702–11).

Despite this, other authors cite pneumoperitoneum, prolonged surgery, high insufflation pressure, and overzealous use of energy to cut and coagulate as reasons why laparoscopic surgery increases risk of adhesions.

The economic impact of adhesions is staggering, in excess of $1.3 billion in the United States per year.

For this current excerpt of the Master Class in Gynecologic Surgery, I have solicited the wisdom of Dr. Michael Diamond. He is the Kamran S. Moghissi Professor of Obstetrics and Gynecology and associate chairman of the department of obstetrics and gynecology at Wayne State University, Detroit. Dr. Diamond also is director of the division of reproductive endocrinology and infertility and assistant dean for clinical and translational research at the university. Dr. Diamond has spent much of his academic career involved in the pathogenesis, prevention, and treatment of pelvic adhesions. He is truly considered the world's leader in this area, and we are honored to have Dr. Diamond as guest author of this important area of our surgical arena.

The prevention of postsurgical adhesions is one of the greatest unmet needs in medicine today. Surgical series have shown that adhesions are present after 80%-90% of abdominal and pelvic surgeries, and that these abnormal fibrous connections have a tremendous propensity to reform after adhesiolysis. (We will define adhesions here as “attachments between surfaces at nonanatomical locations.”)

In gynecologic surgery, postoperative adhesions are a frequent cause of infertility, pain, bowel obstruction, and difficulty in later procedures. Adhesions can occur after minimally invasive procedures, which have the potential for trocar injury to structures adherent to the anterior abdominal wall. Other intraoperative injuries can occur due to obscured normal anatomy or restricted access. A significant number of patients also undergo second surgeries to treat sequelae that are directly related to adhesions.

The literature is replete with studies of adhesion development and reports of its incidence and its consequences. Still, the problem of postoperative adhesion development often goes underestimated or unrecognized. This is because we don't routinely perform early second-look operations to assess adhesion development, and because there are no serum markers or sensitive imaging techniques to allow their identification. In addition, we do not follow our patients who seek care from other providers as insurance coverage changes or as other health problems arise, such as bowel obstruction being treated by a general surgeon.

As gynecologic surgeons, we must appreciate that while infections, endometriosis, and other peritoneal insults may contribute to adhesion development, surgery is the most common cause. We also must appreciate how tissue injury leads to the development of adhesions, and why adhesion reformation so commonly occurs.

This understanding is critical to our consideration and use of the “barrier” products currently available for reducing postsurgical adhesions — and critical to our efforts to employ the tenets of gynecologic microsurgery and to achieve as optimal a surgical outcome as possible. At this point in time, use of approved surgical adjuvants in combination with good surgical technique offers the best chance at adhesion reduction and prevention.

Incidence of Adhesions

A series of reports published in the early to mid-1980s documented how commonly adhesions develop after various types of reproductive pelvic surgery. Through early second-look laparoscopy, postoperative adhesions were found to occur, in these studies, in 55%–100% of patients after their primary gynecologic surgery.

In a multicenter study published in 1987, my colleagues and I also showed that gynecologic surgeries performed at the time of laparotomy are frequently complicated by both adhesion reformation and de novo adhesion formation. More than half of the 161 women (51%) who had a second-look laparoscopy 1–12 weeks after reproductive pelvic surgery were found to have de novo adhesion formation (adhesions in at least one new location). Adhesion reformation was also widespread: At the initial laparotomy, 121 of the patients (all of whom were treated for infertility) were noted to have some form of adhesion, and adhesion reformation subsequently occurred at the site of adhesiolysis in 85% of these women, with no differences with respect to adhesion type (Fertil. Steril. 1987;47;864–6).

It was hoped, and largely expected, that the growth of laparoscopy and minimally invasive surgery approaches in more recent years would reduce postoperative adhesion development — that minimally invasive techniques would prove to be less adhesiogenic than laparotomy. Questions remain, but thus far, such hopes have diminished and our expectations for significant improvement have gone unsubstantiated.

One multicenter study on adhesion development after initial laparoscopic procedures found that the incidence of adhesions at an early second-look procedure was 97% — no lower than in prior reports of second-look laparoscopy after laparotomy.

In this study, 68 women underwent operative laparoscopic procedures, including adhesiolysis, and had second-look procedures within 90 days. The good news was that de novo adhesion formation between the two laparoscopic procedures occurred in only 8 of the women (12%) and at 11 of 47 possible sites — much less frequently than after laparotomy. Adhesion scores also decreased at the second look compared with the status of the pelvis at the initial procedure. Still, with the high rate of adhesion reformation, almost all of the women developed postoperative adhesions.

Thus, even when the initial procedure was performed laparoscopically, adhesion development was an all-too-common occurrence, and appeared to be independent of the character of the initial adhesion (Fertil. Steril. 1991;55:700–4).

More recently, data from randomized studies of various adhesion barriers and potential anti-adhesion adjuvants have further dashed hopes that laparoscopy per se can reduce adhesion development.

For instance, in a recent small pilot study of a fibrin-based product called Adhexil, “control” ovaries that were not treated had a 27% increase in the mean adhesion score between an initial laparoscopic procedure and second-look laparoscopy. The women in the study had undergone bilateral ovarian surgery, with ovaries randomized for application of the product or no treatment (Fertil. Steril. 2011;95:1086–90). Clearly, a laparoscopic approach to their procedures did not prevent the development of adhesions.

Many of the initial studies on adhesion development were comprised of patients with infertility, but more recent observations have been extended to women without infertility and to men. Studies have covered patients undergoing colectomies, for instance, as well as neonates undergoing cardiothoracic procedures.

In a recent review article on adhesion prevention and reduction, members of an interdisciplinary consensus conference stated that adhesions develop after “nearly all” abdominal and pelvic procedures performed through either standard laparotomy or laparoscopic approaches. With respect to gynecologic surgery, they point out, research has shown that the most common site for postsurgical adhesion development is the ovary (Surg. Innov. 2010;17:183–8).

Consequences

Pelvic adhesions are a well-recognized cause of infertility, contributing to up to an estimated 40% of the cases of infertility in women. Adhesions are also a leading cause of bowel obstruction and a significant cause of chronic or recurrent pelvic pain.

The contribution of pelvic adhesions to chronic pelvic pain is not completely understood. Adhesions may be the cause of pain in some women, and in other women, an incidental finding that is not contributing to pain. In patients who have endometriosis as well, the question remains as to the contribution of endometriosis per se, or adhesions, to the pain. Endometriosis can cause adhesions and chronic pelvic pain, presumably through the cyclic generation of inflammatory molecules.

The relationship between chronic pain and adhesions is further complicated by ensuing questions about the efficacy of adhesiolysis. The two randomized trials that have thus far examined the role of adhesiolysis in the reduction of chronic pelvic pain failed to demonstrate a significant improvement in pain after adhesiolysis; however, the high failure rates after follow-up may be due to adhesion reformation and de novo adhesion formation (Fertil. Steril. 2004;82:1483–91). Performance of more randomized comparisons in the future may yield improved outcomes when adhesiolysis is paired with postprocedure use of anti-adhesion adjuvants.

Despite the uncertainties, multiple studies support the current estimation that adhesions cause or significantly contribute to chronic pelvic pain in up to 30% of women with the problem. As the Ovarian Adhesion Study Group noted in one of its reports, adhesions have been reported as a primary cause of chronic pelvic pain in 13%-36% of women, depending on the study (Obstet. Gynecol. 1995;86:335–40). Economic analyses also have quantified the impact of adhesion-related hospital readmissions. A study done in the United Kingdom, for instance, concluded that 6% of all hospital readmissions in patients who had undergone abdominal or pelvic surgery were directly related to adhesions (Lancet 1999;353:1476–80).httother report on hospitalizations for lower abdominal adhesiolysis in the United States estimated that in 1988, the cost of adhesions stemming from gynecologic procedures alone was almost $1.2 billion. This estimate did not include outpatient and indirect costs (Surg. Gynecol. Obstet. 1993;176:271–6).

Why, How Adhesions Develop

Our current understanding is that adhesions develop as a result of injury to and devascularization of the peritoneum, and the subsequent inflammatory response and peritoneal wound healing process. Tissue hypoxia triggers a cascade of intracellular responses that, in combination with the fibrinous collection of blood and serosanguinous fluid at the tissue surface, may result in adhesion development.

In the initial postsurgical period, either overt bleeding or oozing may occur at the site(s) of tissue injury, forming clots. In combination with serosanguinous fluid, which may leak from damaged peritoneal surfaces, a fibrinous mass thus develops at the surgical sites and sites of tissue injury. This represents an initial step in peritoneal repair.

When surrounding tissue is normal and there is a sufficient amount of plasminogen activator present in the peritoneum — and when numerous other events and conditions are optimal — the resulting fibrinous mass can be degraded. As that occurs, and tissue healing continues, fibroblasts are recruited to the surface of the injury site from underlying tissues.

If the fibrinous mass is no longer present, fibroblasts “stop” at the tissue surfaces, and become covered by mesothelial cells which line the peritoneal surface as the process of remesothelialization occurs. This process appears to be initiated within hours after surgery and is generally believed to be completed in 3–5 days. (In such instances, healing would have occurred without adhesions, although subperitoneal fibrosis may have occurred.)

Various hypoxia-driven responses, however, such as a reduction in plasminogen activator activity, can cause the fibrinous mass to persist during the healing process, before remesothelialization occurs. In this case, fibroblasts migrate not only to, but through, the injury site, and into the persisting fibrinous mass. This is subsequently followed by deposition of collagen, fibronectin, and other extracellular matrix materials — creating the beginnings of a true adhesion.

In such cases, remesothelialization still occurs, but the mesothelial cells cover the adhesion as well as the normal tissue surfaces, forming adhesive bands and other types of connections between opposing serosal tissue surfaces. Angiogenesis then occurs as the hypoxic tissue in the adhesion sends signals (such as vascular endothelial growth factor) in an attempt to reestablish a supply of oxygen and nutrients to the injured and devascularized tissues. Subsequently, as the tissue remodels, there is a propensity for the adhesion to become more vascular and denser.

Understanding this process is important because the products currently available for reducing adhesions act as barriers during this critical period of remesothelialization, keeping peritoneal surfaces apart and minimizing the potential development of a fibrinous mass that bridges tissue surfaces. If an adhesion does not form during the 3–5-day period of remesothelialization, it is theorized that there will not be any adhesion development — unless there's new injury to the tissue surfaces.

Once an adhesion forms, however, it has acquired a particular “adhesion phenotype” — different from that of normal peritoneum — that appears to be irreversible. This is likely why it is so difficult to prevent adhesion reformation after adhesiolysis. Rates of adhesion reformation — even in the best of surgical hands — run between 80% and 90%, compared with a 50% chance of de novo adhesion development after surgery (at new sites of injury).

The identification of an adhesion phenotype came originally from comparisons of normal peritoneal and adhesion tissues harvested from the same patient, and were later confirmed in cell culture studies in which normal peritoneal fibroblasts were subjected to hypoxia (2% O₂ conditions). Fibroblasts cultured under hypoxic conditions were subsequently found to have developed particular molecular biologic characterizations that are different from those of normal peritoneal fibroblasts.

When exposed to normal amounts of oxygen again, the fibroblasts did not go back to being normal fibroblasts — they continued to manifest the adhesion phenotype (J. Am Assoc. Gynecol. Laparosc. 2004;11:307–14). These findings have been confirmed in animal and human studies, and such relationships have also been identified in other peritoneal tissue types such as mesothelial cells and macrophages.

Further research on the pathogenesis of adhesions and the molecular biologic differences between normal peritoneum and adhesions may allow identification of which patients, and which sites within a patient, are most at risk for adhesion development, as well as the discovery of new ways to reduce the development of postoperative adhesions and their clinical sequelae.

It is possible that a future generation of barrier products not only will work as a barrier separating surfaces prior to remesothelialization, but will also have local biologic effects — delivering adhesion-reducing drugs or biologics, for instance, to specific localized tissue sites. A personalized approach to adhesion prevention also might be possible, with particular factors deemed to increase adhesion risk in individual patients (a deficiency of plasminogen activator, for instance) being corrected.

In the meantime, as we've learned more about the pathophysiological state under which adhesions develop, we have found that adhesion development may occur faster than we had thought. In one recent rodent study, we identified postoperative tissue attachments as early as 2 hours after cecal abrasion. We noted considerable local edema and vessel dilatation within 2 hours of injury, angiogenesis and fibrin deposition at 8 hours, and cell proliferation at 24 hours (Fertil. Steril. 2010;93:2734–7). And interestingly, recent studies in mice have shown that laparoscopic insufflation per se can induce peritoneal adhesions, with the adhesions increasing proportionally with both increasing duration of insufflation and an increase in intraperitoneal pressure.

Prevention in Practice

During the past decade a variety of surgical adjuvants — from procoagulants and fibrinolytic agents to anti-inflammatory drugs and antibiotics — have been investigated for use in reducing the occurrence, extent, and severity of adhesions. Unfortunately, most approaches seemingly have been futile. Some products have shown trends toward efficacy in animal or early human studies and need further investigation.

The three synthetic products that are approved by the Food and Drug Administration—Gynecare Interceed, Seprafilm, and Adept — can help reduce postoperative adhesions after gynecologic procedures, and should be considered as potentially useful surgical adjuvants. A meta-analysis of studies of Gynecare Interceed, for instance, found that approximately twice as many operative sites were adhesion free after use of the barrier than after surgery alone (J. Reprod. Med. 1999;44:325–31).

Gynecare Interceed (Johnson & Johnson) and Seprafilm (Genzyme) are approved for use only at laparotomy, while Adept (Baxter International), an icodextrin solution that disperses throughout the abdominopelvic cavity, is approved for use only in laparoscopic surgery.

The key consideration to make when using Interceed — a biodegradable woven fabric composed of oxidized, regenerated cellulose — is the importance of achieving meticulous hemostasis. Its efficacy is reduced, or can even be lost, in the presence of blood. Care also must be taken not to stretch the material or alter its shape and the spacing between the weaves. Otherwise, the material, once gelated, will have a greater potential for spaces in which the tissue surfaces would not be separated and thus a greater potential for blood coagulation and fibroblast in-growth. Multiple pieces of the material may be overlapped, but there have been no benefits demonstrated (at least in animal studies) to using double layers.

Care in application also is critically important for Seprafilm, a film composed of modified hyaluronic acid and carboxymethylcellulose. Seprafilm is brittle and is difficult to apply through small incisions. While it's not impossible to deliver the product laparoscopically, many surgeons have found this very difficult. And in the United States, it is approved for use with laparotomy only.

In applying Seprafilm, it is critical to first get good exposure of the field and then position the film very carefully. Attempts to reposition the product will often result in tears or breaks. Of course, just as with Interceed, this device is believed to work primarily by separating tissue surfaces, and thus it has little to no chance of success if it does not completely separate the surgically injured tissue from other tissue surfaces in the initial postoperative period while remesothelialization is occurring.

The use of adjuvants, moreover, is no substitute for good surgical technique that aims to minimize tissue injury, tissue devascularization, and inflammation. This is easier to achieve, of course, during a microsurgical procedure such as a tubal anastomosis than in a patient with severe endometriosis or many large fibroids. Still, to the extent possible for the procedure being conducted, the tenets of gynecologic microsurgery should always be considered:

▸ Handle as little tissue as possible, as minimally as possible. To the extent possible, handle only those portions that will subsequently be excised.

▸ Keep tissues moist. Tissue drying leads to injury and loss of mesothelial cells. Raw surfaces are more prone to develop adhesions.

▸ Take special care in the use of suture. Consider whether clinical situations will allow use of less reactive and smaller-caliber suture. When using suture to tie off blood vessels, skeletonize the vessels so as to minimize the amount of tissue distal to the suture that will become hypoxic and serve as a nidus to adhesion development.

▸ Target the use of electrosurgery and other energy sources. Use it in specific localized sites where it's needed, such as to stop bleeding, but avoid widely dispersed use, when possible, again to minimize the amount of residual devitalized tissue remaining in the pelvis at the conclusion of the surgical procedure.

Pelvic Adhesions — An Update

www.isge.org

www.aagl.org

“A number of human interventional trials and animal studies have evaluated techniques and materials designed to prevent and reduce postsurgical adhesions. The results have been inconclusive and sometimes contradictory. Thus, preventing postsurgical adhesions remains an art, rather than a science.” So I began my introduction to the program on adhesion prevention at the 2010 Congress of the Society of Laparoscopic Surgeons in New York City.

Patients with adhesions can present with small bowel obstruction or with complaints of infertility, chronic pain, or dyspareunia. Unfortunately, adhesive disease is problematic. Four percent of the patients undergoing abdominal and pelvic surgery will be readmitted due to adhesion-related complications. In excess of 400,000 surgical procedures are performed annually in the United States for lysis of adhesions. In a Scottish National Health Service Study of nearly 9,000 women who previously underwent open gynecologic surgery, just less than 3% were readmitted secondary to adhesions; the highest readmit rate was ovarian surgery (BJOG 2000;107:855–62).

While one would expect a reduction in the number of patients undergoing laparoscopic surgery, in reality, the verdict is not yet clear. A 1998 meta-analysis showed a decrease in both reformed (26.6% vs. 14.3%) and de novo adhesions (45.2% vs. 37.2%) in the laparoscopic group, compared with laparotomy (Fertil. Steril. 1998;70:702–11).

Despite this, other authors cite pneumoperitoneum, prolonged surgery, high insufflation pressure, and overzealous use of energy to cut and coagulate as reasons why laparoscopic surgery increases risk of adhesions.

The economic impact of adhesions is staggering, in excess of $1.3 billion in the United States per year.

For this current excerpt of the Master Class in Gynecologic Surgery, I have solicited the wisdom of Dr. Michael Diamond. He is the Kamran S. Moghissi Professor of Obstetrics and Gynecology and associate chairman of the department of obstetrics and gynecology at Wayne State University, Detroit. Dr. Diamond also is director of the division of reproductive endocrinology and infertility and assistant dean for clinical and translational research at the university. Dr. Diamond has spent much of his academic career involved in the pathogenesis, prevention, and treatment of pelvic adhesions. He is truly considered the world's leader in this area, and we are honored to have Dr. Diamond as guest author of this important area of our surgical arena.

Over the past century, the management of American hospitals has changed dramatically. These changes have occurred as a result of major shifts in the social and financial environment and have had a major effect on how medicine was practiced in the past and how it will be practiced in the future.

The American hospital as we know it today was established in the late 19th and early 20th centuries largely by the Catholic, Protestant, and Jewish communities to provide care for the elderly and chronically ill patients who otherwise would not be cared for at home.

With the development of surgical techniques from tonsillectomies to cholecystectomies in the mid-20th century, they became the workshop of general surgeons, who largely controlled the hospitals. With the subsequent development of antibiotics and medical treatment for cardiovascular disease, the internal medicine specialties demanded a larger role in institutional management.

The increased complexity and expense of medical care led to concerns about how to provide a financial base for medical care and led to the establishment of private medical insurance programs, and ultimately, to Medicare and Medicaid. Hospitals were no longer concerned about being a health resource but suddenly became a profit center. Community hospitals expanded in order to meet the needs of new technologies with the support of grants and loans from the federal government.

With this growth, the management of the hospital of the 20th century required the creation of a new breed of hospital staff: the hospital administrator. They were hired to manage the financial and administrative aspects of these new and growing organizations. Although the hospital administration was structured to provide equipoise between the medical and financial priorities of the hospital, that balance was not easily maintained, and as the financial aspects became central, the hospital administrator became supreme and physicians lost control.

Today, the American hospital has become central to the support of nonprofit and for-profit regional and national health care conglomerates, and control has become the province of boards of directors with little medical input and larger community control. As a consequence, the physician has now become a real or quasi-employee of the hospital.

In a recent perspective paper, Dr. Richard Gunderson (Acad. Med. 2009;84:1348-51) emphasizes the need to train physicians to provide leadership for the future management of the hospital. He points out that in 1935, physicians were in charge of 35% of the nation's hospitals, but that number has shrunk to 4% of our current 6,500 U.S. hospitals. The academic medical community has largely ignored its role in preparing medical students for administrative leadership as it focused on the clinical knowledge required for the medical competence.

Dr. Gunderson, of Indiana University in Indianapolis, advocates the identification of student leaders in the selection of medical students and proposes the inclusion of courses in medical finance and social issues in the medical school curriculum in order to prepare them for a leadership role in redefining the future of medical care and hospital management.

Amanda Goodall, Ph.D., a senior research fellow at the Institute for the Study of Labor in Bonn, Germany, provides an even more challenging analysis of the importance of medical leadership at the hospital (Social Science Med. 2011;73:535-9). She notes that these changes in leadership are not unique to the United States but also have taken place in European hospitals. Using a quality scoring system, she analyzed the quality performance of 100 of the U.S. News and World Report's Best Hospitals 2009 in the fields of cancer, digestive disorders, and heart and heart surgery. She found a positive correlation between hospital quality ranking and physician CEO leadership.

Those of us who have grown up through this management evolution have seen its real impact on the care of hospital patients. Some of the changes have been positive, while others have proved frustrating for both patients and physicians who practice in the new environment.

The need for leadership by those of us who have direct patient care responsibilities is essential for an inclusive decision-making process. When patient care comes to discussion at the board meeting, physicians and nurses bring to the process a perspective that only they can provide. It is essential that their voices be heard.

Over the past century, the management of American hospitals has changed dramatically. These changes have occurred as a result of major shifts in the social and financial environment and have had a major effect on how medicine was practiced in the past and how it will be practiced in the future.

The American hospital as we know it today was established in the late 19th and early 20th centuries largely by the Catholic, Protestant, and Jewish communities to provide care for the elderly and chronically ill patients who otherwise would not be cared for at home.

With the development of surgical techniques from tonsillectomies to cholecystectomies in the mid-20th century, they became the workshop of general surgeons, who largely controlled the hospitals. With the subsequent development of antibiotics and medical treatment for cardiovascular disease, the internal medicine specialties demanded a larger role in institutional management.

The increased complexity and expense of medical care led to concerns about how to provide a financial base for medical care and led to the establishment of private medical insurance programs, and ultimately, to Medicare and Medicaid. Hospitals were no longer concerned about being a health resource but suddenly became a profit center. Community hospitals expanded in order to meet the needs of new technologies with the support of grants and loans from the federal government.

With this growth, the management of the hospital of the 20th century required the creation of a new breed of hospital staff: the hospital administrator. They were hired to manage the financial and administrative aspects of these new and growing organizations. Although the hospital administration was structured to provide equipoise between the medical and financial priorities of the hospital, that balance was not easily maintained, and as the financial aspects became central, the hospital administrator became supreme and physicians lost control.

Today, the American hospital has become central to the support of nonprofit and for-profit regional and national health care conglomerates, and control has become the province of boards of directors with little medical input and larger community control. As a consequence, the physician has now become a real or quasi-employee of the hospital.

In a recent perspective paper, Dr. Richard Gunderson (Acad. Med. 2009;84:1348-51) emphasizes the need to train physicians to provide leadership for the future management of the hospital. He points out that in 1935, physicians were in charge of 35% of the nation's hospitals, but that number has shrunk to 4% of our current 6,500 U.S. hospitals. The academic medical community has largely ignored its role in preparing medical students for administrative leadership as it focused on the clinical knowledge required for the medical competence.

Dr. Gunderson, of Indiana University in Indianapolis, advocates the identification of student leaders in the selection of medical students and proposes the inclusion of courses in medical finance and social issues in the medical school curriculum in order to prepare them for a leadership role in redefining the future of medical care and hospital management.

Amanda Goodall, Ph.D., a senior research fellow at the Institute for the Study of Labor in Bonn, Germany, provides an even more challenging analysis of the importance of medical leadership at the hospital (Social Science Med. 2011;73:535-9). She notes that these changes in leadership are not unique to the United States but also have taken place in European hospitals. Using a quality scoring system, she analyzed the quality performance of 100 of the U.S. News and World Report's Best Hospitals 2009 in the fields of cancer, digestive disorders, and heart and heart surgery. She found a positive correlation between hospital quality ranking and physician CEO leadership.

Those of us who have grown up through this management evolution have seen its real impact on the care of hospital patients. Some of the changes have been positive, while others have proved frustrating for both patients and physicians who practice in the new environment.

The need for leadership by those of us who have direct patient care responsibilities is essential for an inclusive decision-making process. When patient care comes to discussion at the board meeting, physicians and nurses bring to the process a perspective that only they can provide. It is essential that their voices be heard.

Over the past century, the management of American hospitals has changed dramatically. These changes have occurred as a result of major shifts in the social and financial environment and have had a major effect on how medicine was practiced in the past and how it will be practiced in the future.

The American hospital as we know it today was established in the late 19th and early 20th centuries largely by the Catholic, Protestant, and Jewish communities to provide care for the elderly and chronically ill patients who otherwise would not be cared for at home.

With the development of surgical techniques from tonsillectomies to cholecystectomies in the mid-20th century, they became the workshop of general surgeons, who largely controlled the hospitals. With the subsequent development of antibiotics and medical treatment for cardiovascular disease, the internal medicine specialties demanded a larger role in institutional management.

The increased complexity and expense of medical care led to concerns about how to provide a financial base for medical care and led to the establishment of private medical insurance programs, and ultimately, to Medicare and Medicaid. Hospitals were no longer concerned about being a health resource but suddenly became a profit center. Community hospitals expanded in order to meet the needs of new technologies with the support of grants and loans from the federal government.

With this growth, the management of the hospital of the 20th century required the creation of a new breed of hospital staff: the hospital administrator. They were hired to manage the financial and administrative aspects of these new and growing organizations. Although the hospital administration was structured to provide equipoise between the medical and financial priorities of the hospital, that balance was not easily maintained, and as the financial aspects became central, the hospital administrator became supreme and physicians lost control.

Today, the American hospital has become central to the support of nonprofit and for-profit regional and national health care conglomerates, and control has become the province of boards of directors with little medical input and larger community control. As a consequence, the physician has now become a real or quasi-employee of the hospital.

In a recent perspective paper, Dr. Richard Gunderson (Acad. Med. 2009;84:1348-51) emphasizes the need to train physicians to provide leadership for the future management of the hospital. He points out that in 1935, physicians were in charge of 35% of the nation's hospitals, but that number has shrunk to 4% of our current 6,500 U.S. hospitals. The academic medical community has largely ignored its role in preparing medical students for administrative leadership as it focused on the clinical knowledge required for the medical competence.

Dr. Gunderson, of Indiana University in Indianapolis, advocates the identification of student leaders in the selection of medical students and proposes the inclusion of courses in medical finance and social issues in the medical school curriculum in order to prepare them for a leadership role in redefining the future of medical care and hospital management.

Amanda Goodall, Ph.D., a senior research fellow at the Institute for the Study of Labor in Bonn, Germany, provides an even more challenging analysis of the importance of medical leadership at the hospital (Social Science Med. 2011;73:535-9). She notes that these changes in leadership are not unique to the United States but also have taken place in European hospitals. Using a quality scoring system, she analyzed the quality performance of 100 of the U.S. News and World Report's Best Hospitals 2009 in the fields of cancer, digestive disorders, and heart and heart surgery. She found a positive correlation between hospital quality ranking and physician CEO leadership.

Those of us who have grown up through this management evolution have seen its real impact on the care of hospital patients. Some of the changes have been positive, while others have proved frustrating for both patients and physicians who practice in the new environment.

The need for leadership by those of us who have direct patient care responsibilities is essential for an inclusive decision-making process. When patient care comes to discussion at the board meeting, physicians and nurses bring to the process a perspective that only they can provide. It is essential that their voices be heard.

Induced pluripotent stem cells
Credit: James Thomson

Using induced pluripotent stem (iPS) cells, researchers have corrected the genetic alteration that causes sickle cell disease (SCD).

The corrected stem cells were coaxed in vitro into immature red blood cells that then turned on a normal version of the gene.

The researchers caution that the work is years away from clinical use in patients, but it should provide tools for developing gene therapies for SCD and a variety of other hematologic disorders.

“We’re now one step closer to developing a combination cell and gene therapy method that will allow us to use patients’ own cells to treat them,” said lead study author Linzhao Cheng, PhD, of The Johns Hopkins School of Medicine.

Using an adult patient at The Johns Hopkins Hospital as their first case, the researchers isolated the patient’s bone marrow cells. After generating iPS cells from the bone marrow, the team put a normal copy of the hemoglobin gene in place of the defective one using genetic engineering techniques.

The researchers sequenced the DNA from 300 different samples of iPS cells to identify those that contained correct copies of the hemoglobin gene and found 4. Three of these iPS cell lines didn’t pass muster in subsequent tests.

“The beauty of iPS cells is that we can grow a lot of them and then coax them into becoming cells of any kind, including red blood cells,” Dr Cheng said.

In their process, his team converted the corrected iPS cells into immature red blood cells by giving them growth factors. Further testing showed that the normal hemoglobin gene was turned on properly in these cells, although at less than half of normal levels.

“We think these immature red blood cells still behave like embryonic cells and, as a result, are unable to turn on high enough levels of the adult hemoglobin gene,” Dr Cheng said. “We next have to learn how to properly convert these cells into mature red blood cells.”

This research was recently published online in Blood.

Induced pluripotent stem cells
Credit: James Thomson

Using induced pluripotent stem (iPS) cells, researchers have corrected the genetic alteration that causes sickle cell disease (SCD).

The corrected stem cells were coaxed in vitro into immature red blood cells that then turned on a normal version of the gene.

The researchers caution that the work is years away from clinical use in patients, but it should provide tools for developing gene therapies for SCD and a variety of other hematologic disorders.

“We’re now one step closer to developing a combination cell and gene therapy method that will allow us to use patients’ own cells to treat them,” said lead study author Linzhao Cheng, PhD, of The Johns Hopkins School of Medicine.

Using an adult patient at The Johns Hopkins Hospital as their first case, the researchers isolated the patient’s bone marrow cells. After generating iPS cells from the bone marrow, the team put a normal copy of the hemoglobin gene in place of the defective one using genetic engineering techniques.

The researchers sequenced the DNA from 300 different samples of iPS cells to identify those that contained correct copies of the hemoglobin gene and found 4. Three of these iPS cell lines didn’t pass muster in subsequent tests.

“The beauty of iPS cells is that we can grow a lot of them and then coax them into becoming cells of any kind, including red blood cells,” Dr Cheng said.

In their process, his team converted the corrected iPS cells into immature red blood cells by giving them growth factors. Further testing showed that the normal hemoglobin gene was turned on properly in these cells, although at less than half of normal levels.

“We think these immature red blood cells still behave like embryonic cells and, as a result, are unable to turn on high enough levels of the adult hemoglobin gene,” Dr Cheng said. “We next have to learn how to properly convert these cells into mature red blood cells.”

This research was recently published online in Blood.

Induced pluripotent stem cells
Credit: James Thomson

Using induced pluripotent stem (iPS) cells, researchers have corrected the genetic alteration that causes sickle cell disease (SCD).

The corrected stem cells were coaxed in vitro into immature red blood cells that then turned on a normal version of the gene.

The researchers caution that the work is years away from clinical use in patients, but it should provide tools for developing gene therapies for SCD and a variety of other hematologic disorders.

“We’re now one step closer to developing a combination cell and gene therapy method that will allow us to use patients’ own cells to treat them,” said lead study author Linzhao Cheng, PhD, of The Johns Hopkins School of Medicine.

Using an adult patient at The Johns Hopkins Hospital as their first case, the researchers isolated the patient’s bone marrow cells. After generating iPS cells from the bone marrow, the team put a normal copy of the hemoglobin gene in place of the defective one using genetic engineering techniques.

The researchers sequenced the DNA from 300 different samples of iPS cells to identify those that contained correct copies of the hemoglobin gene and found 4. Three of these iPS cell lines didn’t pass muster in subsequent tests.

“The beauty of iPS cells is that we can grow a lot of them and then coax them into becoming cells of any kind, including red blood cells,” Dr Cheng said.

In their process, his team converted the corrected iPS cells into immature red blood cells by giving them growth factors. Further testing showed that the normal hemoglobin gene was turned on properly in these cells, although at less than half of normal levels.

“We think these immature red blood cells still behave like embryonic cells and, as a result, are unable to turn on high enough levels of the adult hemoglobin gene,” Dr Cheng said. “We next have to learn how to properly convert these cells into mature red blood cells.”

This research was recently published online in Blood.