Chronic constipation has a variety of possible causes and mechanisms. Although traditional conservative treatments are still valid and first-line, if these fail, clinicians can choose from a growing list of new treatments, tailored to the cause in the individual patient.

This article discusses how defecation works (or doesn’t), the types of chronic constipation, the available diagnostic tools, and traditional and newer treatments, including some still in development.

THE EPIDEMIOLOGY OF CONSTIPATION

Chronic constipation is one of the most common gastrointestinal disorders, affecting about 15% of all adults and 30% of those over the age of 60.¹ It can be a primary disorder or secondary to other factors.

Constipation is more prevalent in women and in institutionalized elderly people.² It is associated with lower socioeconomic status, depression, less self-reported physical activity, certain medications, and stressful life events.³ Given its high prevalence and its impact on quality of life, it is also associated with significant utilization of healthcare resources.⁴

Constipation defined by Rome IV criteria

Physicians and patients may disagree about what constitutes constipation. Physicians primarily regard it as infrequent bowel movements, while patients tend to have a broader definition. According to the Rome IV criteria,⁵ chronic constipation is defined by the presence of the following for at least 3 months (with symptom onset at least 6 months prior to diagnosis):

 (1) Two or more of the following for more than 25% of defecations:

• Straining
• Lumpy or hard stools
• Sensation of incomplete evacuation
• Sensation of anorectal obstruction or blockage
• Manual maneuvers to facilitate evacuation
• Fewer than 3 spontaneous bowel movements per week.

 (2) Loose stools are rarely present without the use of laxatives.

 (3) The patient does not meet the criteria for diagnosis of irritable bowel syndrome.

DEFECATION IS COMPLEX

Defecation begins when the rectum fills with stool, causing relaxation of the internal anal sphincter and the urge to defecate. The external anal sphincter, which is under voluntary control, can then either contract to delay defecation or relax to allow the stool to be expelled.⁶

Colonic muscles propel stool toward the rectum in repetitive localized contractions that help mix and promote absorption of the content, and larger coordinated (high-amplitude propagating) contractions that, in healthy individuals, move the stool forward from the proximal to the distal colon multiple times daily. These contractions usually occur in the morning and are accentuated by gastric distention from food and the resulting gastrocolic reflex.

Serotonin (5-HT) is released by enterochromaffin cells in response to distention of the gut wall. It mediates peristaltic movements of the gastrointestinal tract by binding to receptors (especially 5-HT4), stimulating release of neurotransmitters such as acetylcholine, causing smooth-muscle contraction behind the luminal contents and propelling them forward.

PRIMARY CONSTIPATION DISORDERS

The American Gastroenterological Association⁷ classifies constipation into 3 groups on the basis of colonic transit time and anorectal function:

Normal-transit constipation

Stool normally takes 20 to 72 hours to pass through the colon, with transit time affected by diet, drugs, level of physical activity, and emotional status.⁸

Normal-transit constipation is the most common type of constipation. The term is sometimes used interchangeably with constipation-predominant irritable bowel syndrome, but the latter is a distinct entity characterized by abdominal pain relieved by defecation as the primary symptom, as well as having occasional loose stools. These 2 conditions can be hard to tell apart, especially if the patient cannot describe the symptoms precisely.

Slow-transit constipation

Slow-transit constipation—also called delayed-transit constipation, colonoparesis, colonic inertia, and pseudo-obstruction—is defined as prolonged stool transit in the colon, ie, for more than 5 days.⁹ It can be the result of colonic smooth muscle dysfunction, compromised colonic neural pathways, or both, leading to slow colon peristalsis.

Factors that can affect colonic motility such as opioid use and hypothyroidism should be carefully considered in these patients. Opioids are notorious for causing constipation by decreasing bowel tone and contractility and thereby increasing colonic transit time. They also tighten up the anal sphincters, resulting in decreased rectal evacuation.¹⁰

Outlet dysfunction

Outlet dysfunction, also called pelvic floor dysfunction or defecatory disorder, is associated with incomplete rectal evacuation. It can be a consequence of weak rectal expulsion forces (slow colonic transit, rectal hyposensitivity), functional resistance to rectal evacuation (high anal resting pressure, anismus, incomplete relaxation of the anal sphincter, dyssynergic defecation), or structural outlet obstruction (excessive perineal descent, rectoceles, rectal intussusception). About 50% of patients with outlet dysfunction have concurrent slow-transit constipation.

Dyssynergic defecation is the most common outlet dysfunction disorder, accounting for about half of the cases referred to tertiary centers. It is defined as a paradoxical elevation in anal sphincter tone or less than 20% relaxation of the resting anal sphincter pressure with weak abdominal and pelvic propulsive forces.¹¹ Anorectal biofeedback is a therapeutic option for dyssynergic defecation, as we discuss later in this article.

SECONDARY CONSTIPATION

Constipation can be secondary to several conditions and factors (Table 1), including:

• Neurologic disorders that affect gastrointestinal motility (eg, Hirschsprung disease, Parkinson disease, multiple sclerosis, spinal cord injury, stroke, spinal or ganglionic  tumor, hypothyroidism, amyloidosis, diabetes mellitus, hypercalcemia)
• Drugs used to treat neurologic disorders
• Mechanical obstruction
• Diet (eg, low fiber, decreased fluid intake).

EVALUATION OF CONSTIPATION

It is crucial for physicians to efficiently use the available diagnostic tools for constipation to tailor the treatment to the patient.

Evaluation of chronic constipation begins with a thorough history and physical examination to rule out secondary constipation (Figure 1). Red flags such as unintentional weight loss, blood in the stool, rectal pain, fever, and iron-deficiency anemia should prompt referral for colonoscopy to evaluate for malignancy, colitis, or other potential colonic abnormalities.¹²

A detailed perineal and rectal examination can help diagnose defecatory disorders and should include evaluation of the resting anal tone and the sphincter during simulated evacuation.

Laboratory tests of thyroid function, electrolytes, and a complete blood cell count should be ordered if clinically indicated.¹³

Further tests

Further diagnostic tests can be considered if symptoms persist despite conservative treatment or if a defecatory disorder is suspected. These include anorectal manometry, colonic transit studies, defecography, and colonic manometry.

Anorectal manometry and the rectal balloon expulsion test are usually done first because of their high sensitivity (88%) and specificity (89%) for defecatory disorders.¹⁴ These tests measure the function of the internal and external anal sphincters at rest and with straining and assess rectal sensitivity and compliance. Anorectal manometry is also used in biofeedback therapy in patients with dyssynergic defecation.¹⁵

Colonic transit time can be measured if anorectal manometry and the balloon expulsion test are normal. The study uses radiopaque markers, radioisotopes, or wireless motility capsules to confirm slow-transit constipation and to identify areas of delayed transit in the colon.¹⁶

Defecography is usually the next step in diagnosis if anorectal manometry and balloon expulsion tests are inconclusive or if an anatomic abnormality of the pelvic floor is suspected. It can be done with a variety of techniques. Barium defecography can identify anatomic defects, scintigraphy can quantify evacuation of artificial stools, and magnetic resonance defecography visualizes anatomic landmarks to assess pelvic floor motion without exposing the patient to radiation.^17,18

Colonic manometry is most useful in patients with refractory slow-transit constipation and can identify patients with isolated colonic motor dysfunction with no pelvic floor dysfunction who may benefit from subtotal colectomy and end-ileostomy.⁷

TRADITIONAL TREATMENTS STILL THE MAINSTAY

Nonpharmacologic treatments are the first-line options for patients with normal-transit and slow-transit constipation and should precede diagnostic testing. Lifestyle modifications and dietary changes (Table 2) aim to augment the known factors that stimulate the gastrocolic reflex and increase intestinal motility by high-amplitude propagated contractions.

Increasing physical activity increases intestinal gas clearance, decreases bloating, and lessens constipation.^19,20

Toilet training is an integral part of lifestyle modifications.²¹

Diet. Drinking hot caffeinated beverages, eating breakfast within an hour of waking up, and consuming fiber in the morning (25–30 g of fiber daily) have traditionally been recommended as the first-line measures for chronic constipation. Dehydrated patients with constipation also benefit from increasing their fluid intake.²²

LAXATIVES

Fiber (bulk-forming laxatives) for normal-transit constipation

Fiber remains a key part of the initial management of chronic constipation, as it is cheap, available, and safe. Increasing fiber intake is effective for normal-transit constipation, but patients with slow-transit constipation or refractory outlet dysfunction are less likely to benefit.²³ Other laxatives are incorporated into the regimen if first-line nonpharmacologic interventions fail (Table 3).

Bulk-forming laxatives include insoluble fiber (wheat bran) and soluble fiber (psyllium, methylcellulose, inulin, calcium polycarbo­phil). Insoluble fiber, though often used, has little impact on symptoms of chronic constipation after 1 month of use, and up to 60% of patients report adverse effects from it.²⁴ On the other hand, clinical trials have shown that soluble fiber such as psyllium facilitates defecation and improves functional bowel symptoms in patients with normal-transit constipation.²⁵

Patients should be instructed to increase their dietary fiber intake gradually to avoid adverse effects and should be told to expect significant symptomatic improvement only after a few weeks. They should also be informed that increasing dietary fiber intake can cause bloating but that the bloating is temporary. If it continues, a different fiber can be tried.

Osmotic laxatives

Osmotic laxatives are often employed as a first- line laxative treatment option for patients with constipation. They draw water into the lumen by osmosis, helping to soften stool and speed intestinal transit. They include macrogols (inert polymers of ethylene glycol), nonabsorbable carbohydrates (lactulose, sorbitol), magnesium products, and sodium phosphate products.

Polyethylene glycol, the most studied osmotic laxative, has been shown to maintain therapeutic efficacy for up to 2 years, though it is not generally used this long.²⁶ A meta-analysis of 10 randomized clinical trials found it to be superior to lactulose in improving stool consistency and frequency, and rates of adverse effects were similar to those with placebo.²⁷

Lactulose and sorbitol are semisynthetic disaccharides that are not absorbed from the gastrointestinal tract. Apart from the osmotic effect of the disaccharide, these sugars are metabolized by colonic bacteria to acetic acid and other short-chain fatty acids, resulting in acidification of the stool, which exerts an osmotic effect in the colonic lumen.

Lactulose and sorbitol were shown to have similar efficacy in increasing the frequency of bowel movements in a small study, though patients taking lactulose had a higher rate of nausea.²⁸

The usual recommended dose is 15 to 30 mL once or twice daily.

Adverse effects include gas, bloating, and abdominal distention (due to fermentation by colonic bacteria) and can limit long-term use.

Magnesium citrate and magnesium hydroxide are strong osmotic laxatives, but so far no clinical trial has been done to assess their efficacy in constipation. Although the risk of hypermagnesemia is low with magnesium-based products, this group of laxatives is generally avoided in patients with renal or cardiac disease.²⁹

Sodium phosphate enemas (Fleet enemas) are used for bowel cleansing before certain procedures but have only limited use in constipation because of potential adverse effects such as hyperphosphatemia, hypocalcemia, and the rarer but more serious complication of acute phosphate nephropathy.³⁰

Stimulant laxatives for short-term use only

Stimulant laxatives include glycerin, bisacodyl, senna, and sodium picosulfate. Sodium piosulfate and bisacodyl have been validated for treatment of chronic constipation for up to 4 weeks.^31–33

Stimulant laxative suppositories should be used 30 minutes after meals to augment the physiologic gastrocolic reflex.

As more evidence is available for osmotic laxatives such as polyethylene glycol, they tend to be preferred over stimulant agents, especially for long-term use. Clinicians have traditionally hesitated to prescribe stimulant laxatives for long-term use, as they were thought to damage the enteric nervous system.³⁴ Although more recent studies have not shown this potential effect,³⁵ more research is warranted on the use of stimulant laxatives for longer than 4 weeks.

Stool softeners enhance the interaction of stool and water, leading to softer stool and easier evacuation. Docusate sodium and docusate calcium are thought to facilitate the mixing of aqueous and fatty substances, thereby softening the stool.

However, there is little evidence to support the use of docusate for constipation in hospitalized adults or in ambulatory care. A recent review reported that docusate was no better than placebo in diminishing symptoms of constipation.³⁶

INTESTINAL SECRETAGOGUES

The secretagogues include lubiprostone, linaclotide, and plecanatide. These medications are preferred therapy for patients with normal- or slow-transit constipation once conservative therapies have failed. Even though there is no current consensus, lifestyle measures and conservative treatment options should be tried for about 8 weeks.

Lubiprostone and linaclotide are approved by the US Food and Drug Administration (FDA) for both constipation and constipation-predominant irritable bowel syndrome. They activate chloride channels on the apical surface of enterocytes, increasing intestinal secretion of chloride, which in turn increases luminal sodium efflux to maintain electroneutrality, leading to secretion of water into the intestinal lumen. This eventually facilitates intestinal transit and increases the passage of stool.

Lubiprostone

Lubiprostone, a prostaglandin E1 derivative, is approved for treating chronic constipation, constipation-predominant irritable bowel syndrome in women, and opioid-induced constipation in patients with chronic noncancer pain.

Adverse effects in clinical trials were nausea (up to 30%) and headache.^37,38

Linaclotide

Linaclotide, a minimally absorbed 14-amino acid peptide, increases intestinal secretion of chloride and bicarbonate, increasing intestinal fluid and promoting intestinal transit.³⁹ It also decreases the firing rate of the visceral afferent pain fibers and helps reduce visceral pain, especially in patients with constipation-predominant irritable bowel syndrome.⁴⁰ It is approved for chronic constipation and constipation-predominant irritable bowel syndrome.^41–43

Dosage starts at 145 μg/day for chronic constipation, and can be titrated up to 290 μg if there is no response or if a diagnosis of constipation-predominant irritable bowel syndrome is under consideration. Linaclotide should be taken 30 to 60 minutes before breakfast to reduce the likelihood of diarrhea.⁴⁴

Adverse effects. Diarrhea led to treatment discontinuation in 4.5% of patients in one study.⁴²

Plecanatide

Plecanatide is a guanylate cyclase-c agonist with a mode of action similar to that of linaclotide. It was recently approved by the FDA for chronic idiopathic constipation in adults. The recommended dose is 3 mg once daily.

Data from phase 2 trials in chronic constipation showed improvement in straining, abdominal discomfort, and stool frequency after 14 days of treatment.⁴⁵

A phase 3 trial showed that plecanatide was more effective than placebo when used for 12 weeks in 951 patients with chronic constipation (P = .009).⁴⁶ The most common adverse effect reported was diarrhea.

SEROTONIN RECEPTOR AGONISTS

Activation of serotonin 5-HT4 receptors in the gut leads to release of acetylcholine, which in turn induces mucosal secretion by activating submucosal neurons and increasing gut motility.⁴⁷

Two 5-HT4 receptor agonists were withdrawn from the market (cisapride in 2000 and tegaserod in 2007) due to serious cardiovascular adverse events (fatal arrhythmias, heart attacks, and strokes) resulting from their affinity for hERG-K+ cardiac channels.  

The newer agents prucalopride,⁴⁸ velusetrag, and naronapride are highly selective 5-HT4 agonists with low affinity for hERG-K+ receptors and do not have proarrhythmic properties, based on extensive assessment in clinical trials.

Prucalopride

Prucalopride has been shown to accelerate gastrointestinal and colonic transit in patients with chronic constipation, with improvement in bowel movements, symptoms of chronic constipation, and quality of life.^49–52

Adverse effects reported with its use have been headache, nausea, abdominal pain, and cramps.

Prucalopride is approved in Europe and Canada for chronic constipation in women but is not yet approved in the United States.

Dosage is 2 mg orally once daily. Caution is advised in elderly patients, in whom the preferred maximum dose is 1 mg daily, as there are only limited data available on the safety of this medication in the elderly.

Velusetrag

Velusetrag has been shown to increase colonic motility and improve symptoms of chronic constipation. In a phase 2 trial,⁵³ the most effective dose was 15 mg once daily. Higher doses were associated with a higher incidence of adverse effects such as diarrhea, headache, nausea, and vomiting.

Naronapride

Naronapride (ATI-7505) is in phase 2 trials for chronic constipation. Reported adverse effects were headache, diarrhea, nausea, and vomiting.⁵⁴

BILE SALT ABSORPTION INHIBITORS

Bile acids exert prosecretory and prokinetic effects by increasing colonic secretion of water and electrolytes through the activation of adenylate cyclase. This happens as a result of their deconjugation after passage into the colon.

Elobixibat is an ileal bile acid transporter inhibitor that prevents absorption of nonconjugated bile salts in the distal ileum. It has few side effects because its systemic absorption is minimal. Phase 3 trials are under way. Dosage is 5 to 20 mg daily. Adverse effects are few because systemic absorption is minimal, but include abdominal pain and diarrhea.^55,56

Opioids cause constipation by binding to mu receptors in the enteric nervous system. Activation of these receptors decreases bowel tone and contractility, which increases transit time. Stimulation of these receptors also increases anal sphincter tone, resulting in decreased rectal evacuation.⁵⁷

Though underrecognized, opioid-induced constipation affects 40% of patients who take these drugs for nonmalignant pain and 90% of those taking them for cancer pain. Patients with this condition were found to take more time off work and feel more impaired in their domestic and work-related obligations than patients who did not develop constipation with use of opioids.⁵⁸

Initial management of opioid-induced constipation includes increasing intake of fluids and dietary fiber (fiber alone can worsen abdominal pain in this condition by increasing stool bulk without a concomitant improvement in peristalsis) and increasing physical activity. It is common clinical practice to use a stool softener along with a stimulant laxative if lifestyle modifications are inadequate.⁵⁹ If these measures are ineffective, osmotic agents can be added.

If these conventional measures fail, a peripherally acting mu-opioid receptor antagonist such as methylnaltrexone or naloxegol should be considered.

Methylnaltrexone

Methylnaltrexone^60,61 is a peripherally acting mu receptor antagonist with a rapid onset of action. It does not cross the blood-brain barrier, as it contains a methyl group. It was approved by the FDA in 2008 to treat opioid-induced constipation in adults with advanced illnesses when other approaches are ineffective.

Adverse effects. Although the mu receptor antagonist alvimopan had been shown to be associated with cardiovascular events hypothesized to be a consequence of opioid withdrawal, methylnaltrexone has been deemed to have a safe cardiovascular profile without any potential effects on platelets, corrected QT interval, metabolism, heart rate, or blood pressure.⁶¹ Side effects include abdominal pain, nausea, diarrhea, hot flashes, tremor, and chills.

Contraindications. Methylnaltrexone is contraindicated in patients with structural diseases of the gastrointestinal tract, ie, peptic ulcer disease, inflammatory bowel disease, diverticulitis, stomach or intestinal cancer) since it can increase the risk of perforation.

Dosing is 1 dose subcutaneously every other day, as needed, and no more than 1 dose in a 24-hour period. Dosage is based on weight: 0.15 mg/kg/dose for patients weighing less than 38 kg or more than 114 kg; 8 mg for those weighing 38 to 62 kg; and 12 mg for those weighing 62 to 114 kg.⁶²

Naloxegol

Naloxegol, FDA-approved for treating opioid-induced constipation in 2014, consists of naloxone conjugated with polyethylene glycol, which prevents it from crossing the blood-brain barrier and diminishing the central effects of opioid-induced analgesia. Unlike methylnaltrexone, which is given by subcutaneous injection, naloxegol is taken orally.

Adverse effects reported in clinical trials^63,64 were abdominal pain, diarrhea, nausea, headache, and flatulence. No clinically relevant association with QT and corrected QT interval prolongation or cardiac repolarization was noted.⁶⁴

Dosing is 25 mg by mouth once daily, which can be decreased to 12.5 mg if the initial dose is difficult to tolerate. It should be taken on an empty stomach at least 1 hour before the first meal of the day or 2 hours after the meal. In patients with renal impairment (creatinine clearance < 60 mL/min), the dose is 12.5 mg once daily.⁶⁵

CONSTIPATION-PREDOMINANT IRRITABLE BOWEL SYNDROME

Irritable bowel syndrome is the reason for 3.1 million office visits and 59 million prescriptions in the United States every year, with patients equally distributed between diarrhea-predominant, constipation-predominant, and mixed subtypes.⁶⁶

To be diagnosed with constipation-predominant irritable bowel syndrome, patients must meet the Rome IV criteria, more than 25% of bowel movements should have Bristol stool form types 1 or 2, and less than 25% of bowel movements should have Bristol stool form types 6 or 7. In practice, patients reporting that their bowel movements are usually constipated often suffices to make the diagnosis.⁵

Osmotic laxatives are often tried first, but despite improving stool frequency and consistency, they have little efficacy in satisfying complaints of bloating or abdominal pain in patients with constipation-predominant irritable syndrome.⁶⁷ Stimulant laxatives have not yet been tested in clinical trials. Lubiprostone and linaclotide are FDA-approved for this condition; in women, lubiprostone is approved only for those over age 18.

Antidepressant therapy

Patients often derive additional benefit from treatment with antidepressants. A meta-analysis demonstrated a number needed to treat of 4 for selective serotonin reuptake inhibitors and tricyclic antidepressants in managing abdominal pain associated with irritable bowel syndrome.⁶⁸ The major limiting factor is usually adverse effects of these drugs.

For constipation-predominant irritable bowel syndrome, selective serotonin reuptake inhibitors are preferred over tricyclics because of their additional prokinetic properties. Starting at a low dose and titrating upward slowly avoids potential adverse effects.

Cognitive behavioral therapy has also been beneficial in treating irritable bowel syndrome.⁶⁹

Adjunctive therapies

Adjunctive therapies including peppermint oil, probiotics (eg, Lactobacillus, Bifidobacterium), and acupuncture have also shown promise in managing irritable bowel syndrome, but more data are needed on the use of these therapies for constipation-predominant irritable bowel syndrome before any definite conclusions can be drawn.⁷⁰ Other emerging pharmacologic therapies are plecanatide (discussed earlier) and tenapanor.

Peppermint oil is an antispasmodic that inhibits calcium channels, leading to relaxation of smooth muscles in the gastrointestinal tract. Different dosages and treatment durations have been studied—450 to 900 mg daily in 2 to 3 divided doses over 1 to 3 months.^71,72 The most common adverse effect reported was gastroesophageal reflux, related in part to the oil’s relaxing effect on the lower esophageal sphincter. Observation of this led to the development of enteric-coated preparations that have the potential to bypass the upper gastrointestinal tract.⁷³

Tenapanor inhibits the sodium-hydrogen exchanger 3 channel (a regulator of sodium and water uptake in intestinal lumen), which in turn leads to a higher sodium level in the entire gastrointestinal tract (whereas linaclotide’s action is limited to the duodenum and jejunem), resulting in more fluid volume and increased luminal transit.⁷⁴ It was found effective in a phase 2 clinical trial,⁷⁵ and the most effective dose was 50 mg twice daily.

Since tenapanor is minimally absorbed, it has few side effects, the major ones being diarrhea (11.2% vs 0% with placebo) and urinary tract infection (5.6% vs 4.4% with placebo).⁷⁵ Further study is needed to confirm these findings.

Tenapanor also has the advantage of inhibiting luminal phosphorus absorption. This has led to exploration of its use as a phosphate binder in patients with end-stage renal disease.

DYSSYNERGIC DEFECATION AND ANORECTAL BIOFEEDBACK

According to the Rome IV criteria,⁵ dyssynergic defecation is present if the criteria for chronic constipation are met, if a dyssynergic pattern of defecation is confirmed by manometry, imaging, or electromyography, and if 1 or more of the following are present: inability to expel an artificial stool (a 50-mL water-filled balloon) within 1 minute, prolonged colonic transit time, inability to evacuate, or 50% or more retention of barium during defecography.⁵

Even though biofeedback has been controversial as a treatment for dyssynergic defecation because of conflicting results in older studies,⁷⁶ 3 trials have shown it to be better than placebo, laxatives, and muscle relaxants, with symptomatic improvement in 70% of patients.^77–79

Biofeedback therapy involves an instrument-based auditory or visual tool (using electromyographic sensors or anorectal manometry) to help patients coordinate abdominal, rectal, puborectalis, and anal sphincter muscles and produce a propulsive force using their abdominal muscles to achieve complete evacuation. Important components of this therapy include:

Proper evacuation positioning (brace-pump technique, which involves sitting on the toilet leaning forward with forearms resting on thighs, shoulders relaxed, and feet placed on a small footstool

Breathing relaxation and training exercises during defecation (no straining, keeping a normal pattern of breathing, and avoiding holding the breath while defecating)

Use of the abdominal muscles by pushing the abdomen forward, along with relaxation of the anal sphincter.⁸⁰

The anorectal feedback program usually consists of 6 weekly sessions of 45 to 60 minutes each. Limitations of this therapy include unavailability, lack of trained therapists, lack of insurance coverage, and inapplicability to certain patient groups, such as those with dementia or learning disabilities.

SURGERY FOR CHRONIC CONSTIPATION

Surgery for constipation is reserved for patients who continue to have symptoms despite optimal medical therapy.

Total abdominal colectomy and ileorectal anastomosis

Total abdominal colectomy with ileorectal anastomosis is a surgical option for medically intractable slow-transit constipation. Before considering surgery, complete diagnostic testing should be done, including colonic manometry and documentation of whether the patient also has outlet dysfunction. 

Even though it has shown excellent outcomes and satisfaction rates as high as 100% in patients with pure slow-transit constipation,^81–83 results in older studies in patients with mixed disorders (eg, slow-transit constipation with features of outlet dysfunction) were less predictable.⁸⁴ More recent studies have reported comparable long-term morbidity and postoperative satisfaction rates in those with pure slow-transit constipation and those with a mixed disorder, indicating that careful patient selection is likely the key to a favorable outcome.⁸⁵

Partial colectomies based on segmental colon transit time measurements can also be considered in some patients.⁸⁶

Stapled transanal resection

Stapled transanal resection involves circumferential transanal stapling of the redundant rectal mucosa. It is an option for patients with defecatory disorders, specifically large rectoceles and rectal intussusception not amenable to therapy with pelvic floor retraining exercises.⁸⁷

The efficacy of this procedure in controlling symptoms and improving quality of life is around 77% to 81% at 12 months, though complication rates as high as 46% and disappointing long-term outcomes have been a deterrent to its widespread acceptance in the United States.^88–91

Chronic constipation has a variety of possible causes and mechanisms. Although traditional conservative treatments are still valid and first-line, if these fail, clinicians can choose from a growing list of new treatments, tailored to the cause in the individual patient.

This article discusses how defecation works (or doesn’t), the types of chronic constipation, the available diagnostic tools, and traditional and newer treatments, including some still in development.

THE EPIDEMIOLOGY OF CONSTIPATION

Chronic constipation is one of the most common gastrointestinal disorders, affecting about 15% of all adults and 30% of those over the age of 60.¹ It can be a primary disorder or secondary to other factors.

Constipation is more prevalent in women and in institutionalized elderly people.² It is associated with lower socioeconomic status, depression, less self-reported physical activity, certain medications, and stressful life events.³ Given its high prevalence and its impact on quality of life, it is also associated with significant utilization of healthcare resources.⁴

Constipation defined by Rome IV criteria

Physicians and patients may disagree about what constitutes constipation. Physicians primarily regard it as infrequent bowel movements, while patients tend to have a broader definition. According to the Rome IV criteria,⁵ chronic constipation is defined by the presence of the following for at least 3 months (with symptom onset at least 6 months prior to diagnosis):

 (1) Two or more of the following for more than 25% of defecations:

• Straining
• Lumpy or hard stools
• Sensation of incomplete evacuation
• Sensation of anorectal obstruction or blockage
• Manual maneuvers to facilitate evacuation
• Fewer than 3 spontaneous bowel movements per week.

 (2) Loose stools are rarely present without the use of laxatives.

 (3) The patient does not meet the criteria for diagnosis of irritable bowel syndrome.

DEFECATION IS COMPLEX

Defecation begins when the rectum fills with stool, causing relaxation of the internal anal sphincter and the urge to defecate. The external anal sphincter, which is under voluntary control, can then either contract to delay defecation or relax to allow the stool to be expelled.⁶

Colonic muscles propel stool toward the rectum in repetitive localized contractions that help mix and promote absorption of the content, and larger coordinated (high-amplitude propagating) contractions that, in healthy individuals, move the stool forward from the proximal to the distal colon multiple times daily. These contractions usually occur in the morning and are accentuated by gastric distention from food and the resulting gastrocolic reflex.

Serotonin (5-HT) is released by enterochromaffin cells in response to distention of the gut wall. It mediates peristaltic movements of the gastrointestinal tract by binding to receptors (especially 5-HT4), stimulating release of neurotransmitters such as acetylcholine, causing smooth-muscle contraction behind the luminal contents and propelling them forward.

PRIMARY CONSTIPATION DISORDERS

The American Gastroenterological Association⁷ classifies constipation into 3 groups on the basis of colonic transit time and anorectal function:

Normal-transit constipation

Stool normally takes 20 to 72 hours to pass through the colon, with transit time affected by diet, drugs, level of physical activity, and emotional status.⁸

Normal-transit constipation is the most common type of constipation. The term is sometimes used interchangeably with constipation-predominant irritable bowel syndrome, but the latter is a distinct entity characterized by abdominal pain relieved by defecation as the primary symptom, as well as having occasional loose stools. These 2 conditions can be hard to tell apart, especially if the patient cannot describe the symptoms precisely.

Slow-transit constipation

Slow-transit constipation—also called delayed-transit constipation, colonoparesis, colonic inertia, and pseudo-obstruction—is defined as prolonged stool transit in the colon, ie, for more than 5 days.⁹ It can be the result of colonic smooth muscle dysfunction, compromised colonic neural pathways, or both, leading to slow colon peristalsis.

Factors that can affect colonic motility such as opioid use and hypothyroidism should be carefully considered in these patients. Opioids are notorious for causing constipation by decreasing bowel tone and contractility and thereby increasing colonic transit time. They also tighten up the anal sphincters, resulting in decreased rectal evacuation.¹⁰

Outlet dysfunction

Outlet dysfunction, also called pelvic floor dysfunction or defecatory disorder, is associated with incomplete rectal evacuation. It can be a consequence of weak rectal expulsion forces (slow colonic transit, rectal hyposensitivity), functional resistance to rectal evacuation (high anal resting pressure, anismus, incomplete relaxation of the anal sphincter, dyssynergic defecation), or structural outlet obstruction (excessive perineal descent, rectoceles, rectal intussusception). About 50% of patients with outlet dysfunction have concurrent slow-transit constipation.

Dyssynergic defecation is the most common outlet dysfunction disorder, accounting for about half of the cases referred to tertiary centers. It is defined as a paradoxical elevation in anal sphincter tone or less than 20% relaxation of the resting anal sphincter pressure with weak abdominal and pelvic propulsive forces.¹¹ Anorectal biofeedback is a therapeutic option for dyssynergic defecation, as we discuss later in this article.

SECONDARY CONSTIPATION

Constipation can be secondary to several conditions and factors (Table 1), including:

• Neurologic disorders that affect gastrointestinal motility (eg, Hirschsprung disease, Parkinson disease, multiple sclerosis, spinal cord injury, stroke, spinal or ganglionic  tumor, hypothyroidism, amyloidosis, diabetes mellitus, hypercalcemia)
• Drugs used to treat neurologic disorders
• Mechanical obstruction
• Diet (eg, low fiber, decreased fluid intake).

EVALUATION OF CONSTIPATION

It is crucial for physicians to efficiently use the available diagnostic tools for constipation to tailor the treatment to the patient.

Evaluation of chronic constipation begins with a thorough history and physical examination to rule out secondary constipation (Figure 1). Red flags such as unintentional weight loss, blood in the stool, rectal pain, fever, and iron-deficiency anemia should prompt referral for colonoscopy to evaluate for malignancy, colitis, or other potential colonic abnormalities.¹²

A detailed perineal and rectal examination can help diagnose defecatory disorders and should include evaluation of the resting anal tone and the sphincter during simulated evacuation.

Laboratory tests of thyroid function, electrolytes, and a complete blood cell count should be ordered if clinically indicated.¹³

Further tests

Further diagnostic tests can be considered if symptoms persist despite conservative treatment or if a defecatory disorder is suspected. These include anorectal manometry, colonic transit studies, defecography, and colonic manometry.

Anorectal manometry and the rectal balloon expulsion test are usually done first because of their high sensitivity (88%) and specificity (89%) for defecatory disorders.¹⁴ These tests measure the function of the internal and external anal sphincters at rest and with straining and assess rectal sensitivity and compliance. Anorectal manometry is also used in biofeedback therapy in patients with dyssynergic defecation.¹⁵

Colonic transit time can be measured if anorectal manometry and the balloon expulsion test are normal. The study uses radiopaque markers, radioisotopes, or wireless motility capsules to confirm slow-transit constipation and to identify areas of delayed transit in the colon.¹⁶

Defecography is usually the next step in diagnosis if anorectal manometry and balloon expulsion tests are inconclusive or if an anatomic abnormality of the pelvic floor is suspected. It can be done with a variety of techniques. Barium defecography can identify anatomic defects, scintigraphy can quantify evacuation of artificial stools, and magnetic resonance defecography visualizes anatomic landmarks to assess pelvic floor motion without exposing the patient to radiation.^17,18

Colonic manometry is most useful in patients with refractory slow-transit constipation and can identify patients with isolated colonic motor dysfunction with no pelvic floor dysfunction who may benefit from subtotal colectomy and end-ileostomy.⁷

TRADITIONAL TREATMENTS STILL THE MAINSTAY

Nonpharmacologic treatments are the first-line options for patients with normal-transit and slow-transit constipation and should precede diagnostic testing. Lifestyle modifications and dietary changes (Table 2) aim to augment the known factors that stimulate the gastrocolic reflex and increase intestinal motility by high-amplitude propagated contractions.

Increasing physical activity increases intestinal gas clearance, decreases bloating, and lessens constipation.^19,20

Toilet training is an integral part of lifestyle modifications.²¹

Diet. Drinking hot caffeinated beverages, eating breakfast within an hour of waking up, and consuming fiber in the morning (25–30 g of fiber daily) have traditionally been recommended as the first-line measures for chronic constipation. Dehydrated patients with constipation also benefit from increasing their fluid intake.²²

LAXATIVES

Fiber (bulk-forming laxatives) for normal-transit constipation

Fiber remains a key part of the initial management of chronic constipation, as it is cheap, available, and safe. Increasing fiber intake is effective for normal-transit constipation, but patients with slow-transit constipation or refractory outlet dysfunction are less likely to benefit.²³ Other laxatives are incorporated into the regimen if first-line nonpharmacologic interventions fail (Table 3).

Bulk-forming laxatives include insoluble fiber (wheat bran) and soluble fiber (psyllium, methylcellulose, inulin, calcium polycarbo­phil). Insoluble fiber, though often used, has little impact on symptoms of chronic constipation after 1 month of use, and up to 60% of patients report adverse effects from it.²⁴ On the other hand, clinical trials have shown that soluble fiber such as psyllium facilitates defecation and improves functional bowel symptoms in patients with normal-transit constipation.²⁵

Patients should be instructed to increase their dietary fiber intake gradually to avoid adverse effects and should be told to expect significant symptomatic improvement only after a few weeks. They should also be informed that increasing dietary fiber intake can cause bloating but that the bloating is temporary. If it continues, a different fiber can be tried.

Osmotic laxatives

Osmotic laxatives are often employed as a first- line laxative treatment option for patients with constipation. They draw water into the lumen by osmosis, helping to soften stool and speed intestinal transit. They include macrogols (inert polymers of ethylene glycol), nonabsorbable carbohydrates (lactulose, sorbitol), magnesium products, and sodium phosphate products.

Polyethylene glycol, the most studied osmotic laxative, has been shown to maintain therapeutic efficacy for up to 2 years, though it is not generally used this long.²⁶ A meta-analysis of 10 randomized clinical trials found it to be superior to lactulose in improving stool consistency and frequency, and rates of adverse effects were similar to those with placebo.²⁷

Lactulose and sorbitol are semisynthetic disaccharides that are not absorbed from the gastrointestinal tract. Apart from the osmotic effect of the disaccharide, these sugars are metabolized by colonic bacteria to acetic acid and other short-chain fatty acids, resulting in acidification of the stool, which exerts an osmotic effect in the colonic lumen.

Lactulose and sorbitol were shown to have similar efficacy in increasing the frequency of bowel movements in a small study, though patients taking lactulose had a higher rate of nausea.²⁸

The usual recommended dose is 15 to 30 mL once or twice daily.

Adverse effects include gas, bloating, and abdominal distention (due to fermentation by colonic bacteria) and can limit long-term use.

Magnesium citrate and magnesium hydroxide are strong osmotic laxatives, but so far no clinical trial has been done to assess their efficacy in constipation. Although the risk of hypermagnesemia is low with magnesium-based products, this group of laxatives is generally avoided in patients with renal or cardiac disease.²⁹

Sodium phosphate enemas (Fleet enemas) are used for bowel cleansing before certain procedures but have only limited use in constipation because of potential adverse effects such as hyperphosphatemia, hypocalcemia, and the rarer but more serious complication of acute phosphate nephropathy.³⁰

Stimulant laxatives for short-term use only

Stimulant laxatives include glycerin, bisacodyl, senna, and sodium picosulfate. Sodium piosulfate and bisacodyl have been validated for treatment of chronic constipation for up to 4 weeks.^31–33

Stimulant laxative suppositories should be used 30 minutes after meals to augment the physiologic gastrocolic reflex.

As more evidence is available for osmotic laxatives such as polyethylene glycol, they tend to be preferred over stimulant agents, especially for long-term use. Clinicians have traditionally hesitated to prescribe stimulant laxatives for long-term use, as they were thought to damage the enteric nervous system.³⁴ Although more recent studies have not shown this potential effect,³⁵ more research is warranted on the use of stimulant laxatives for longer than 4 weeks.

Stool softeners enhance the interaction of stool and water, leading to softer stool and easier evacuation. Docusate sodium and docusate calcium are thought to facilitate the mixing of aqueous and fatty substances, thereby softening the stool.

However, there is little evidence to support the use of docusate for constipation in hospitalized adults or in ambulatory care. A recent review reported that docusate was no better than placebo in diminishing symptoms of constipation.³⁶

INTESTINAL SECRETAGOGUES

The secretagogues include lubiprostone, linaclotide, and plecanatide. These medications are preferred therapy for patients with normal- or slow-transit constipation once conservative therapies have failed. Even though there is no current consensus, lifestyle measures and conservative treatment options should be tried for about 8 weeks.

Lubiprostone and linaclotide are approved by the US Food and Drug Administration (FDA) for both constipation and constipation-predominant irritable bowel syndrome. They activate chloride channels on the apical surface of enterocytes, increasing intestinal secretion of chloride, which in turn increases luminal sodium efflux to maintain electroneutrality, leading to secretion of water into the intestinal lumen. This eventually facilitates intestinal transit and increases the passage of stool.

Lubiprostone

Lubiprostone, a prostaglandin E1 derivative, is approved for treating chronic constipation, constipation-predominant irritable bowel syndrome in women, and opioid-induced constipation in patients with chronic noncancer pain.

Adverse effects in clinical trials were nausea (up to 30%) and headache.^37,38

Linaclotide

Linaclotide, a minimally absorbed 14-amino acid peptide, increases intestinal secretion of chloride and bicarbonate, increasing intestinal fluid and promoting intestinal transit.³⁹ It also decreases the firing rate of the visceral afferent pain fibers and helps reduce visceral pain, especially in patients with constipation-predominant irritable bowel syndrome.⁴⁰ It is approved for chronic constipation and constipation-predominant irritable bowel syndrome.^41–43

Dosage starts at 145 μg/day for chronic constipation, and can be titrated up to 290 μg if there is no response or if a diagnosis of constipation-predominant irritable bowel syndrome is under consideration. Linaclotide should be taken 30 to 60 minutes before breakfast to reduce the likelihood of diarrhea.⁴⁴

Adverse effects. Diarrhea led to treatment discontinuation in 4.5% of patients in one study.⁴²

Plecanatide

Plecanatide is a guanylate cyclase-c agonist with a mode of action similar to that of linaclotide. It was recently approved by the FDA for chronic idiopathic constipation in adults. The recommended dose is 3 mg once daily.

Data from phase 2 trials in chronic constipation showed improvement in straining, abdominal discomfort, and stool frequency after 14 days of treatment.⁴⁵

A phase 3 trial showed that plecanatide was more effective than placebo when used for 12 weeks in 951 patients with chronic constipation (P = .009).⁴⁶ The most common adverse effect reported was diarrhea.

SEROTONIN RECEPTOR AGONISTS

Activation of serotonin 5-HT4 receptors in the gut leads to release of acetylcholine, which in turn induces mucosal secretion by activating submucosal neurons and increasing gut motility.⁴⁷

Two 5-HT4 receptor agonists were withdrawn from the market (cisapride in 2000 and tegaserod in 2007) due to serious cardiovascular adverse events (fatal arrhythmias, heart attacks, and strokes) resulting from their affinity for hERG-K+ cardiac channels.  

The newer agents prucalopride,⁴⁸ velusetrag, and naronapride are highly selective 5-HT4 agonists with low affinity for hERG-K+ receptors and do not have proarrhythmic properties, based on extensive assessment in clinical trials.

Prucalopride

Prucalopride has been shown to accelerate gastrointestinal and colonic transit in patients with chronic constipation, with improvement in bowel movements, symptoms of chronic constipation, and quality of life.^49–52

Adverse effects reported with its use have been headache, nausea, abdominal pain, and cramps.

Prucalopride is approved in Europe and Canada for chronic constipation in women but is not yet approved in the United States.

Dosage is 2 mg orally once daily. Caution is advised in elderly patients, in whom the preferred maximum dose is 1 mg daily, as there are only limited data available on the safety of this medication in the elderly.

Velusetrag

Velusetrag has been shown to increase colonic motility and improve symptoms of chronic constipation. In a phase 2 trial,⁵³ the most effective dose was 15 mg once daily. Higher doses were associated with a higher incidence of adverse effects such as diarrhea, headache, nausea, and vomiting.

Naronapride

Naronapride (ATI-7505) is in phase 2 trials for chronic constipation. Reported adverse effects were headache, diarrhea, nausea, and vomiting.⁵⁴

BILE SALT ABSORPTION INHIBITORS

Bile acids exert prosecretory and prokinetic effects by increasing colonic secretion of water and electrolytes through the activation of adenylate cyclase. This happens as a result of their deconjugation after passage into the colon.

Elobixibat is an ileal bile acid transporter inhibitor that prevents absorption of nonconjugated bile salts in the distal ileum. It has few side effects because its systemic absorption is minimal. Phase 3 trials are under way. Dosage is 5 to 20 mg daily. Adverse effects are few because systemic absorption is minimal, but include abdominal pain and diarrhea.^55,56

Opioids cause constipation by binding to mu receptors in the enteric nervous system. Activation of these receptors decreases bowel tone and contractility, which increases transit time. Stimulation of these receptors also increases anal sphincter tone, resulting in decreased rectal evacuation.⁵⁷

Though underrecognized, opioid-induced constipation affects 40% of patients who take these drugs for nonmalignant pain and 90% of those taking them for cancer pain. Patients with this condition were found to take more time off work and feel more impaired in their domestic and work-related obligations than patients who did not develop constipation with use of opioids.⁵⁸

Initial management of opioid-induced constipation includes increasing intake of fluids and dietary fiber (fiber alone can worsen abdominal pain in this condition by increasing stool bulk without a concomitant improvement in peristalsis) and increasing physical activity. It is common clinical practice to use a stool softener along with a stimulant laxative if lifestyle modifications are inadequate.⁵⁹ If these measures are ineffective, osmotic agents can be added.

If these conventional measures fail, a peripherally acting mu-opioid receptor antagonist such as methylnaltrexone or naloxegol should be considered.

Methylnaltrexone

Methylnaltrexone^60,61 is a peripherally acting mu receptor antagonist with a rapid onset of action. It does not cross the blood-brain barrier, as it contains a methyl group. It was approved by the FDA in 2008 to treat opioid-induced constipation in adults with advanced illnesses when other approaches are ineffective.

Adverse effects. Although the mu receptor antagonist alvimopan had been shown to be associated with cardiovascular events hypothesized to be a consequence of opioid withdrawal, methylnaltrexone has been deemed to have a safe cardiovascular profile without any potential effects on platelets, corrected QT interval, metabolism, heart rate, or blood pressure.⁶¹ Side effects include abdominal pain, nausea, diarrhea, hot flashes, tremor, and chills.

Contraindications. Methylnaltrexone is contraindicated in patients with structural diseases of the gastrointestinal tract, ie, peptic ulcer disease, inflammatory bowel disease, diverticulitis, stomach or intestinal cancer) since it can increase the risk of perforation.

Dosing is 1 dose subcutaneously every other day, as needed, and no more than 1 dose in a 24-hour period. Dosage is based on weight: 0.15 mg/kg/dose for patients weighing less than 38 kg or more than 114 kg; 8 mg for those weighing 38 to 62 kg; and 12 mg for those weighing 62 to 114 kg.⁶²

Naloxegol

Naloxegol, FDA-approved for treating opioid-induced constipation in 2014, consists of naloxone conjugated with polyethylene glycol, which prevents it from crossing the blood-brain barrier and diminishing the central effects of opioid-induced analgesia. Unlike methylnaltrexone, which is given by subcutaneous injection, naloxegol is taken orally.

Adverse effects reported in clinical trials^63,64 were abdominal pain, diarrhea, nausea, headache, and flatulence. No clinically relevant association with QT and corrected QT interval prolongation or cardiac repolarization was noted.⁶⁴

Dosing is 25 mg by mouth once daily, which can be decreased to 12.5 mg if the initial dose is difficult to tolerate. It should be taken on an empty stomach at least 1 hour before the first meal of the day or 2 hours after the meal. In patients with renal impairment (creatinine clearance < 60 mL/min), the dose is 12.5 mg once daily.⁶⁵

CONSTIPATION-PREDOMINANT IRRITABLE BOWEL SYNDROME

Irritable bowel syndrome is the reason for 3.1 million office visits and 59 million prescriptions in the United States every year, with patients equally distributed between diarrhea-predominant, constipation-predominant, and mixed subtypes.⁶⁶

To be diagnosed with constipation-predominant irritable bowel syndrome, patients must meet the Rome IV criteria, more than 25% of bowel movements should have Bristol stool form types 1 or 2, and less than 25% of bowel movements should have Bristol stool form types 6 or 7. In practice, patients reporting that their bowel movements are usually constipated often suffices to make the diagnosis.⁵

Osmotic laxatives are often tried first, but despite improving stool frequency and consistency, they have little efficacy in satisfying complaints of bloating or abdominal pain in patients with constipation-predominant irritable syndrome.⁶⁷ Stimulant laxatives have not yet been tested in clinical trials. Lubiprostone and linaclotide are FDA-approved for this condition; in women, lubiprostone is approved only for those over age 18.

Antidepressant therapy

Patients often derive additional benefit from treatment with antidepressants. A meta-analysis demonstrated a number needed to treat of 4 for selective serotonin reuptake inhibitors and tricyclic antidepressants in managing abdominal pain associated with irritable bowel syndrome.⁶⁸ The major limiting factor is usually adverse effects of these drugs.

For constipation-predominant irritable bowel syndrome, selective serotonin reuptake inhibitors are preferred over tricyclics because of their additional prokinetic properties. Starting at a low dose and titrating upward slowly avoids potential adverse effects.

Cognitive behavioral therapy has also been beneficial in treating irritable bowel syndrome.⁶⁹

Adjunctive therapies

Adjunctive therapies including peppermint oil, probiotics (eg, Lactobacillus, Bifidobacterium), and acupuncture have also shown promise in managing irritable bowel syndrome, but more data are needed on the use of these therapies for constipation-predominant irritable bowel syndrome before any definite conclusions can be drawn.⁷⁰ Other emerging pharmacologic therapies are plecanatide (discussed earlier) and tenapanor.

Peppermint oil is an antispasmodic that inhibits calcium channels, leading to relaxation of smooth muscles in the gastrointestinal tract. Different dosages and treatment durations have been studied—450 to 900 mg daily in 2 to 3 divided doses over 1 to 3 months.^71,72 The most common adverse effect reported was gastroesophageal reflux, related in part to the oil’s relaxing effect on the lower esophageal sphincter. Observation of this led to the development of enteric-coated preparations that have the potential to bypass the upper gastrointestinal tract.⁷³

Tenapanor inhibits the sodium-hydrogen exchanger 3 channel (a regulator of sodium and water uptake in intestinal lumen), which in turn leads to a higher sodium level in the entire gastrointestinal tract (whereas linaclotide’s action is limited to the duodenum and jejunem), resulting in more fluid volume and increased luminal transit.⁷⁴ It was found effective in a phase 2 clinical trial,⁷⁵ and the most effective dose was 50 mg twice daily.

Since tenapanor is minimally absorbed, it has few side effects, the major ones being diarrhea (11.2% vs 0% with placebo) and urinary tract infection (5.6% vs 4.4% with placebo).⁷⁵ Further study is needed to confirm these findings.

Tenapanor also has the advantage of inhibiting luminal phosphorus absorption. This has led to exploration of its use as a phosphate binder in patients with end-stage renal disease.

DYSSYNERGIC DEFECATION AND ANORECTAL BIOFEEDBACK

According to the Rome IV criteria,⁵ dyssynergic defecation is present if the criteria for chronic constipation are met, if a dyssynergic pattern of defecation is confirmed by manometry, imaging, or electromyography, and if 1 or more of the following are present: inability to expel an artificial stool (a 50-mL water-filled balloon) within 1 minute, prolonged colonic transit time, inability to evacuate, or 50% or more retention of barium during defecography.⁵

Even though biofeedback has been controversial as a treatment for dyssynergic defecation because of conflicting results in older studies,⁷⁶ 3 trials have shown it to be better than placebo, laxatives, and muscle relaxants, with symptomatic improvement in 70% of patients.^77–79

Biofeedback therapy involves an instrument-based auditory or visual tool (using electromyographic sensors or anorectal manometry) to help patients coordinate abdominal, rectal, puborectalis, and anal sphincter muscles and produce a propulsive force using their abdominal muscles to achieve complete evacuation. Important components of this therapy include:

Proper evacuation positioning (brace-pump technique, which involves sitting on the toilet leaning forward with forearms resting on thighs, shoulders relaxed, and feet placed on a small footstool

Breathing relaxation and training exercises during defecation (no straining, keeping a normal pattern of breathing, and avoiding holding the breath while defecating)

Use of the abdominal muscles by pushing the abdomen forward, along with relaxation of the anal sphincter.⁸⁰

The anorectal feedback program usually consists of 6 weekly sessions of 45 to 60 minutes each. Limitations of this therapy include unavailability, lack of trained therapists, lack of insurance coverage, and inapplicability to certain patient groups, such as those with dementia or learning disabilities.

SURGERY FOR CHRONIC CONSTIPATION

Surgery for constipation is reserved for patients who continue to have symptoms despite optimal medical therapy.

Total abdominal colectomy and ileorectal anastomosis

Total abdominal colectomy with ileorectal anastomosis is a surgical option for medically intractable slow-transit constipation. Before considering surgery, complete diagnostic testing should be done, including colonic manometry and documentation of whether the patient also has outlet dysfunction. 

Even though it has shown excellent outcomes and satisfaction rates as high as 100% in patients with pure slow-transit constipation,^81–83 results in older studies in patients with mixed disorders (eg, slow-transit constipation with features of outlet dysfunction) were less predictable.⁸⁴ More recent studies have reported comparable long-term morbidity and postoperative satisfaction rates in those with pure slow-transit constipation and those with a mixed disorder, indicating that careful patient selection is likely the key to a favorable outcome.⁸⁵

Partial colectomies based on segmental colon transit time measurements can also be considered in some patients.⁸⁶

Stapled transanal resection

Stapled transanal resection involves circumferential transanal stapling of the redundant rectal mucosa. It is an option for patients with defecatory disorders, specifically large rectoceles and rectal intussusception not amenable to therapy with pelvic floor retraining exercises.⁸⁷

The efficacy of this procedure in controlling symptoms and improving quality of life is around 77% to 81% at 12 months, though complication rates as high as 46% and disappointing long-term outcomes have been a deterrent to its widespread acceptance in the United States.^88–91

Chronic constipation has a variety of possible causes and mechanisms. Although traditional conservative treatments are still valid and first-line, if these fail, clinicians can choose from a growing list of new treatments, tailored to the cause in the individual patient.

This article discusses how defecation works (or doesn’t), the types of chronic constipation, the available diagnostic tools, and traditional and newer treatments, including some still in development.

THE EPIDEMIOLOGY OF CONSTIPATION

Chronic constipation is one of the most common gastrointestinal disorders, affecting about 15% of all adults and 30% of those over the age of 60.¹ It can be a primary disorder or secondary to other factors.

Constipation is more prevalent in women and in institutionalized elderly people.² It is associated with lower socioeconomic status, depression, less self-reported physical activity, certain medications, and stressful life events.³ Given its high prevalence and its impact on quality of life, it is also associated with significant utilization of healthcare resources.⁴

Constipation defined by Rome IV criteria

Physicians and patients may disagree about what constitutes constipation. Physicians primarily regard it as infrequent bowel movements, while patients tend to have a broader definition. According to the Rome IV criteria,⁵ chronic constipation is defined by the presence of the following for at least 3 months (with symptom onset at least 6 months prior to diagnosis):

 (1) Two or more of the following for more than 25% of defecations:

• Straining
• Lumpy or hard stools
• Sensation of incomplete evacuation
• Sensation of anorectal obstruction or blockage
• Manual maneuvers to facilitate evacuation
• Fewer than 3 spontaneous bowel movements per week.

 (2) Loose stools are rarely present without the use of laxatives.

 (3) The patient does not meet the criteria for diagnosis of irritable bowel syndrome.

DEFECATION IS COMPLEX

Defecation begins when the rectum fills with stool, causing relaxation of the internal anal sphincter and the urge to defecate. The external anal sphincter, which is under voluntary control, can then either contract to delay defecation or relax to allow the stool to be expelled.⁶

Colonic muscles propel stool toward the rectum in repetitive localized contractions that help mix and promote absorption of the content, and larger coordinated (high-amplitude propagating) contractions that, in healthy individuals, move the stool forward from the proximal to the distal colon multiple times daily. These contractions usually occur in the morning and are accentuated by gastric distention from food and the resulting gastrocolic reflex.

Serotonin (5-HT) is released by enterochromaffin cells in response to distention of the gut wall. It mediates peristaltic movements of the gastrointestinal tract by binding to receptors (especially 5-HT4), stimulating release of neurotransmitters such as acetylcholine, causing smooth-muscle contraction behind the luminal contents and propelling them forward.

PRIMARY CONSTIPATION DISORDERS

The American Gastroenterological Association⁷ classifies constipation into 3 groups on the basis of colonic transit time and anorectal function:

Normal-transit constipation

Stool normally takes 20 to 72 hours to pass through the colon, with transit time affected by diet, drugs, level of physical activity, and emotional status.⁸

Normal-transit constipation is the most common type of constipation. The term is sometimes used interchangeably with constipation-predominant irritable bowel syndrome, but the latter is a distinct entity characterized by abdominal pain relieved by defecation as the primary symptom, as well as having occasional loose stools. These 2 conditions can be hard to tell apart, especially if the patient cannot describe the symptoms precisely.

Slow-transit constipation

Slow-transit constipation—also called delayed-transit constipation, colonoparesis, colonic inertia, and pseudo-obstruction—is defined as prolonged stool transit in the colon, ie, for more than 5 days.⁹ It can be the result of colonic smooth muscle dysfunction, compromised colonic neural pathways, or both, leading to slow colon peristalsis.

Factors that can affect colonic motility such as opioid use and hypothyroidism should be carefully considered in these patients. Opioids are notorious for causing constipation by decreasing bowel tone and contractility and thereby increasing colonic transit time. They also tighten up the anal sphincters, resulting in decreased rectal evacuation.¹⁰

Outlet dysfunction

Outlet dysfunction, also called pelvic floor dysfunction or defecatory disorder, is associated with incomplete rectal evacuation. It can be a consequence of weak rectal expulsion forces (slow colonic transit, rectal hyposensitivity), functional resistance to rectal evacuation (high anal resting pressure, anismus, incomplete relaxation of the anal sphincter, dyssynergic defecation), or structural outlet obstruction (excessive perineal descent, rectoceles, rectal intussusception). About 50% of patients with outlet dysfunction have concurrent slow-transit constipation.

Dyssynergic defecation is the most common outlet dysfunction disorder, accounting for about half of the cases referred to tertiary centers. It is defined as a paradoxical elevation in anal sphincter tone or less than 20% relaxation of the resting anal sphincter pressure with weak abdominal and pelvic propulsive forces.¹¹ Anorectal biofeedback is a therapeutic option for dyssynergic defecation, as we discuss later in this article.

SECONDARY CONSTIPATION

Constipation can be secondary to several conditions and factors (Table 1), including:

• Neurologic disorders that affect gastrointestinal motility (eg, Hirschsprung disease, Parkinson disease, multiple sclerosis, spinal cord injury, stroke, spinal or ganglionic  tumor, hypothyroidism, amyloidosis, diabetes mellitus, hypercalcemia)
• Drugs used to treat neurologic disorders
• Mechanical obstruction
• Diet (eg, low fiber, decreased fluid intake).

EVALUATION OF CONSTIPATION

It is crucial for physicians to efficiently use the available diagnostic tools for constipation to tailor the treatment to the patient.

Evaluation of chronic constipation begins with a thorough history and physical examination to rule out secondary constipation (Figure 1). Red flags such as unintentional weight loss, blood in the stool, rectal pain, fever, and iron-deficiency anemia should prompt referral for colonoscopy to evaluate for malignancy, colitis, or other potential colonic abnormalities.¹²

A detailed perineal and rectal examination can help diagnose defecatory disorders and should include evaluation of the resting anal tone and the sphincter during simulated evacuation.

Laboratory tests of thyroid function, electrolytes, and a complete blood cell count should be ordered if clinically indicated.¹³

Further tests

Further diagnostic tests can be considered if symptoms persist despite conservative treatment or if a defecatory disorder is suspected. These include anorectal manometry, colonic transit studies, defecography, and colonic manometry.

Anorectal manometry and the rectal balloon expulsion test are usually done first because of their high sensitivity (88%) and specificity (89%) for defecatory disorders.¹⁴ These tests measure the function of the internal and external anal sphincters at rest and with straining and assess rectal sensitivity and compliance. Anorectal manometry is also used in biofeedback therapy in patients with dyssynergic defecation.¹⁵

Colonic transit time can be measured if anorectal manometry and the balloon expulsion test are normal. The study uses radiopaque markers, radioisotopes, or wireless motility capsules to confirm slow-transit constipation and to identify areas of delayed transit in the colon.¹⁶

Defecography is usually the next step in diagnosis if anorectal manometry and balloon expulsion tests are inconclusive or if an anatomic abnormality of the pelvic floor is suspected. It can be done with a variety of techniques. Barium defecography can identify anatomic defects, scintigraphy can quantify evacuation of artificial stools, and magnetic resonance defecography visualizes anatomic landmarks to assess pelvic floor motion without exposing the patient to radiation.^17,18

Colonic manometry is most useful in patients with refractory slow-transit constipation and can identify patients with isolated colonic motor dysfunction with no pelvic floor dysfunction who may benefit from subtotal colectomy and end-ileostomy.⁷

TRADITIONAL TREATMENTS STILL THE MAINSTAY

Nonpharmacologic treatments are the first-line options for patients with normal-transit and slow-transit constipation and should precede diagnostic testing. Lifestyle modifications and dietary changes (Table 2) aim to augment the known factors that stimulate the gastrocolic reflex and increase intestinal motility by high-amplitude propagated contractions.

Increasing physical activity increases intestinal gas clearance, decreases bloating, and lessens constipation.^19,20

Toilet training is an integral part of lifestyle modifications.²¹

Diet. Drinking hot caffeinated beverages, eating breakfast within an hour of waking up, and consuming fiber in the morning (25–30 g of fiber daily) have traditionally been recommended as the first-line measures for chronic constipation. Dehydrated patients with constipation also benefit from increasing their fluid intake.²²

LAXATIVES

Fiber (bulk-forming laxatives) for normal-transit constipation

Fiber remains a key part of the initial management of chronic constipation, as it is cheap, available, and safe. Increasing fiber intake is effective for normal-transit constipation, but patients with slow-transit constipation or refractory outlet dysfunction are less likely to benefit.²³ Other laxatives are incorporated into the regimen if first-line nonpharmacologic interventions fail (Table 3).

Bulk-forming laxatives include insoluble fiber (wheat bran) and soluble fiber (psyllium, methylcellulose, inulin, calcium polycarbo­phil). Insoluble fiber, though often used, has little impact on symptoms of chronic constipation after 1 month of use, and up to 60% of patients report adverse effects from it.²⁴ On the other hand, clinical trials have shown that soluble fiber such as psyllium facilitates defecation and improves functional bowel symptoms in patients with normal-transit constipation.²⁵

Patients should be instructed to increase their dietary fiber intake gradually to avoid adverse effects and should be told to expect significant symptomatic improvement only after a few weeks. They should also be informed that increasing dietary fiber intake can cause bloating but that the bloating is temporary. If it continues, a different fiber can be tried.

Osmotic laxatives

Osmotic laxatives are often employed as a first- line laxative treatment option for patients with constipation. They draw water into the lumen by osmosis, helping to soften stool and speed intestinal transit. They include macrogols (inert polymers of ethylene glycol), nonabsorbable carbohydrates (lactulose, sorbitol), magnesium products, and sodium phosphate products.

Polyethylene glycol, the most studied osmotic laxative, has been shown to maintain therapeutic efficacy for up to 2 years, though it is not generally used this long.²⁶ A meta-analysis of 10 randomized clinical trials found it to be superior to lactulose in improving stool consistency and frequency, and rates of adverse effects were similar to those with placebo.²⁷

Lactulose and sorbitol are semisynthetic disaccharides that are not absorbed from the gastrointestinal tract. Apart from the osmotic effect of the disaccharide, these sugars are metabolized by colonic bacteria to acetic acid and other short-chain fatty acids, resulting in acidification of the stool, which exerts an osmotic effect in the colonic lumen.

Lactulose and sorbitol were shown to have similar efficacy in increasing the frequency of bowel movements in a small study, though patients taking lactulose had a higher rate of nausea.²⁸

The usual recommended dose is 15 to 30 mL once or twice daily.

Adverse effects include gas, bloating, and abdominal distention (due to fermentation by colonic bacteria) and can limit long-term use.

Magnesium citrate and magnesium hydroxide are strong osmotic laxatives, but so far no clinical trial has been done to assess their efficacy in constipation. Although the risk of hypermagnesemia is low with magnesium-based products, this group of laxatives is generally avoided in patients with renal or cardiac disease.²⁹

Sodium phosphate enemas (Fleet enemas) are used for bowel cleansing before certain procedures but have only limited use in constipation because of potential adverse effects such as hyperphosphatemia, hypocalcemia, and the rarer but more serious complication of acute phosphate nephropathy.³⁰

Stimulant laxatives for short-term use only

Stimulant laxatives include glycerin, bisacodyl, senna, and sodium picosulfate. Sodium piosulfate and bisacodyl have been validated for treatment of chronic constipation for up to 4 weeks.^31–33

Stimulant laxative suppositories should be used 30 minutes after meals to augment the physiologic gastrocolic reflex.

As more evidence is available for osmotic laxatives such as polyethylene glycol, they tend to be preferred over stimulant agents, especially for long-term use. Clinicians have traditionally hesitated to prescribe stimulant laxatives for long-term use, as they were thought to damage the enteric nervous system.³⁴ Although more recent studies have not shown this potential effect,³⁵ more research is warranted on the use of stimulant laxatives for longer than 4 weeks.

Stool softeners enhance the interaction of stool and water, leading to softer stool and easier evacuation. Docusate sodium and docusate calcium are thought to facilitate the mixing of aqueous and fatty substances, thereby softening the stool.

However, there is little evidence to support the use of docusate for constipation in hospitalized adults or in ambulatory care. A recent review reported that docusate was no better than placebo in diminishing symptoms of constipation.³⁶

INTESTINAL SECRETAGOGUES

The secretagogues include lubiprostone, linaclotide, and plecanatide. These medications are preferred therapy for patients with normal- or slow-transit constipation once conservative therapies have failed. Even though there is no current consensus, lifestyle measures and conservative treatment options should be tried for about 8 weeks.

Lubiprostone and linaclotide are approved by the US Food and Drug Administration (FDA) for both constipation and constipation-predominant irritable bowel syndrome. They activate chloride channels on the apical surface of enterocytes, increasing intestinal secretion of chloride, which in turn increases luminal sodium efflux to maintain electroneutrality, leading to secretion of water into the intestinal lumen. This eventually facilitates intestinal transit and increases the passage of stool.

Lubiprostone

Lubiprostone, a prostaglandin E1 derivative, is approved for treating chronic constipation, constipation-predominant irritable bowel syndrome in women, and opioid-induced constipation in patients with chronic noncancer pain.

Adverse effects in clinical trials were nausea (up to 30%) and headache.^37,38

Linaclotide

Linaclotide, a minimally absorbed 14-amino acid peptide, increases intestinal secretion of chloride and bicarbonate, increasing intestinal fluid and promoting intestinal transit.³⁹ It also decreases the firing rate of the visceral afferent pain fibers and helps reduce visceral pain, especially in patients with constipation-predominant irritable bowel syndrome.⁴⁰ It is approved for chronic constipation and constipation-predominant irritable bowel syndrome.^41–43

Dosage starts at 145 μg/day for chronic constipation, and can be titrated up to 290 μg if there is no response or if a diagnosis of constipation-predominant irritable bowel syndrome is under consideration. Linaclotide should be taken 30 to 60 minutes before breakfast to reduce the likelihood of diarrhea.⁴⁴

Adverse effects. Diarrhea led to treatment discontinuation in 4.5% of patients in one study.⁴²

Plecanatide

Plecanatide is a guanylate cyclase-c agonist with a mode of action similar to that of linaclotide. It was recently approved by the FDA for chronic idiopathic constipation in adults. The recommended dose is 3 mg once daily.

Data from phase 2 trials in chronic constipation showed improvement in straining, abdominal discomfort, and stool frequency after 14 days of treatment.⁴⁵

A phase 3 trial showed that plecanatide was more effective than placebo when used for 12 weeks in 951 patients with chronic constipation (P = .009).⁴⁶ The most common adverse effect reported was diarrhea.

SEROTONIN RECEPTOR AGONISTS

Activation of serotonin 5-HT4 receptors in the gut leads to release of acetylcholine, which in turn induces mucosal secretion by activating submucosal neurons and increasing gut motility.⁴⁷

Two 5-HT4 receptor agonists were withdrawn from the market (cisapride in 2000 and tegaserod in 2007) due to serious cardiovascular adverse events (fatal arrhythmias, heart attacks, and strokes) resulting from their affinity for hERG-K+ cardiac channels.  

The newer agents prucalopride,⁴⁸ velusetrag, and naronapride are highly selective 5-HT4 agonists with low affinity for hERG-K+ receptors and do not have proarrhythmic properties, based on extensive assessment in clinical trials.

Prucalopride

Prucalopride has been shown to accelerate gastrointestinal and colonic transit in patients with chronic constipation, with improvement in bowel movements, symptoms of chronic constipation, and quality of life.^49–52

Adverse effects reported with its use have been headache, nausea, abdominal pain, and cramps.

Prucalopride is approved in Europe and Canada for chronic constipation in women but is not yet approved in the United States.

Dosage is 2 mg orally once daily. Caution is advised in elderly patients, in whom the preferred maximum dose is 1 mg daily, as there are only limited data available on the safety of this medication in the elderly.

Velusetrag

Velusetrag has been shown to increase colonic motility and improve symptoms of chronic constipation. In a phase 2 trial,⁵³ the most effective dose was 15 mg once daily. Higher doses were associated with a higher incidence of adverse effects such as diarrhea, headache, nausea, and vomiting.

Naronapride

Naronapride (ATI-7505) is in phase 2 trials for chronic constipation. Reported adverse effects were headache, diarrhea, nausea, and vomiting.⁵⁴

BILE SALT ABSORPTION INHIBITORS

Bile acids exert prosecretory and prokinetic effects by increasing colonic secretion of water and electrolytes through the activation of adenylate cyclase. This happens as a result of their deconjugation after passage into the colon.

Elobixibat is an ileal bile acid transporter inhibitor that prevents absorption of nonconjugated bile salts in the distal ileum. It has few side effects because its systemic absorption is minimal. Phase 3 trials are under way. Dosage is 5 to 20 mg daily. Adverse effects are few because systemic absorption is minimal, but include abdominal pain and diarrhea.^55,56

Opioids cause constipation by binding to mu receptors in the enteric nervous system. Activation of these receptors decreases bowel tone and contractility, which increases transit time. Stimulation of these receptors also increases anal sphincter tone, resulting in decreased rectal evacuation.⁵⁷

Though underrecognized, opioid-induced constipation affects 40% of patients who take these drugs for nonmalignant pain and 90% of those taking them for cancer pain. Patients with this condition were found to take more time off work and feel more impaired in their domestic and work-related obligations than patients who did not develop constipation with use of opioids.⁵⁸

Initial management of opioid-induced constipation includes increasing intake of fluids and dietary fiber (fiber alone can worsen abdominal pain in this condition by increasing stool bulk without a concomitant improvement in peristalsis) and increasing physical activity. It is common clinical practice to use a stool softener along with a stimulant laxative if lifestyle modifications are inadequate.⁵⁹ If these measures are ineffective, osmotic agents can be added.

If these conventional measures fail, a peripherally acting mu-opioid receptor antagonist such as methylnaltrexone or naloxegol should be considered.

Methylnaltrexone

Methylnaltrexone^60,61 is a peripherally acting mu receptor antagonist with a rapid onset of action. It does not cross the blood-brain barrier, as it contains a methyl group. It was approved by the FDA in 2008 to treat opioid-induced constipation in adults with advanced illnesses when other approaches are ineffective.

Adverse effects. Although the mu receptor antagonist alvimopan had been shown to be associated with cardiovascular events hypothesized to be a consequence of opioid withdrawal, methylnaltrexone has been deemed to have a safe cardiovascular profile without any potential effects on platelets, corrected QT interval, metabolism, heart rate, or blood pressure.⁶¹ Side effects include abdominal pain, nausea, diarrhea, hot flashes, tremor, and chills.

Contraindications. Methylnaltrexone is contraindicated in patients with structural diseases of the gastrointestinal tract, ie, peptic ulcer disease, inflammatory bowel disease, diverticulitis, stomach or intestinal cancer) since it can increase the risk of perforation.

Dosing is 1 dose subcutaneously every other day, as needed, and no more than 1 dose in a 24-hour period. Dosage is based on weight: 0.15 mg/kg/dose for patients weighing less than 38 kg or more than 114 kg; 8 mg for those weighing 38 to 62 kg; and 12 mg for those weighing 62 to 114 kg.⁶²

Naloxegol

Naloxegol, FDA-approved for treating opioid-induced constipation in 2014, consists of naloxone conjugated with polyethylene glycol, which prevents it from crossing the blood-brain barrier and diminishing the central effects of opioid-induced analgesia. Unlike methylnaltrexone, which is given by subcutaneous injection, naloxegol is taken orally.

Adverse effects reported in clinical trials^63,64 were abdominal pain, diarrhea, nausea, headache, and flatulence. No clinically relevant association with QT and corrected QT interval prolongation or cardiac repolarization was noted.⁶⁴

Dosing is 25 mg by mouth once daily, which can be decreased to 12.5 mg if the initial dose is difficult to tolerate. It should be taken on an empty stomach at least 1 hour before the first meal of the day or 2 hours after the meal. In patients with renal impairment (creatinine clearance < 60 mL/min), the dose is 12.5 mg once daily.⁶⁵

CONSTIPATION-PREDOMINANT IRRITABLE BOWEL SYNDROME

Irritable bowel syndrome is the reason for 3.1 million office visits and 59 million prescriptions in the United States every year, with patients equally distributed between diarrhea-predominant, constipation-predominant, and mixed subtypes.⁶⁶

To be diagnosed with constipation-predominant irritable bowel syndrome, patients must meet the Rome IV criteria, more than 25% of bowel movements should have Bristol stool form types 1 or 2, and less than 25% of bowel movements should have Bristol stool form types 6 or 7. In practice, patients reporting that their bowel movements are usually constipated often suffices to make the diagnosis.⁵

Osmotic laxatives are often tried first, but despite improving stool frequency and consistency, they have little efficacy in satisfying complaints of bloating or abdominal pain in patients with constipation-predominant irritable syndrome.⁶⁷ Stimulant laxatives have not yet been tested in clinical trials. Lubiprostone and linaclotide are FDA-approved for this condition; in women, lubiprostone is approved only for those over age 18.

Antidepressant therapy

Patients often derive additional benefit from treatment with antidepressants. A meta-analysis demonstrated a number needed to treat of 4 for selective serotonin reuptake inhibitors and tricyclic antidepressants in managing abdominal pain associated with irritable bowel syndrome.⁶⁸ The major limiting factor is usually adverse effects of these drugs.

For constipation-predominant irritable bowel syndrome, selective serotonin reuptake inhibitors are preferred over tricyclics because of their additional prokinetic properties. Starting at a low dose and titrating upward slowly avoids potential adverse effects.

Cognitive behavioral therapy has also been beneficial in treating irritable bowel syndrome.⁶⁹

Adjunctive therapies

Adjunctive therapies including peppermint oil, probiotics (eg, Lactobacillus, Bifidobacterium), and acupuncture have also shown promise in managing irritable bowel syndrome, but more data are needed on the use of these therapies for constipation-predominant irritable bowel syndrome before any definite conclusions can be drawn.⁷⁰ Other emerging pharmacologic therapies are plecanatide (discussed earlier) and tenapanor.

Peppermint oil is an antispasmodic that inhibits calcium channels, leading to relaxation of smooth muscles in the gastrointestinal tract. Different dosages and treatment durations have been studied—450 to 900 mg daily in 2 to 3 divided doses over 1 to 3 months.^71,72 The most common adverse effect reported was gastroesophageal reflux, related in part to the oil’s relaxing effect on the lower esophageal sphincter. Observation of this led to the development of enteric-coated preparations that have the potential to bypass the upper gastrointestinal tract.⁷³

Tenapanor inhibits the sodium-hydrogen exchanger 3 channel (a regulator of sodium and water uptake in intestinal lumen), which in turn leads to a higher sodium level in the entire gastrointestinal tract (whereas linaclotide’s action is limited to the duodenum and jejunem), resulting in more fluid volume and increased luminal transit.⁷⁴ It was found effective in a phase 2 clinical trial,⁷⁵ and the most effective dose was 50 mg twice daily.

Since tenapanor is minimally absorbed, it has few side effects, the major ones being diarrhea (11.2% vs 0% with placebo) and urinary tract infection (5.6% vs 4.4% with placebo).⁷⁵ Further study is needed to confirm these findings.

Tenapanor also has the advantage of inhibiting luminal phosphorus absorption. This has led to exploration of its use as a phosphate binder in patients with end-stage renal disease.

DYSSYNERGIC DEFECATION AND ANORECTAL BIOFEEDBACK

According to the Rome IV criteria,⁵ dyssynergic defecation is present if the criteria for chronic constipation are met, if a dyssynergic pattern of defecation is confirmed by manometry, imaging, or electromyography, and if 1 or more of the following are present: inability to expel an artificial stool (a 50-mL water-filled balloon) within 1 minute, prolonged colonic transit time, inability to evacuate, or 50% or more retention of barium during defecography.⁵

Even though biofeedback has been controversial as a treatment for dyssynergic defecation because of conflicting results in older studies,⁷⁶ 3 trials have shown it to be better than placebo, laxatives, and muscle relaxants, with symptomatic improvement in 70% of patients.^77–79

Biofeedback therapy involves an instrument-based auditory or visual tool (using electromyographic sensors or anorectal manometry) to help patients coordinate abdominal, rectal, puborectalis, and anal sphincter muscles and produce a propulsive force using their abdominal muscles to achieve complete evacuation. Important components of this therapy include:

Proper evacuation positioning (brace-pump technique, which involves sitting on the toilet leaning forward with forearms resting on thighs, shoulders relaxed, and feet placed on a small footstool

Breathing relaxation and training exercises during defecation (no straining, keeping a normal pattern of breathing, and avoiding holding the breath while defecating)

Use of the abdominal muscles by pushing the abdomen forward, along with relaxation of the anal sphincter.⁸⁰

The anorectal feedback program usually consists of 6 weekly sessions of 45 to 60 minutes each. Limitations of this therapy include unavailability, lack of trained therapists, lack of insurance coverage, and inapplicability to certain patient groups, such as those with dementia or learning disabilities.

SURGERY FOR CHRONIC CONSTIPATION

Surgery for constipation is reserved for patients who continue to have symptoms despite optimal medical therapy.

Total abdominal colectomy and ileorectal anastomosis

Total abdominal colectomy with ileorectal anastomosis is a surgical option for medically intractable slow-transit constipation. Before considering surgery, complete diagnostic testing should be done, including colonic manometry and documentation of whether the patient also has outlet dysfunction. 

Even though it has shown excellent outcomes and satisfaction rates as high as 100% in patients with pure slow-transit constipation,^81–83 results in older studies in patients with mixed disorders (eg, slow-transit constipation with features of outlet dysfunction) were less predictable.⁸⁴ More recent studies have reported comparable long-term morbidity and postoperative satisfaction rates in those with pure slow-transit constipation and those with a mixed disorder, indicating that careful patient selection is likely the key to a favorable outcome.⁸⁵

Partial colectomies based on segmental colon transit time measurements can also be considered in some patients.⁸⁶

Stapled transanal resection

Stapled transanal resection involves circumferential transanal stapling of the redundant rectal mucosa. It is an option for patients with defecatory disorders, specifically large rectoceles and rectal intussusception not amenable to therapy with pelvic floor retraining exercises.⁸⁷

The efficacy of this procedure in controlling symptoms and improving quality of life is around 77% to 81% at 12 months, though complication rates as high as 46% and disappointing long-term outcomes have been a deterrent to its widespread acceptance in the United States.^88–91

Many women experience some form of sexual dysfunction, be it lack of desire, lack of arousal, failure to achieve orgasm, or pain during sexual activity.

Sexual health may be difficult to discuss, for both the patient and the provider. Here, we describe how primary care physicians can approach this topic, assess potential problems, and begin treatment.

A COMMON PROBLEM

The age-adjusted prevalence of sexual dysfunction in US women was reported at 44% in the Prevalence of Female Sexual Problems Associated With Distress and Determinants of Treatment Seeking (PRESIDE) study,¹ but the prevalence of distress associated with sexual dysfunction was 12%. The most common type of sexual dysfunction reported by women was low sexual desire, a finding consistent with that of another large population-based study.²

While the prevalence of any type of sexual dysfunction was highest in women over age 65,¹ the prevalence of distress was lowest in this age group and highest in midlife between the ages of 45 and 65. The diagnostic criteria require both a problem and distress over the problem.

Sexual dysfunction negatively affects quality of life and emotional health, regardless of age.³

LIFESTYLE AND SEXUAL FUNCTION

Various lifestyle factors have been linked to either more or less sexual activity. For example, a Mediterranean diet was associated with increased sexual activity, as were social activity, social support, psychological well-being, self-reported good quality of life, moderate alcohol intake, absence of tobacco use, a normal body mass index, and exercise.^4–6 A higher sense of purpose in life has been associated with greater sexual enjoyment.⁷

Conversely, sexual inactivity has been associated with alcohol misuse, an elevated body mass index, and somatization.^4–6

SEXUAL RESPONSE: LINEAR OR CIRCULAR?

Masters and Johnson⁸ initially proposed a linear model of human sexual response, which Kaplan later modified to include desire and applied to both men and women.^9,10 This model presumed that sexual response begins with spontaneous sexual desire, followed by arousal, and then (sometimes) orgasm and resolution.

Adapted with permission from Basson R. Human sex-response cycles. J Sex Marital Ther 2001; 27:33–43.

In 2000, Basson¹¹ proposed a circular, intimacy-based model of sexual response in women that acknowledged the complexities involved in a woman’s motivation to be sexual (Figure 1). While a woman may enter the cycle with spontaneous sexual desire, she may also enter it as sexually neutral, with arousal in response to a sexual stimulus. Emotional intimacy is an important part of the cycle, and emotional closeness and bonding with the partner may provide motivation for a woman to enter into the cycle again in the future.

In a Danish survey,¹² more people of both sexes said the 2 linear models described their experiences better than the circular model, but more women than men endorsed the circular model, and more men than women endorsed a linear model.

In evaluating women who complain of low sexual desire, clinicians should be aware that women, particularly those who are postmenopausal, may not enter the cycle with spontaneous sexual desire, but instead may experience arousal in response to a sexual stimulus followed by desire—ie, responsive rather than spontaneous sexual desire. Sexual arousal may precede desire, especially for women in long-term relationships, and emotional intimacy is a key driver for sexual engagement in women.¹¹

The World Health Organization defines sexual health as “a state of physical, emotional, mental, and social well-being in relation to sexuality” and “not merely the absence of disease, dysfunction, or infirmity.”¹³

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),¹⁴ published in 2013, defines three categories of sexual dysfunction in women:

• Female sexual interest and arousal disorder
• Female sexual orgasmic disorder
• Genitopelvic pain/penetration disorder.

To meet the diagnosis of any of these, symptoms must:

• Persist for at least 6 months
• Occur in 75% to 100% of sexual encounters
• Be accompanied by personal distress
• Not be related to another psychological or medical condition, medication or substance use, or relationship distress.

Sexual problems may be lifelong or acquired after a period of normal functioning, and may be situational (present only in certain situations) or generalized (present in all situations).

Female sexual interest and arousal disorder used to be 2 separate categories in earlier editions of the DSM. Proponents of merging the 2 categories in DSM-5 cited several reasons, including difficulty in clearly distinguishing desire from other motivations for sexual activity, the relatively low reporting of fantasy in women, the complexity of distinguishing spontaneous from responsive desire, and the common co-occurrence of decreased desire and arousal difficulties.¹⁵

Other experts, however, have recommended keeping the old, separate categories of hypoactive sexual desire disorder and arousal disorder.¹⁶ The recommendation to preserve the diagnostic category of hypoactive sexual desire disorder is based on robust observational and registry data, as well as the results of randomized controlled trials that used the old criteria for hypoactive sexual desire disorder to assess responses to pharmacologic treatment of this condition.^17–19 In addition, this classification as a separate and distinct diagnosis is consistent with the nomenclature used in the International Statistical Classification of Diseases and Related Health Problems, 10th Revision and was endorsed by the International Consultation on Sexual Medicine in 2015.¹⁶

HOW TO ASK ABOUT SEXUAL HEALTH

Assessment of sexual health concerns should be a part of a routine health examination, particularly after childbirth and other major medical, surgical, psychological, and life events. Women are unlikely to bring up sexual health concerns with their healthcare providers, but instead hope that their providers will bring up the topic.²⁰

Barriers to the discussion include lack of provider education and training, patient and provider discomfort, perceived lack of time during an office visit, and lack of approved treatments.^21,22 Additionally, older women are less likely than men to discuss sexual health with their providers.²³ Other potential barriers to communication include negative societal attitudes about sexuality in women and in older individuals.^24,25 To overcome these barriers:

Legitimize sexual health as an important health concern and normalize its discussion as part of a routine clinical health assessment. Prefacing a query about sexual health with a normalizing and universalizing statement can help: eg, “Many women going through menopause have concerns about their sexual health. Do you have any sexual problems or concerns?” Table 1 contains examples of questions to use for initial screening for sexual dysfunction.^22,26

Flynn et al²⁷ proposed a validated single-question checklist to screen for sexual dysfunction that is an efficient way to identify specific sexual concerns, guide selection of interventions, and facilitate patient-provider communication (Table 2).

Don’t judge and don’t make assumptions about sexuality and sexual practices.

Assure confidentiality.

Use simple, direct language that is appropriate for the patient’s age, ethnicity, culture, and level of health literacy.³

Take a thorough history (sexual and reproductive, medical-surgical, and psychosocial).

Perform a focused physical examination to evaluate for potential causes of pain (eg, infectious causes, vulvar dermatoses, pelvic floor muscle dysfunction). The examination is also an opportunity to teach the patient about anatomy and normal sexual function.

No standard laboratory tests or imaging studies are required for the assessment of sexual dysfunction.²⁸

IT’S NOT JUST PHYSICAL

Evaluation and treatment of female sexual dysfunction is guided by the biopsychosocial model, with potential influences from the biological, psychological, sociocultural, and interpersonal realms (Table 3).^29,30

Biological factors include pelvic surgery, cancer and its treatment, neurologic diseases, and vascular diseases. Medications, including antidepressants, narcotics, anticholinergics, antihistamines, antihypertensives, oral contraceptives, and antiestrogens may also adversely affect sexual response.²⁶

Psychological factors include a history of sexual abuse or trauma, body image concerns, distraction, stress, anxiety, depression, and personality disorders.²²

Sociocultural factors include lack of sex education, unrealistic expectations, cultural norms, and religious influences.

Relationship factors include conflict with one’s partner, lack of emotional intimacy, absence of a partner, and partner sexual dysfunction. While there appears to be a close link between sexual satisfaction and a woman’s relationship with her partner in correlational studies and in clinical experience, there has been little research about relationship factors and their contribution to desire and arousal concerns.³¹ Sexual dysfunction in one’s partner (eg, erectile dysfunction) has been shown to negatively affect the female partner’s sexual desire.³²

GENERAL APPROACH TO TREATMENT

In treating sexual health problems in women, we address contributing factors identified during the initial assessment.

A multidisciplinary approach

As sexual dysfunction in women is often multifactorial, management of the problem is well suited to a multidisciplinary approach. The team of providers may include:

• A medical provider (primary care provider, gynecologist, or sexual health specialist) to coordinate care and manage biological factors contributing to sexual dysfunction
• A physical therapist with expertise in treating pelvic floor disorders
• A psychologist to address psychological, relational, and sociocultural contributors to sexual dysfunction
• A sex therapist (womenshealthapta.org, aasect.org) to facilitate treatment of tight, tender pelvic floor muscles through education and guidance about kinesthetic awareness, muscle relaxation, and dilator therapy.³³

Even in the initial visit, the primary care provider can educate, reassure regarding normal sexual function, and treat conditions such as genitourinary syndrome of menopause and antidepressant-associated sexual dysfunction. The PLISSIT model (Permission, Limited Information, Specific Suggestions, and Intensive Therapy) is a useful tool for initiating counseling about sexual health (Table 4).³⁴

AGING VS MENOPAUSE

Aging can affect sexual function in both men and women. About 40% of women experience changes in sexual function around the menopausal transition, with common complaints being loss of sexual responsiveness and desire, sexual pain, decreased sexual activity, and partner sexual dysfunction.³⁵ However, studies seem to show that while menopause results in hormonal changes that affect sexual function, other factors may have a greater impact.

The Study of Women’s Health Across the Nation³⁶ found vaginal and pelvic pain and decreased sexual desire were associated with the menopausal transition, but other sexual health outcomes (frequency of sexual activities, arousal, importance of sex, emotional satisfaction, or physical pleasure) were not. Physical and psychological health, marital status, and a change in relationship were all associated with differences in sexual health.

The Massachusetts Women’s Health Study II³⁷ found a greater association between physical and mental health, relationship status, and smoking and women’s sexual functioning than menopausal status.

The Penn Ovarian Aging Study³⁸ found that sexual function declined across the menopausal transition. Risk factors for sexual dysfunction included postmenopausal status, anxiety, and absence of a sexual partner.

The Melbourne Women’s Midlife Health Project³⁹ also found that sexual function declined across the menopausal transition. Sexual dysfunction with distress was associated with relationship factors and depression.³⁷

Genitourinary syndrome of menopause and its treatment

As the ovaries shut down during menopause, estradiol levels decrease. Nearly 50% of women experience symptoms related to genitourinary syndrome of menopause (formerly called atrophic vaginitis or vulvovaginal atrophy).^40,41 These symptoms include vaginal dryness and discomfort or pain with sexual activity, but menopausal hormone loss can also result in reduced genital blood flow, decreased sensory perception, and decreased sexual responsiveness.²²

Estrogen is the most effective treatment for genitourinary syndrome of menopause, with low-dose vaginal preparations preferred over systemic ones for isolated vulvar and vaginal symptoms.⁴⁰ While estrogen is effective for vaginal dryness and sexual pain associated with estrogen loss, replacing estrogen systemically has not been associated with improvements in sexual desire.⁴²

Depression increases the risk of sexual dysfunction, and vice versa.

A meta-analysis that included 12 studies involving almost 15,000 patients confirmed that depression increased the risk of sexual dysfunction, and sexual dysfunction increased the risk of depression.⁴³ This interaction may be related to the overlap in affected neuro­transmitters and neuroendocrine systems.⁴⁴

In the Sequenced Treatment Alternatives to Relieve Depression trial, Ishak et al⁴⁵ found that patients treated with a selective serotonin reuptake inhibitor (SSRI) who experienced remission of depression had a lower prevalence of impaired sexual satisfaction and much greater improvements in sexual satisfaction than did those who remained depressed. The severity of depressive symptoms predicted impairment in sexual satisfaction, which in turn predicted poorer quality of life. The authors suggested that physicians encourage patients to remain on SSRI treatment, given that improvement in depressive symptoms is likely to improve sexual satisfaction.

Antidepressant-induced sexual dysfunction

As many as 70% of patients taking an SSRI or serotonin-norepinephrine reuptake inhibitor (SNRI) experience antidepressant-induced sexual dysfunction, though this is difficult to estimate across studies of different medications due to differences in methods and because many patients only report it when directly asked about it.⁴⁶

Treatment of antidepressant-induced sexual dysfunction includes not only optimal management of depression but reassessment of the antidepressant treatment. If using only nondrug treatments for the mood disorder is not feasible, switching to (or ideally, starting with) an antidepressant with fewer sexual side effects such as mirtazapine, vilazodone, or bupropion is an option.⁴⁶

A drug holiday (suspending antidepressant treatment for 1 or 2 days) has been suggested as a means of treating antidepressant-induced sexual dysfunction, but this may result in poorer control of depressive symptoms and discontinuation symptoms, and it encourages medication noncompliance.^46,47

Treatment with a phosphodiesterase type 5 inhibitor (eg, sildenafil) has been studied in women with antidepressant-induced sexual dysfunction, with modest results.⁴⁸

A Cochrane review reported that treatment with bupropion shows promise at higher doses (300 mg daily).⁴⁹

Exercise for 20 minutes 3 times weekly is associated with improvement in antidepressant-induced sexual dysfunction when the exercise is performed immediately before sexual activity.⁵⁰

LOW SEXUAL DESIRE

Hypoactive sexual desire disorder is defined as persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity associated with marked distress and not due exclusively to a medication, substance abuse, or a medical condition.

Low or decreased sexual desire is the most commonly reported sexual health concern in women of all ages, with an unadjusted prevalence of 39.7%. When the criterion of personal distress is included, the prevalence is 8.9% in women ages 18 to 44, 12.3% in women ages 45 to 64, and 7.4% in women ages 65 and older.¹

Multiple biological, psychological, and social factors may contribute to the problem. Identifying the ones that are present can help in planning treatment. A multifaceted approach may be appropriate.

Mindfulness and cognitive behavioral therapy for low sexual desire

Mindfulness-based cognitive therapy is designed to improve awareness, focusing on and accepting the present moment, and directing attention away from and lessening self-criticism and evaluation of one’s sexual responsiveness.

Mindfulness-based therapy has been associated with improvements in sexual desire and associated distress.⁵¹ Similarly, the effectiveness of cognitive behavioral therapy for treating hypoactive sexual desire disorder is supported by 3 controlled trials, although concerns exist about the adequacy of these trials, and further study is needed.⁵²

Androgen therapy in women

In randomized controlled trials in women with low sexual desire who were either naturally or surgically menopausal, sexual function improved with testosterone therapy that resulted in mostly supraphysiologic total testosterone levels (which may not reflect free testosterone levels) with or without concurrent estrogen treatment.^53–57

Testosterone is not approved by the US Food and Drug Administration (FDA) for use in women, primarily because of the lack of long-term safety and efficacy data (ie, beyond 24 months). However, studies have shown no evidence of increased risk of endometrial cancer or cardiovascular disease with testosterone dosed to achieve physiologic premenopausal levels.⁵⁸ Data on breast cancer risk are less clear, but observational studies over the last decade do not support an association with testosterone use in women.⁵⁸ There is no clearly defined androgen deficiency syndrome in women, and androgen levels do not reliably correlate with symptoms.⁵⁹

The Endocrine Society⁵⁹ guidelines endorse the use of testosterone in postmenopausal women with hypoactive sexual desire disorder. They say to aim for the midnormal premenopausal range and suggest discontinuing the drug if there is no response in 6 months. They recommend checking testosterone levels at baseline, after 3 to 6 weeks of therapy, and every 6 months to monitor for excessive use, to avoid supraphysiologic dosing and to evaluate for signs of androgen excess (eg, acne, hair growth). The use of products formulated for men or those formulated by pharmacies is discouraged; however, no FDA-approved products are currently available for use in women in the United States.

Flibanserin

A postsynaptic serotonin 5-HT1A receptor agonist and 5-HT2A receptor agonist, flibanserin was approved by the FDA in 2015 for treatment of hypoactive sexual desire disorder in premenopausal women. Its mechanism of action is likely through an effect on neurotransmitters that suppresses serotonin (which has sexually inhibitory effects) and promotes dopamine and norepinephrine (which have excitatory effects).⁶⁰

The efficacy of flibanserin has been demonstrated in 3 randomized controlled trials, with significant increases in the number of sexually satisfying events and in sexual desire scores and a decrease in distress associated with low sexual desire.^17­–19 While the increase in sexually satisfying events was modest (about 1 extra event per month), some have suggested that the frequency of sexual activity may not be the best measure of sexual function in women.⁶¹ Further, responders to this drug showed a return to near-normal premenopausal frequencies of sexual activity in a separate analysis.⁶¹

The drug is generally well tolerated, with common adverse effects being somnolence, dizziness, and fatigue.^18,19 Flibanserin has been associated with orthostatic hypotension with alcohol use and carries a boxed warning highlighting this potential interaction.⁶² Use of this drug is contraindicated in women who drink alcohol or take medications that are moderate or strong inhibitors of CYP-3A4 (eg, some antiretroviral drugs, antihypertensive drugs, antibiotics, and fluconazole, which can increase systemic exposure to flibanserin and potential side effects), and in those with liver impairment.

Female sexual arousal disorder is the persistent or recurrent inability to attain or maintain an adequate lubrication-swelling response of sexual excitement. Sexual arousal results from a complex interaction between genital response, central nervous system activity, and information processing of the sexual stimulus. Difficulty with sexual arousal can result from neurovascular or neuroendocrine dysfunction or impaired central nervous system processing.

Women may experience a mismatch between subjective and objective genital arousal. A subjective report of decreased genital arousal may not be confirmed with measurement of vaginal pulse amplitude by photoplethysmography.⁶³ Even in postmenopausal women, in the absence of significant neurovascular or neuroendocrine dysfunction, it is likely that either contextual or relational variables resulting in inadequate sexual stimulation or cognitive inhibition are more important factors contributing to difficulty with sexual arousal.⁶³

Although there are no standard recommendations for evaluation of arousal disorders and advanced testing is often unnecessary, nerve function can be assessed with genital sensory testing utilizing thermal and vibratory threshholds⁶⁴; vaginal blood flow can be assessed with vaginal photoplethysmography⁶³; and imaging of the spine and pelvis can help to rule out neurovascular pathology.

Treatment of arousal disorders

As with other forms of female sexual dysfunction, treatment of arousal disorders includes addressing contributing factors.

Although there are few data from randomized controlled trials, psychological treatments such as sensate focus exercises and masturbation training have been suggested, centered on women becoming more self-focused and assertive.³¹ Sensate focus exercises are a series of graded, nondemand, sensual touching exercises aimed at reducing anxiety and avoidance of sexual activity, and improving sexual communication and intimacy by the gradual reintroduction of sexual activity.⁶⁵ More recently, mindfulness-based cognitive therapy has been associated with improvements in sexual arousal as well as other parameters of sexual function.⁵¹

Currently, no pharmacologic treatments are recommended for arousal disorders because of a lack of evidence of efficacy and because of adverse effects.³¹

ORGASMIC DISORDER

Female orgasmic disorder is the marked delay, marked infrequency, or absence of orgasm, or markedly reduced intensity of orgasm.

Important considerations in evaluating orgasm disorders include psychosocial factors (eg, lack of sex education, negative feelings about sex, religiosity), psychological factors (eg, anxiety, depression, body image concerns), relational factors (eg, communication issues, lack of emotional intimacy, partner sexual dysfunction), adverse childhood or adult experiences (eg, physical, sexual, or emotional or verbal abuse), medical history (pelvic surgery, neurologic, or vascular disease) and medications (eg, SSRIs, SNRIs, and antipsychotic medications).⁶⁶

Treatment of orgasmic disorder

Involving the partner in treatment is important, particularly if the difficulty with orgasm is acquired and only occurs with sex with a partner. Using the PLISSIT model to provide targeted, office-based interventions can be helpful.

Behavioral therapies such as directed masturbation, sensate focus exercises, or a combination of these have been shown to be effective, as has coital alignment during intercourse (positioning of male partner with his pelvis above the pubic bone of his partner to maximize clitoral stimulation with penile penetration).⁶⁶

Hormonal therapy may be useful in postmenopausal women. However, there are no data on it for women whose primary complaint is female orgasmic disorder, and further study is needed.⁶⁶

SEXUAL PAIN DISORDERS

The DSM-5 describes genitopelvic pain/penetration disorder as fear or anxiety, marked tightening or tensing of abdominal and pelvic muscles, or actual pain with vaginal penetration that is recurrent or persistent for a minimum of 6 months.¹⁴ Pain may occur with initial penetration, with deeper thrusting, or both.

Although the DSM-5 definition focuses on pain with penetration, it is important to recognize and ask about noncoital sexual pain. Women may also present with persistent vulvar pain or pain at the vulvar vestibule with provocation, (eg, sexual activity, tampon insertion, sitting), also known as provoked vestibulodynia.

Assessment of vaginal and vulvar pain includes a directed history and physical examination aimed at identifying potential etiologies or contributing factors, including infectious, inflammatory, neoplastic, neurologic, traumatic, iatrogenic, or factors related to hormonal deficiency.⁶⁷

Treatment of sexual pain

Removal of offending agents is a first step. This includes a thorough review of vulvar and vaginal hygiene practices and emphasis on avoiding the use of any product containing potential irritants (eg, soaps or detergents containing perfumes or dyes) and using lubricants and moisturizers without gimmicks (no warming or tingling agents or flavors). Oral contraceptives have been associated with vestibulodynia, and women in whom the sexual pain started when they started an oral contraceptive may benefit from switching to an alternate form of contraception.⁶⁸

Dysfunction of pelvic floor muscles may result in sexual pain and may be a primary problem or a secondary complication related to other issues such as symptomatic genitourinary syndrome of menopause. The symptoms of nonrelaxing pelvic floor dysfunction (also known as hypertonic pelvic floor dysfunction or pelvic floor tension myalgia) include pain in the pelvis with sexual activity that may linger for hours or even days, and may also include bowel and bladder dysfunction and low back pain or hip pain radiating to the thighs or groin.³³ Physical therapy under the care of a physical therapist with expertise in the management of pelvic floor disorders is the cornerstone of treatment for this condition.³³

Treatment of the genital and urinary symptoms related to loss of estrogen after menopause (genitourinary syndrome of menopause) includes the use of vaginal lubricants with sexual activity and vaginal moisturizers on a regular basis (2 to 5 times per week).⁴⁰ Low-dose vaginal estrogen creams, rings, or tablets and the oral selective estrogen receptor antagonist ospemifene are recommended for moderate to severe symptoms of genitourinary syndrome of menopause.⁴⁰ Intravaginal dehydroepiandrosterone was recently approved by the FDA for treatment of dyspareunia associated with menopause.⁶⁹ Topical lidocaine applied to the introitus before sexual activity has been found to be effective for reducing sexual pain in women with breast cancer, and when used in combination with vaginal lubricants and moisturizers is a practical option for women, particularly those unable to use estrogen-based therapies.⁷⁰

Many women experience some form of sexual dysfunction, be it lack of desire, lack of arousal, failure to achieve orgasm, or pain during sexual activity.

Sexual health may be difficult to discuss, for both the patient and the provider. Here, we describe how primary care physicians can approach this topic, assess potential problems, and begin treatment.

A COMMON PROBLEM

The age-adjusted prevalence of sexual dysfunction in US women was reported at 44% in the Prevalence of Female Sexual Problems Associated With Distress and Determinants of Treatment Seeking (PRESIDE) study,¹ but the prevalence of distress associated with sexual dysfunction was 12%. The most common type of sexual dysfunction reported by women was low sexual desire, a finding consistent with that of another large population-based study.²

While the prevalence of any type of sexual dysfunction was highest in women over age 65,¹ the prevalence of distress was lowest in this age group and highest in midlife between the ages of 45 and 65. The diagnostic criteria require both a problem and distress over the problem.

Sexual dysfunction negatively affects quality of life and emotional health, regardless of age.³

LIFESTYLE AND SEXUAL FUNCTION

Various lifestyle factors have been linked to either more or less sexual activity. For example, a Mediterranean diet was associated with increased sexual activity, as were social activity, social support, psychological well-being, self-reported good quality of life, moderate alcohol intake, absence of tobacco use, a normal body mass index, and exercise.^4–6 A higher sense of purpose in life has been associated with greater sexual enjoyment.⁷

Conversely, sexual inactivity has been associated with alcohol misuse, an elevated body mass index, and somatization.^4–6

SEXUAL RESPONSE: LINEAR OR CIRCULAR?

Masters and Johnson⁸ initially proposed a linear model of human sexual response, which Kaplan later modified to include desire and applied to both men and women.^9,10 This model presumed that sexual response begins with spontaneous sexual desire, followed by arousal, and then (sometimes) orgasm and resolution.

Adapted with permission from Basson R. Human sex-response cycles. J Sex Marital Ther 2001; 27:33–43.

In 2000, Basson¹¹ proposed a circular, intimacy-based model of sexual response in women that acknowledged the complexities involved in a woman’s motivation to be sexual (Figure 1). While a woman may enter the cycle with spontaneous sexual desire, she may also enter it as sexually neutral, with arousal in response to a sexual stimulus. Emotional intimacy is an important part of the cycle, and emotional closeness and bonding with the partner may provide motivation for a woman to enter into the cycle again in the future.

In a Danish survey,¹² more people of both sexes said the 2 linear models described their experiences better than the circular model, but more women than men endorsed the circular model, and more men than women endorsed a linear model.

In evaluating women who complain of low sexual desire, clinicians should be aware that women, particularly those who are postmenopausal, may not enter the cycle with spontaneous sexual desire, but instead may experience arousal in response to a sexual stimulus followed by desire—ie, responsive rather than spontaneous sexual desire. Sexual arousal may precede desire, especially for women in long-term relationships, and emotional intimacy is a key driver for sexual engagement in women.¹¹

The World Health Organization defines sexual health as “a state of physical, emotional, mental, and social well-being in relation to sexuality” and “not merely the absence of disease, dysfunction, or infirmity.”¹³

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),¹⁴ published in 2013, defines three categories of sexual dysfunction in women:

• Female sexual interest and arousal disorder
• Female sexual orgasmic disorder
• Genitopelvic pain/penetration disorder.

To meet the diagnosis of any of these, symptoms must:

• Persist for at least 6 months
• Occur in 75% to 100% of sexual encounters
• Be accompanied by personal distress
• Not be related to another psychological or medical condition, medication or substance use, or relationship distress.

Sexual problems may be lifelong or acquired after a period of normal functioning, and may be situational (present only in certain situations) or generalized (present in all situations).

Female sexual interest and arousal disorder used to be 2 separate categories in earlier editions of the DSM. Proponents of merging the 2 categories in DSM-5 cited several reasons, including difficulty in clearly distinguishing desire from other motivations for sexual activity, the relatively low reporting of fantasy in women, the complexity of distinguishing spontaneous from responsive desire, and the common co-occurrence of decreased desire and arousal difficulties.¹⁵

Other experts, however, have recommended keeping the old, separate categories of hypoactive sexual desire disorder and arousal disorder.¹⁶ The recommendation to preserve the diagnostic category of hypoactive sexual desire disorder is based on robust observational and registry data, as well as the results of randomized controlled trials that used the old criteria for hypoactive sexual desire disorder to assess responses to pharmacologic treatment of this condition.^17–19 In addition, this classification as a separate and distinct diagnosis is consistent with the nomenclature used in the International Statistical Classification of Diseases and Related Health Problems, 10th Revision and was endorsed by the International Consultation on Sexual Medicine in 2015.¹⁶

HOW TO ASK ABOUT SEXUAL HEALTH

Assessment of sexual health concerns should be a part of a routine health examination, particularly after childbirth and other major medical, surgical, psychological, and life events. Women are unlikely to bring up sexual health concerns with their healthcare providers, but instead hope that their providers will bring up the topic.²⁰

Barriers to the discussion include lack of provider education and training, patient and provider discomfort, perceived lack of time during an office visit, and lack of approved treatments.^21,22 Additionally, older women are less likely than men to discuss sexual health with their providers.²³ Other potential barriers to communication include negative societal attitudes about sexuality in women and in older individuals.^24,25 To overcome these barriers:

Legitimize sexual health as an important health concern and normalize its discussion as part of a routine clinical health assessment. Prefacing a query about sexual health with a normalizing and universalizing statement can help: eg, “Many women going through menopause have concerns about their sexual health. Do you have any sexual problems or concerns?” Table 1 contains examples of questions to use for initial screening for sexual dysfunction.^22,26

Flynn et al²⁷ proposed a validated single-question checklist to screen for sexual dysfunction that is an efficient way to identify specific sexual concerns, guide selection of interventions, and facilitate patient-provider communication (Table 2).

Don’t judge and don’t make assumptions about sexuality and sexual practices.

Assure confidentiality.

Use simple, direct language that is appropriate for the patient’s age, ethnicity, culture, and level of health literacy.³

Take a thorough history (sexual and reproductive, medical-surgical, and psychosocial).

Perform a focused physical examination to evaluate for potential causes of pain (eg, infectious causes, vulvar dermatoses, pelvic floor muscle dysfunction). The examination is also an opportunity to teach the patient about anatomy and normal sexual function.

No standard laboratory tests or imaging studies are required for the assessment of sexual dysfunction.²⁸

IT’S NOT JUST PHYSICAL

Evaluation and treatment of female sexual dysfunction is guided by the biopsychosocial model, with potential influences from the biological, psychological, sociocultural, and interpersonal realms (Table 3).^29,30

Biological factors include pelvic surgery, cancer and its treatment, neurologic diseases, and vascular diseases. Medications, including antidepressants, narcotics, anticholinergics, antihistamines, antihypertensives, oral contraceptives, and antiestrogens may also adversely affect sexual response.²⁶

Psychological factors include a history of sexual abuse or trauma, body image concerns, distraction, stress, anxiety, depression, and personality disorders.²²

Sociocultural factors include lack of sex education, unrealistic expectations, cultural norms, and religious influences.

Relationship factors include conflict with one’s partner, lack of emotional intimacy, absence of a partner, and partner sexual dysfunction. While there appears to be a close link between sexual satisfaction and a woman’s relationship with her partner in correlational studies and in clinical experience, there has been little research about relationship factors and their contribution to desire and arousal concerns.³¹ Sexual dysfunction in one’s partner (eg, erectile dysfunction) has been shown to negatively affect the female partner’s sexual desire.³²

GENERAL APPROACH TO TREATMENT

In treating sexual health problems in women, we address contributing factors identified during the initial assessment.

A multidisciplinary approach

As sexual dysfunction in women is often multifactorial, management of the problem is well suited to a multidisciplinary approach. The team of providers may include:

• A medical provider (primary care provider, gynecologist, or sexual health specialist) to coordinate care and manage biological factors contributing to sexual dysfunction
• A physical therapist with expertise in treating pelvic floor disorders
• A psychologist to address psychological, relational, and sociocultural contributors to sexual dysfunction
• A sex therapist (womenshealthapta.org, aasect.org) to facilitate treatment of tight, tender pelvic floor muscles through education and guidance about kinesthetic awareness, muscle relaxation, and dilator therapy.³³

Even in the initial visit, the primary care provider can educate, reassure regarding normal sexual function, and treat conditions such as genitourinary syndrome of menopause and antidepressant-associated sexual dysfunction. The PLISSIT model (Permission, Limited Information, Specific Suggestions, and Intensive Therapy) is a useful tool for initiating counseling about sexual health (Table 4).³⁴

AGING VS MENOPAUSE

Aging can affect sexual function in both men and women. About 40% of women experience changes in sexual function around the menopausal transition, with common complaints being loss of sexual responsiveness and desire, sexual pain, decreased sexual activity, and partner sexual dysfunction.³⁵ However, studies seem to show that while menopause results in hormonal changes that affect sexual function, other factors may have a greater impact.

The Study of Women’s Health Across the Nation³⁶ found vaginal and pelvic pain and decreased sexual desire were associated with the menopausal transition, but other sexual health outcomes (frequency of sexual activities, arousal, importance of sex, emotional satisfaction, or physical pleasure) were not. Physical and psychological health, marital status, and a change in relationship were all associated with differences in sexual health.

The Massachusetts Women’s Health Study II³⁷ found a greater association between physical and mental health, relationship status, and smoking and women’s sexual functioning than menopausal status.

The Penn Ovarian Aging Study³⁸ found that sexual function declined across the menopausal transition. Risk factors for sexual dysfunction included postmenopausal status, anxiety, and absence of a sexual partner.

The Melbourne Women’s Midlife Health Project³⁹ also found that sexual function declined across the menopausal transition. Sexual dysfunction with distress was associated with relationship factors and depression.³⁷

Genitourinary syndrome of menopause and its treatment

As the ovaries shut down during menopause, estradiol levels decrease. Nearly 50% of women experience symptoms related to genitourinary syndrome of menopause (formerly called atrophic vaginitis or vulvovaginal atrophy).^40,41 These symptoms include vaginal dryness and discomfort or pain with sexual activity, but menopausal hormone loss can also result in reduced genital blood flow, decreased sensory perception, and decreased sexual responsiveness.²²

Estrogen is the most effective treatment for genitourinary syndrome of menopause, with low-dose vaginal preparations preferred over systemic ones for isolated vulvar and vaginal symptoms.⁴⁰ While estrogen is effective for vaginal dryness and sexual pain associated with estrogen loss, replacing estrogen systemically has not been associated with improvements in sexual desire.⁴²

Depression increases the risk of sexual dysfunction, and vice versa.

A meta-analysis that included 12 studies involving almost 15,000 patients confirmed that depression increased the risk of sexual dysfunction, and sexual dysfunction increased the risk of depression.⁴³ This interaction may be related to the overlap in affected neuro­transmitters and neuroendocrine systems.⁴⁴

In the Sequenced Treatment Alternatives to Relieve Depression trial, Ishak et al⁴⁵ found that patients treated with a selective serotonin reuptake inhibitor (SSRI) who experienced remission of depression had a lower prevalence of impaired sexual satisfaction and much greater improvements in sexual satisfaction than did those who remained depressed. The severity of depressive symptoms predicted impairment in sexual satisfaction, which in turn predicted poorer quality of life. The authors suggested that physicians encourage patients to remain on SSRI treatment, given that improvement in depressive symptoms is likely to improve sexual satisfaction.

Antidepressant-induced sexual dysfunction

As many as 70% of patients taking an SSRI or serotonin-norepinephrine reuptake inhibitor (SNRI) experience antidepressant-induced sexual dysfunction, though this is difficult to estimate across studies of different medications due to differences in methods and because many patients only report it when directly asked about it.⁴⁶

Treatment of antidepressant-induced sexual dysfunction includes not only optimal management of depression but reassessment of the antidepressant treatment. If using only nondrug treatments for the mood disorder is not feasible, switching to (or ideally, starting with) an antidepressant with fewer sexual side effects such as mirtazapine, vilazodone, or bupropion is an option.⁴⁶

A drug holiday (suspending antidepressant treatment for 1 or 2 days) has been suggested as a means of treating antidepressant-induced sexual dysfunction, but this may result in poorer control of depressive symptoms and discontinuation symptoms, and it encourages medication noncompliance.^46,47

Treatment with a phosphodiesterase type 5 inhibitor (eg, sildenafil) has been studied in women with antidepressant-induced sexual dysfunction, with modest results.⁴⁸

A Cochrane review reported that treatment with bupropion shows promise at higher doses (300 mg daily).⁴⁹

Exercise for 20 minutes 3 times weekly is associated with improvement in antidepressant-induced sexual dysfunction when the exercise is performed immediately before sexual activity.⁵⁰

LOW SEXUAL DESIRE

Hypoactive sexual desire disorder is defined as persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity associated with marked distress and not due exclusively to a medication, substance abuse, or a medical condition.

Low or decreased sexual desire is the most commonly reported sexual health concern in women of all ages, with an unadjusted prevalence of 39.7%. When the criterion of personal distress is included, the prevalence is 8.9% in women ages 18 to 44, 12.3% in women ages 45 to 64, and 7.4% in women ages 65 and older.¹

Multiple biological, psychological, and social factors may contribute to the problem. Identifying the ones that are present can help in planning treatment. A multifaceted approach may be appropriate.

Mindfulness and cognitive behavioral therapy for low sexual desire

Mindfulness-based cognitive therapy is designed to improve awareness, focusing on and accepting the present moment, and directing attention away from and lessening self-criticism and evaluation of one’s sexual responsiveness.

Mindfulness-based therapy has been associated with improvements in sexual desire and associated distress.⁵¹ Similarly, the effectiveness of cognitive behavioral therapy for treating hypoactive sexual desire disorder is supported by 3 controlled trials, although concerns exist about the adequacy of these trials, and further study is needed.⁵²

Androgen therapy in women

In randomized controlled trials in women with low sexual desire who were either naturally or surgically menopausal, sexual function improved with testosterone therapy that resulted in mostly supraphysiologic total testosterone levels (which may not reflect free testosterone levels) with or without concurrent estrogen treatment.^53–57

Testosterone is not approved by the US Food and Drug Administration (FDA) for use in women, primarily because of the lack of long-term safety and efficacy data (ie, beyond 24 months). However, studies have shown no evidence of increased risk of endometrial cancer or cardiovascular disease with testosterone dosed to achieve physiologic premenopausal levels.⁵⁸ Data on breast cancer risk are less clear, but observational studies over the last decade do not support an association with testosterone use in women.⁵⁸ There is no clearly defined androgen deficiency syndrome in women, and androgen levels do not reliably correlate with symptoms.⁵⁹

The Endocrine Society⁵⁹ guidelines endorse the use of testosterone in postmenopausal women with hypoactive sexual desire disorder. They say to aim for the midnormal premenopausal range and suggest discontinuing the drug if there is no response in 6 months. They recommend checking testosterone levels at baseline, after 3 to 6 weeks of therapy, and every 6 months to monitor for excessive use, to avoid supraphysiologic dosing and to evaluate for signs of androgen excess (eg, acne, hair growth). The use of products formulated for men or those formulated by pharmacies is discouraged; however, no FDA-approved products are currently available for use in women in the United States.

Flibanserin

A postsynaptic serotonin 5-HT1A receptor agonist and 5-HT2A receptor agonist, flibanserin was approved by the FDA in 2015 for treatment of hypoactive sexual desire disorder in premenopausal women. Its mechanism of action is likely through an effect on neurotransmitters that suppresses serotonin (which has sexually inhibitory effects) and promotes dopamine and norepinephrine (which have excitatory effects).⁶⁰

The efficacy of flibanserin has been demonstrated in 3 randomized controlled trials, with significant increases in the number of sexually satisfying events and in sexual desire scores and a decrease in distress associated with low sexual desire.^17­–19 While the increase in sexually satisfying events was modest (about 1 extra event per month), some have suggested that the frequency of sexual activity may not be the best measure of sexual function in women.⁶¹ Further, responders to this drug showed a return to near-normal premenopausal frequencies of sexual activity in a separate analysis.⁶¹

The drug is generally well tolerated, with common adverse effects being somnolence, dizziness, and fatigue.^18,19 Flibanserin has been associated with orthostatic hypotension with alcohol use and carries a boxed warning highlighting this potential interaction.⁶² Use of this drug is contraindicated in women who drink alcohol or take medications that are moderate or strong inhibitors of CYP-3A4 (eg, some antiretroviral drugs, antihypertensive drugs, antibiotics, and fluconazole, which can increase systemic exposure to flibanserin and potential side effects), and in those with liver impairment.

Female sexual arousal disorder is the persistent or recurrent inability to attain or maintain an adequate lubrication-swelling response of sexual excitement. Sexual arousal results from a complex interaction between genital response, central nervous system activity, and information processing of the sexual stimulus. Difficulty with sexual arousal can result from neurovascular or neuroendocrine dysfunction or impaired central nervous system processing.

Women may experience a mismatch between subjective and objective genital arousal. A subjective report of decreased genital arousal may not be confirmed with measurement of vaginal pulse amplitude by photoplethysmography.⁶³ Even in postmenopausal women, in the absence of significant neurovascular or neuroendocrine dysfunction, it is likely that either contextual or relational variables resulting in inadequate sexual stimulation or cognitive inhibition are more important factors contributing to difficulty with sexual arousal.⁶³

Although there are no standard recommendations for evaluation of arousal disorders and advanced testing is often unnecessary, nerve function can be assessed with genital sensory testing utilizing thermal and vibratory threshholds⁶⁴; vaginal blood flow can be assessed with vaginal photoplethysmography⁶³; and imaging of the spine and pelvis can help to rule out neurovascular pathology.

Treatment of arousal disorders

As with other forms of female sexual dysfunction, treatment of arousal disorders includes addressing contributing factors.

Although there are few data from randomized controlled trials, psychological treatments such as sensate focus exercises and masturbation training have been suggested, centered on women becoming more self-focused and assertive.³¹ Sensate focus exercises are a series of graded, nondemand, sensual touching exercises aimed at reducing anxiety and avoidance of sexual activity, and improving sexual communication and intimacy by the gradual reintroduction of sexual activity.⁶⁵ More recently, mindfulness-based cognitive therapy has been associated with improvements in sexual arousal as well as other parameters of sexual function.⁵¹

Currently, no pharmacologic treatments are recommended for arousal disorders because of a lack of evidence of efficacy and because of adverse effects.³¹

ORGASMIC DISORDER

Female orgasmic disorder is the marked delay, marked infrequency, or absence of orgasm, or markedly reduced intensity of orgasm.

Important considerations in evaluating orgasm disorders include psychosocial factors (eg, lack of sex education, negative feelings about sex, religiosity), psychological factors (eg, anxiety, depression, body image concerns), relational factors (eg, communication issues, lack of emotional intimacy, partner sexual dysfunction), adverse childhood or adult experiences (eg, physical, sexual, or emotional or verbal abuse), medical history (pelvic surgery, neurologic, or vascular disease) and medications (eg, SSRIs, SNRIs, and antipsychotic medications).⁶⁶

Treatment of orgasmic disorder

Involving the partner in treatment is important, particularly if the difficulty with orgasm is acquired and only occurs with sex with a partner. Using the PLISSIT model to provide targeted, office-based interventions can be helpful.

Behavioral therapies such as directed masturbation, sensate focus exercises, or a combination of these have been shown to be effective, as has coital alignment during intercourse (positioning of male partner with his pelvis above the pubic bone of his partner to maximize clitoral stimulation with penile penetration).⁶⁶

Hormonal therapy may be useful in postmenopausal women. However, there are no data on it for women whose primary complaint is female orgasmic disorder, and further study is needed.⁶⁶

SEXUAL PAIN DISORDERS

The DSM-5 describes genitopelvic pain/penetration disorder as fear or anxiety, marked tightening or tensing of abdominal and pelvic muscles, or actual pain with vaginal penetration that is recurrent or persistent for a minimum of 6 months.¹⁴ Pain may occur with initial penetration, with deeper thrusting, or both.

Although the DSM-5 definition focuses on pain with penetration, it is important to recognize and ask about noncoital sexual pain. Women may also present with persistent vulvar pain or pain at the vulvar vestibule with provocation, (eg, sexual activity, tampon insertion, sitting), also known as provoked vestibulodynia.

Assessment of vaginal and vulvar pain includes a directed history and physical examination aimed at identifying potential etiologies or contributing factors, including infectious, inflammatory, neoplastic, neurologic, traumatic, iatrogenic, or factors related to hormonal deficiency.⁶⁷

Treatment of sexual pain

Removal of offending agents is a first step. This includes a thorough review of vulvar and vaginal hygiene practices and emphasis on avoiding the use of any product containing potential irritants (eg, soaps or detergents containing perfumes or dyes) and using lubricants and moisturizers without gimmicks (no warming or tingling agents or flavors). Oral contraceptives have been associated with vestibulodynia, and women in whom the sexual pain started when they started an oral contraceptive may benefit from switching to an alternate form of contraception.⁶⁸

Dysfunction of pelvic floor muscles may result in sexual pain and may be a primary problem or a secondary complication related to other issues such as symptomatic genitourinary syndrome of menopause. The symptoms of nonrelaxing pelvic floor dysfunction (also known as hypertonic pelvic floor dysfunction or pelvic floor tension myalgia) include pain in the pelvis with sexual activity that may linger for hours or even days, and may also include bowel and bladder dysfunction and low back pain or hip pain radiating to the thighs or groin.³³ Physical therapy under the care of a physical therapist with expertise in the management of pelvic floor disorders is the cornerstone of treatment for this condition.³³

Treatment of the genital and urinary symptoms related to loss of estrogen after menopause (genitourinary syndrome of menopause) includes the use of vaginal lubricants with sexual activity and vaginal moisturizers on a regular basis (2 to 5 times per week).⁴⁰ Low-dose vaginal estrogen creams, rings, or tablets and the oral selective estrogen receptor antagonist ospemifene are recommended for moderate to severe symptoms of genitourinary syndrome of menopause.⁴⁰ Intravaginal dehydroepiandrosterone was recently approved by the FDA for treatment of dyspareunia associated with menopause.⁶⁹ Topical lidocaine applied to the introitus before sexual activity has been found to be effective for reducing sexual pain in women with breast cancer, and when used in combination with vaginal lubricants and moisturizers is a practical option for women, particularly those unable to use estrogen-based therapies.⁷⁰

Many women experience some form of sexual dysfunction, be it lack of desire, lack of arousal, failure to achieve orgasm, or pain during sexual activity.

Sexual health may be difficult to discuss, for both the patient and the provider. Here, we describe how primary care physicians can approach this topic, assess potential problems, and begin treatment.

A COMMON PROBLEM

The age-adjusted prevalence of sexual dysfunction in US women was reported at 44% in the Prevalence of Female Sexual Problems Associated With Distress and Determinants of Treatment Seeking (PRESIDE) study,¹ but the prevalence of distress associated with sexual dysfunction was 12%. The most common type of sexual dysfunction reported by women was low sexual desire, a finding consistent with that of another large population-based study.²

While the prevalence of any type of sexual dysfunction was highest in women over age 65,¹ the prevalence of distress was lowest in this age group and highest in midlife between the ages of 45 and 65. The diagnostic criteria require both a problem and distress over the problem.

Sexual dysfunction negatively affects quality of life and emotional health, regardless of age.³

LIFESTYLE AND SEXUAL FUNCTION

Various lifestyle factors have been linked to either more or less sexual activity. For example, a Mediterranean diet was associated with increased sexual activity, as were social activity, social support, psychological well-being, self-reported good quality of life, moderate alcohol intake, absence of tobacco use, a normal body mass index, and exercise.^4–6 A higher sense of purpose in life has been associated with greater sexual enjoyment.⁷

Conversely, sexual inactivity has been associated with alcohol misuse, an elevated body mass index, and somatization.^4–6

SEXUAL RESPONSE: LINEAR OR CIRCULAR?

Masters and Johnson⁸ initially proposed a linear model of human sexual response, which Kaplan later modified to include desire and applied to both men and women.^9,10 This model presumed that sexual response begins with spontaneous sexual desire, followed by arousal, and then (sometimes) orgasm and resolution.

Adapted with permission from Basson R. Human sex-response cycles. J Sex Marital Ther 2001; 27:33–43.

In 2000, Basson¹¹ proposed a circular, intimacy-based model of sexual response in women that acknowledged the complexities involved in a woman’s motivation to be sexual (Figure 1). While a woman may enter the cycle with spontaneous sexual desire, she may also enter it as sexually neutral, with arousal in response to a sexual stimulus. Emotional intimacy is an important part of the cycle, and emotional closeness and bonding with the partner may provide motivation for a woman to enter into the cycle again in the future.

In a Danish survey,¹² more people of both sexes said the 2 linear models described their experiences better than the circular model, but more women than men endorsed the circular model, and more men than women endorsed a linear model.

In evaluating women who complain of low sexual desire, clinicians should be aware that women, particularly those who are postmenopausal, may not enter the cycle with spontaneous sexual desire, but instead may experience arousal in response to a sexual stimulus followed by desire—ie, responsive rather than spontaneous sexual desire. Sexual arousal may precede desire, especially for women in long-term relationships, and emotional intimacy is a key driver for sexual engagement in women.¹¹

The World Health Organization defines sexual health as “a state of physical, emotional, mental, and social well-being in relation to sexuality” and “not merely the absence of disease, dysfunction, or infirmity.”¹³

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),¹⁴ published in 2013, defines three categories of sexual dysfunction in women:

• Female sexual interest and arousal disorder
• Female sexual orgasmic disorder
• Genitopelvic pain/penetration disorder.

To meet the diagnosis of any of these, symptoms must:

• Persist for at least 6 months
• Occur in 75% to 100% of sexual encounters
• Be accompanied by personal distress
• Not be related to another psychological or medical condition, medication or substance use, or relationship distress.

Sexual problems may be lifelong or acquired after a period of normal functioning, and may be situational (present only in certain situations) or generalized (present in all situations).

Female sexual interest and arousal disorder used to be 2 separate categories in earlier editions of the DSM. Proponents of merging the 2 categories in DSM-5 cited several reasons, including difficulty in clearly distinguishing desire from other motivations for sexual activity, the relatively low reporting of fantasy in women, the complexity of distinguishing spontaneous from responsive desire, and the common co-occurrence of decreased desire and arousal difficulties.¹⁵

Other experts, however, have recommended keeping the old, separate categories of hypoactive sexual desire disorder and arousal disorder.¹⁶ The recommendation to preserve the diagnostic category of hypoactive sexual desire disorder is based on robust observational and registry data, as well as the results of randomized controlled trials that used the old criteria for hypoactive sexual desire disorder to assess responses to pharmacologic treatment of this condition.^17–19 In addition, this classification as a separate and distinct diagnosis is consistent with the nomenclature used in the International Statistical Classification of Diseases and Related Health Problems, 10th Revision and was endorsed by the International Consultation on Sexual Medicine in 2015.¹⁶

HOW TO ASK ABOUT SEXUAL HEALTH

Assessment of sexual health concerns should be a part of a routine health examination, particularly after childbirth and other major medical, surgical, psychological, and life events. Women are unlikely to bring up sexual health concerns with their healthcare providers, but instead hope that their providers will bring up the topic.²⁰

Barriers to the discussion include lack of provider education and training, patient and provider discomfort, perceived lack of time during an office visit, and lack of approved treatments.^21,22 Additionally, older women are less likely than men to discuss sexual health with their providers.²³ Other potential barriers to communication include negative societal attitudes about sexuality in women and in older individuals.^24,25 To overcome these barriers:

Legitimize sexual health as an important health concern and normalize its discussion as part of a routine clinical health assessment. Prefacing a query about sexual health with a normalizing and universalizing statement can help: eg, “Many women going through menopause have concerns about their sexual health. Do you have any sexual problems or concerns?” Table 1 contains examples of questions to use for initial screening for sexual dysfunction.^22,26

Flynn et al²⁷ proposed a validated single-question checklist to screen for sexual dysfunction that is an efficient way to identify specific sexual concerns, guide selection of interventions, and facilitate patient-provider communication (Table 2).

Don’t judge and don’t make assumptions about sexuality and sexual practices.

Assure confidentiality.

Use simple, direct language that is appropriate for the patient’s age, ethnicity, culture, and level of health literacy.³

Take a thorough history (sexual and reproductive, medical-surgical, and psychosocial).

Perform a focused physical examination to evaluate for potential causes of pain (eg, infectious causes, vulvar dermatoses, pelvic floor muscle dysfunction). The examination is also an opportunity to teach the patient about anatomy and normal sexual function.

No standard laboratory tests or imaging studies are required for the assessment of sexual dysfunction.²⁸

IT’S NOT JUST PHYSICAL

Evaluation and treatment of female sexual dysfunction is guided by the biopsychosocial model, with potential influences from the biological, psychological, sociocultural, and interpersonal realms (Table 3).^29,30

Biological factors include pelvic surgery, cancer and its treatment, neurologic diseases, and vascular diseases. Medications, including antidepressants, narcotics, anticholinergics, antihistamines, antihypertensives, oral contraceptives, and antiestrogens may also adversely affect sexual response.²⁶

Psychological factors include a history of sexual abuse or trauma, body image concerns, distraction, stress, anxiety, depression, and personality disorders.²²

Sociocultural factors include lack of sex education, unrealistic expectations, cultural norms, and religious influences.

Relationship factors include conflict with one’s partner, lack of emotional intimacy, absence of a partner, and partner sexual dysfunction. While there appears to be a close link between sexual satisfaction and a woman’s relationship with her partner in correlational studies and in clinical experience, there has been little research about relationship factors and their contribution to desire and arousal concerns.³¹ Sexual dysfunction in one’s partner (eg, erectile dysfunction) has been shown to negatively affect the female partner’s sexual desire.³²

GENERAL APPROACH TO TREATMENT

In treating sexual health problems in women, we address contributing factors identified during the initial assessment.

A multidisciplinary approach

As sexual dysfunction in women is often multifactorial, management of the problem is well suited to a multidisciplinary approach. The team of providers may include:

• A medical provider (primary care provider, gynecologist, or sexual health specialist) to coordinate care and manage biological factors contributing to sexual dysfunction
• A physical therapist with expertise in treating pelvic floor disorders
• A psychologist to address psychological, relational, and sociocultural contributors to sexual dysfunction
• A sex therapist (womenshealthapta.org, aasect.org) to facilitate treatment of tight, tender pelvic floor muscles through education and guidance about kinesthetic awareness, muscle relaxation, and dilator therapy.³³

Even in the initial visit, the primary care provider can educate, reassure regarding normal sexual function, and treat conditions such as genitourinary syndrome of menopause and antidepressant-associated sexual dysfunction. The PLISSIT model (Permission, Limited Information, Specific Suggestions, and Intensive Therapy) is a useful tool for initiating counseling about sexual health (Table 4).³⁴

AGING VS MENOPAUSE

Aging can affect sexual function in both men and women. About 40% of women experience changes in sexual function around the menopausal transition, with common complaints being loss of sexual responsiveness and desire, sexual pain, decreased sexual activity, and partner sexual dysfunction.³⁵ However, studies seem to show that while menopause results in hormonal changes that affect sexual function, other factors may have a greater impact.

The Study of Women’s Health Across the Nation³⁶ found vaginal and pelvic pain and decreased sexual desire were associated with the menopausal transition, but other sexual health outcomes (frequency of sexual activities, arousal, importance of sex, emotional satisfaction, or physical pleasure) were not. Physical and psychological health, marital status, and a change in relationship were all associated with differences in sexual health.

The Massachusetts Women’s Health Study II³⁷ found a greater association between physical and mental health, relationship status, and smoking and women’s sexual functioning than menopausal status.

The Penn Ovarian Aging Study³⁸ found that sexual function declined across the menopausal transition. Risk factors for sexual dysfunction included postmenopausal status, anxiety, and absence of a sexual partner.

The Melbourne Women’s Midlife Health Project³⁹ also found that sexual function declined across the menopausal transition. Sexual dysfunction with distress was associated with relationship factors and depression.³⁷

Genitourinary syndrome of menopause and its treatment

As the ovaries shut down during menopause, estradiol levels decrease. Nearly 50% of women experience symptoms related to genitourinary syndrome of menopause (formerly called atrophic vaginitis or vulvovaginal atrophy).^40,41 These symptoms include vaginal dryness and discomfort or pain with sexual activity, but menopausal hormone loss can also result in reduced genital blood flow, decreased sensory perception, and decreased sexual responsiveness.²²

Estrogen is the most effective treatment for genitourinary syndrome of menopause, with low-dose vaginal preparations preferred over systemic ones for isolated vulvar and vaginal symptoms.⁴⁰ While estrogen is effective for vaginal dryness and sexual pain associated with estrogen loss, replacing estrogen systemically has not been associated with improvements in sexual desire.⁴²

Depression increases the risk of sexual dysfunction, and vice versa.

A meta-analysis that included 12 studies involving almost 15,000 patients confirmed that depression increased the risk of sexual dysfunction, and sexual dysfunction increased the risk of depression.⁴³ This interaction may be related to the overlap in affected neuro­transmitters and neuroendocrine systems.⁴⁴

In the Sequenced Treatment Alternatives to Relieve Depression trial, Ishak et al⁴⁵ found that patients treated with a selective serotonin reuptake inhibitor (SSRI) who experienced remission of depression had a lower prevalence of impaired sexual satisfaction and much greater improvements in sexual satisfaction than did those who remained depressed. The severity of depressive symptoms predicted impairment in sexual satisfaction, which in turn predicted poorer quality of life. The authors suggested that physicians encourage patients to remain on SSRI treatment, given that improvement in depressive symptoms is likely to improve sexual satisfaction.

Antidepressant-induced sexual dysfunction

As many as 70% of patients taking an SSRI or serotonin-norepinephrine reuptake inhibitor (SNRI) experience antidepressant-induced sexual dysfunction, though this is difficult to estimate across studies of different medications due to differences in methods and because many patients only report it when directly asked about it.⁴⁶

Treatment of antidepressant-induced sexual dysfunction includes not only optimal management of depression but reassessment of the antidepressant treatment. If using only nondrug treatments for the mood disorder is not feasible, switching to (or ideally, starting with) an antidepressant with fewer sexual side effects such as mirtazapine, vilazodone, or bupropion is an option.⁴⁶

A drug holiday (suspending antidepressant treatment for 1 or 2 days) has been suggested as a means of treating antidepressant-induced sexual dysfunction, but this may result in poorer control of depressive symptoms and discontinuation symptoms, and it encourages medication noncompliance.^46,47

Treatment with a phosphodiesterase type 5 inhibitor (eg, sildenafil) has been studied in women with antidepressant-induced sexual dysfunction, with modest results.⁴⁸

A Cochrane review reported that treatment with bupropion shows promise at higher doses (300 mg daily).⁴⁹

Exercise for 20 minutes 3 times weekly is associated with improvement in antidepressant-induced sexual dysfunction when the exercise is performed immediately before sexual activity.⁵⁰

LOW SEXUAL DESIRE

Hypoactive sexual desire disorder is defined as persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity associated with marked distress and not due exclusively to a medication, substance abuse, or a medical condition.

Low or decreased sexual desire is the most commonly reported sexual health concern in women of all ages, with an unadjusted prevalence of 39.7%. When the criterion of personal distress is included, the prevalence is 8.9% in women ages 18 to 44, 12.3% in women ages 45 to 64, and 7.4% in women ages 65 and older.¹

Multiple biological, psychological, and social factors may contribute to the problem. Identifying the ones that are present can help in planning treatment. A multifaceted approach may be appropriate.

Mindfulness and cognitive behavioral therapy for low sexual desire

Mindfulness-based cognitive therapy is designed to improve awareness, focusing on and accepting the present moment, and directing attention away from and lessening self-criticism and evaluation of one’s sexual responsiveness.

Mindfulness-based therapy has been associated with improvements in sexual desire and associated distress.⁵¹ Similarly, the effectiveness of cognitive behavioral therapy for treating hypoactive sexual desire disorder is supported by 3 controlled trials, although concerns exist about the adequacy of these trials, and further study is needed.⁵²

Androgen therapy in women

In randomized controlled trials in women with low sexual desire who were either naturally or surgically menopausal, sexual function improved with testosterone therapy that resulted in mostly supraphysiologic total testosterone levels (which may not reflect free testosterone levels) with or without concurrent estrogen treatment.^53–57

Testosterone is not approved by the US Food and Drug Administration (FDA) for use in women, primarily because of the lack of long-term safety and efficacy data (ie, beyond 24 months). However, studies have shown no evidence of increased risk of endometrial cancer or cardiovascular disease with testosterone dosed to achieve physiologic premenopausal levels.⁵⁸ Data on breast cancer risk are less clear, but observational studies over the last decade do not support an association with testosterone use in women.⁵⁸ There is no clearly defined androgen deficiency syndrome in women, and androgen levels do not reliably correlate with symptoms.⁵⁹

The Endocrine Society⁵⁹ guidelines endorse the use of testosterone in postmenopausal women with hypoactive sexual desire disorder. They say to aim for the midnormal premenopausal range and suggest discontinuing the drug if there is no response in 6 months. They recommend checking testosterone levels at baseline, after 3 to 6 weeks of therapy, and every 6 months to monitor for excessive use, to avoid supraphysiologic dosing and to evaluate for signs of androgen excess (eg, acne, hair growth). The use of products formulated for men or those formulated by pharmacies is discouraged; however, no FDA-approved products are currently available for use in women in the United States.

Flibanserin

A postsynaptic serotonin 5-HT1A receptor agonist and 5-HT2A receptor agonist, flibanserin was approved by the FDA in 2015 for treatment of hypoactive sexual desire disorder in premenopausal women. Its mechanism of action is likely through an effect on neurotransmitters that suppresses serotonin (which has sexually inhibitory effects) and promotes dopamine and norepinephrine (which have excitatory effects).⁶⁰

The efficacy of flibanserin has been demonstrated in 3 randomized controlled trials, with significant increases in the number of sexually satisfying events and in sexual desire scores and a decrease in distress associated with low sexual desire.^17­–19 While the increase in sexually satisfying events was modest (about 1 extra event per month), some have suggested that the frequency of sexual activity may not be the best measure of sexual function in women.⁶¹ Further, responders to this drug showed a return to near-normal premenopausal frequencies of sexual activity in a separate analysis.⁶¹

The drug is generally well tolerated, with common adverse effects being somnolence, dizziness, and fatigue.^18,19 Flibanserin has been associated with orthostatic hypotension with alcohol use and carries a boxed warning highlighting this potential interaction.⁶² Use of this drug is contraindicated in women who drink alcohol or take medications that are moderate or strong inhibitors of CYP-3A4 (eg, some antiretroviral drugs, antihypertensive drugs, antibiotics, and fluconazole, which can increase systemic exposure to flibanserin and potential side effects), and in those with liver impairment.

Female sexual arousal disorder is the persistent or recurrent inability to attain or maintain an adequate lubrication-swelling response of sexual excitement. Sexual arousal results from a complex interaction between genital response, central nervous system activity, and information processing of the sexual stimulus. Difficulty with sexual arousal can result from neurovascular or neuroendocrine dysfunction or impaired central nervous system processing.

Women may experience a mismatch between subjective and objective genital arousal. A subjective report of decreased genital arousal may not be confirmed with measurement of vaginal pulse amplitude by photoplethysmography.⁶³ Even in postmenopausal women, in the absence of significant neurovascular or neuroendocrine dysfunction, it is likely that either contextual or relational variables resulting in inadequate sexual stimulation or cognitive inhibition are more important factors contributing to difficulty with sexual arousal.⁶³

Although there are no standard recommendations for evaluation of arousal disorders and advanced testing is often unnecessary, nerve function can be assessed with genital sensory testing utilizing thermal and vibratory threshholds⁶⁴; vaginal blood flow can be assessed with vaginal photoplethysmography⁶³; and imaging of the spine and pelvis can help to rule out neurovascular pathology.

Treatment of arousal disorders

As with other forms of female sexual dysfunction, treatment of arousal disorders includes addressing contributing factors.

Although there are few data from randomized controlled trials, psychological treatments such as sensate focus exercises and masturbation training have been suggested, centered on women becoming more self-focused and assertive.³¹ Sensate focus exercises are a series of graded, nondemand, sensual touching exercises aimed at reducing anxiety and avoidance of sexual activity, and improving sexual communication and intimacy by the gradual reintroduction of sexual activity.⁶⁵ More recently, mindfulness-based cognitive therapy has been associated with improvements in sexual arousal as well as other parameters of sexual function.⁵¹

Currently, no pharmacologic treatments are recommended for arousal disorders because of a lack of evidence of efficacy and because of adverse effects.³¹

ORGASMIC DISORDER

Female orgasmic disorder is the marked delay, marked infrequency, or absence of orgasm, or markedly reduced intensity of orgasm.

Important considerations in evaluating orgasm disorders include psychosocial factors (eg, lack of sex education, negative feelings about sex, religiosity), psychological factors (eg, anxiety, depression, body image concerns), relational factors (eg, communication issues, lack of emotional intimacy, partner sexual dysfunction), adverse childhood or adult experiences (eg, physical, sexual, or emotional or verbal abuse), medical history (pelvic surgery, neurologic, or vascular disease) and medications (eg, SSRIs, SNRIs, and antipsychotic medications).⁶⁶

Treatment of orgasmic disorder

Involving the partner in treatment is important, particularly if the difficulty with orgasm is acquired and only occurs with sex with a partner. Using the PLISSIT model to provide targeted, office-based interventions can be helpful.

Behavioral therapies such as directed masturbation, sensate focus exercises, or a combination of these have been shown to be effective, as has coital alignment during intercourse (positioning of male partner with his pelvis above the pubic bone of his partner to maximize clitoral stimulation with penile penetration).⁶⁶

Hormonal therapy may be useful in postmenopausal women. However, there are no data on it for women whose primary complaint is female orgasmic disorder, and further study is needed.⁶⁶

SEXUAL PAIN DISORDERS

The DSM-5 describes genitopelvic pain/penetration disorder as fear or anxiety, marked tightening or tensing of abdominal and pelvic muscles, or actual pain with vaginal penetration that is recurrent or persistent for a minimum of 6 months.¹⁴ Pain may occur with initial penetration, with deeper thrusting, or both.

Although the DSM-5 definition focuses on pain with penetration, it is important to recognize and ask about noncoital sexual pain. Women may also present with persistent vulvar pain or pain at the vulvar vestibule with provocation, (eg, sexual activity, tampon insertion, sitting), also known as provoked vestibulodynia.

Assessment of vaginal and vulvar pain includes a directed history and physical examination aimed at identifying potential etiologies or contributing factors, including infectious, inflammatory, neoplastic, neurologic, traumatic, iatrogenic, or factors related to hormonal deficiency.⁶⁷

Treatment of sexual pain

Removal of offending agents is a first step. This includes a thorough review of vulvar and vaginal hygiene practices and emphasis on avoiding the use of any product containing potential irritants (eg, soaps or detergents containing perfumes or dyes) and using lubricants and moisturizers without gimmicks (no warming or tingling agents or flavors). Oral contraceptives have been associated with vestibulodynia, and women in whom the sexual pain started when they started an oral contraceptive may benefit from switching to an alternate form of contraception.⁶⁸

Dysfunction of pelvic floor muscles may result in sexual pain and may be a primary problem or a secondary complication related to other issues such as symptomatic genitourinary syndrome of menopause. The symptoms of nonrelaxing pelvic floor dysfunction (also known as hypertonic pelvic floor dysfunction or pelvic floor tension myalgia) include pain in the pelvis with sexual activity that may linger for hours or even days, and may also include bowel and bladder dysfunction and low back pain or hip pain radiating to the thighs or groin.³³ Physical therapy under the care of a physical therapist with expertise in the management of pelvic floor disorders is the cornerstone of treatment for this condition.³³

Treatment of the genital and urinary symptoms related to loss of estrogen after menopause (genitourinary syndrome of menopause) includes the use of vaginal lubricants with sexual activity and vaginal moisturizers on a regular basis (2 to 5 times per week).⁴⁰ Low-dose vaginal estrogen creams, rings, or tablets and the oral selective estrogen receptor antagonist ospemifene are recommended for moderate to severe symptoms of genitourinary syndrome of menopause.⁴⁰ Intravaginal dehydroepiandrosterone was recently approved by the FDA for treatment of dyspareunia associated with menopause.⁶⁹ Topical lidocaine applied to the introitus before sexual activity has been found to be effective for reducing sexual pain in women with breast cancer, and when used in combination with vaginal lubricants and moisturizers is a practical option for women, particularly those unable to use estrogen-based therapies.⁷⁰

A 38-year-old man presented with a burning sensation in the mouth for the previous 2 months. He was currently a smoker. He had no history of any dental procedure or new drug intake.

On examination, his oral hygiene was poor, and a whitish, striated lesion 3-by-3 cm was noted on the left buccal mucosa (Figure 1). Based on the appearance and pattern of the lesion, a clinical diagnosis of reticular-type oral lichen planus was made. The patient was advised to stop smoking. A thorough scaling of the teeth was done, and he was started on topical triamcinolone acetonide ointment for 2 weeks. At a 4-month follow-up visit, the symptoms had resolved.

ORAL LICHEN PLANUS

Oral lichen planus is a chronic inflammatory disease that affects the mucous membrane of the oral cavity. It is a T-cell mediated autoimmune disease in which the cytotoxic CD8+ T cells trigger apoptosis of the basal cells of the oral epithelium.¹ No risk factors have been identified, but the condition has been associated with smoking, chewing tobacco, dental materials such as amalgam, celiac disease, ulcerative colitis, stress, diabetes, and use of systemic drugs such as nonsteroidal anti-inflammatory drugs and beta-blockers.^1,2 Women are affected more than men in a ratio of 1.4:1, frequently in the fourth decade.

The clinical forms are reticular, papular, plaque-like, erosive, atrophic, and bullous types.

Clinical presentation

The lesions are usually asymptomatic. Symptoms such as a burning sensation are associated mainly with the erosive and atrophic types,^1–3 although in rare cases it occurs with the reticular form, as in our patient. Erosive and atrophic types carry a 1% to 2% risk of malignant transformation and require close follow-up.³

Oral mucosal lesions present alone or, in up to 15% to 20% of cases, with concomitant skin lesions.^1,2 The most common oral sites are the buccal mucosa, tongue, and gingiva. Skin lesions present as violaceous flat-topped papules on the ankles, wrists, and genitalia.

DIAGNOSIS AND TREATMENT

The differential diagnosis of oral lichen planus includes cheek-frictional keratosis, lichenoid reaction, leukoplakia, pemphigus, oral candidiasis, and chronic ulcerative stomatitis.^1,2

The diagnosis is clinical, but biopsy is indicated in the erosive or atrophic type and when a malignant lesion is suspected, especially in patients with a history of smoking and tobacco chewing. Oral lichen planus may be associated with oral candidiasis, especially in patients with poor oral hygiene and smoking, and this needs to be addressed before a diagnosis of oral lichen planus can be made.

The mainstay of management is oral or topical corticosteroids.⁴ Calcineurin inhibitors, retinoids, dapsone, hydroxychloroquine, mycophenolate mofetil, and enoxaparin have also been shown to be effective and are used when corticosteroids alone are ineffective or contraindicated.⁴

A 38-year-old man presented with a burning sensation in the mouth for the previous 2 months. He was currently a smoker. He had no history of any dental procedure or new drug intake.

On examination, his oral hygiene was poor, and a whitish, striated lesion 3-by-3 cm was noted on the left buccal mucosa (Figure 1). Based on the appearance and pattern of the lesion, a clinical diagnosis of reticular-type oral lichen planus was made. The patient was advised to stop smoking. A thorough scaling of the teeth was done, and he was started on topical triamcinolone acetonide ointment for 2 weeks. At a 4-month follow-up visit, the symptoms had resolved.

ORAL LICHEN PLANUS

Oral lichen planus is a chronic inflammatory disease that affects the mucous membrane of the oral cavity. It is a T-cell mediated autoimmune disease in which the cytotoxic CD8+ T cells trigger apoptosis of the basal cells of the oral epithelium.¹ No risk factors have been identified, but the condition has been associated with smoking, chewing tobacco, dental materials such as amalgam, celiac disease, ulcerative colitis, stress, diabetes, and use of systemic drugs such as nonsteroidal anti-inflammatory drugs and beta-blockers.^1,2 Women are affected more than men in a ratio of 1.4:1, frequently in the fourth decade.

The clinical forms are reticular, papular, plaque-like, erosive, atrophic, and bullous types.

Clinical presentation

The lesions are usually asymptomatic. Symptoms such as a burning sensation are associated mainly with the erosive and atrophic types,^1–3 although in rare cases it occurs with the reticular form, as in our patient. Erosive and atrophic types carry a 1% to 2% risk of malignant transformation and require close follow-up.³

Oral mucosal lesions present alone or, in up to 15% to 20% of cases, with concomitant skin lesions.^1,2 The most common oral sites are the buccal mucosa, tongue, and gingiva. Skin lesions present as violaceous flat-topped papules on the ankles, wrists, and genitalia.

DIAGNOSIS AND TREATMENT

The differential diagnosis of oral lichen planus includes cheek-frictional keratosis, lichenoid reaction, leukoplakia, pemphigus, oral candidiasis, and chronic ulcerative stomatitis.^1,2

The diagnosis is clinical, but biopsy is indicated in the erosive or atrophic type and when a malignant lesion is suspected, especially in patients with a history of smoking and tobacco chewing. Oral lichen planus may be associated with oral candidiasis, especially in patients with poor oral hygiene and smoking, and this needs to be addressed before a diagnosis of oral lichen planus can be made.

The mainstay of management is oral or topical corticosteroids.⁴ Calcineurin inhibitors, retinoids, dapsone, hydroxychloroquine, mycophenolate mofetil, and enoxaparin have also been shown to be effective and are used when corticosteroids alone are ineffective or contraindicated.⁴

A 38-year-old man presented with a burning sensation in the mouth for the previous 2 months. He was currently a smoker. He had no history of any dental procedure or new drug intake.

On examination, his oral hygiene was poor, and a whitish, striated lesion 3-by-3 cm was noted on the left buccal mucosa (Figure 1). Based on the appearance and pattern of the lesion, a clinical diagnosis of reticular-type oral lichen planus was made. The patient was advised to stop smoking. A thorough scaling of the teeth was done, and he was started on topical triamcinolone acetonide ointment for 2 weeks. At a 4-month follow-up visit, the symptoms had resolved.

ORAL LICHEN PLANUS

Oral lichen planus is a chronic inflammatory disease that affects the mucous membrane of the oral cavity. It is a T-cell mediated autoimmune disease in which the cytotoxic CD8+ T cells trigger apoptosis of the basal cells of the oral epithelium.¹ No risk factors have been identified, but the condition has been associated with smoking, chewing tobacco, dental materials such as amalgam, celiac disease, ulcerative colitis, stress, diabetes, and use of systemic drugs such as nonsteroidal anti-inflammatory drugs and beta-blockers.^1,2 Women are affected more than men in a ratio of 1.4:1, frequently in the fourth decade.

The clinical forms are reticular, papular, plaque-like, erosive, atrophic, and bullous types.

Clinical presentation

The lesions are usually asymptomatic. Symptoms such as a burning sensation are associated mainly with the erosive and atrophic types,^1–3 although in rare cases it occurs with the reticular form, as in our patient. Erosive and atrophic types carry a 1% to 2% risk of malignant transformation and require close follow-up.³

Oral mucosal lesions present alone or, in up to 15% to 20% of cases, with concomitant skin lesions.^1,2 The most common oral sites are the buccal mucosa, tongue, and gingiva. Skin lesions present as violaceous flat-topped papules on the ankles, wrists, and genitalia.

DIAGNOSIS AND TREATMENT

The differential diagnosis of oral lichen planus includes cheek-frictional keratosis, lichenoid reaction, leukoplakia, pemphigus, oral candidiasis, and chronic ulcerative stomatitis.^1,2

The diagnosis is clinical, but biopsy is indicated in the erosive or atrophic type and when a malignant lesion is suspected, especially in patients with a history of smoking and tobacco chewing. Oral lichen planus may be associated with oral candidiasis, especially in patients with poor oral hygiene and smoking, and this needs to be addressed before a diagnosis of oral lichen planus can be made.

The mainstay of management is oral or topical corticosteroids.⁴ Calcineurin inhibitors, retinoids, dapsone, hydroxychloroquine, mycophenolate mofetil, and enoxaparin have also been shown to be effective and are used when corticosteroids alone are ineffective or contraindicated.⁴

We routinely use low-volume (2-L) polyethylene glycol electrolyte preparations such as Moviprep and Miralax in split-dose regimens, in which patients drink half of the preparation the day before the procedure and the other half the day of the procedure. In our experience, these are well tolerated by patients with a history of bariatric surgery and provide adequate colon cleansing before colonoscopy.

RATIONALE

Adequate bowel preparation by the ingestion of a cleansing agent is extremely important before colonoscopy: the quality of colon preparation affects the diagnostic accuracy and safety of the procedure, as inadequate bowel preparation has been associated with failure to detect polyps and with a higher rate of adverse events during the procedure.^1–3

The most commonly used bowel preparations can be divided into high-volume (which require drinking at least 4 L of a cathartic solution) and low-volume (which require drinking about 2 L).⁴ Polyethylene glycol electrolyte solutions are among the most commonly used and are available in both high-volume (eg, Golytely, Nulytely) and low-volume (eg, Moviprep, Miralax) forms.

Other low-volume preparations include sodium picosulfate (Prepopik), magnesium citrate, and sodium phosphate tablets. However, these should be avoided in patients with renal insufficiency.⁴

Prices for bowel preparations vary. For example, the average reported wholesale price of Golytely is $24.56, Moviprep $81.17, and Miralax $10.08.⁴ However, the final cost depends on the patient’s insurance coverage. Generic formulations are available for some preparations.

After bariatric surgery, patients have a smaller stomach

After bariatric surgery, patients have significantly reduced stomach volume, due either to resection of a part of the stomach (such as in partial gastrectomy) or to diversion of the gastrointestinal (GI) tract to bypass most of the stomach (such as in Roux-en-Y gastric bypass). This causes early satiety with smaller amounts of food and leads to weight loss. However, this restriction in stomach volume also makes it more difficult for the patient to tolerate the intake of large volumes of fluids for bowel cleansing before colonoscopy.

Bariatric surgery patients may require colonoscopy for indications such as colorectal cancer screening, chronic diarrhea, or GI bleeding, all of which are commonly encountered during routine clinical practice.

Guidelines are available

Currently, there are no published data available to support the use of one preparation over another in patients with a history of bariatric surgery. However, for patients who have had bariatric surgery, guidelines from the US Multi-Society Task Force on Colorectal Cancer—endorsed by the three major American gastroenterology societies, ie, the American Gastroenterological Association, the American College of Gastroenterology, and the American Society for Gastrointestinal Endoscopy—recommend either a low-volume solution or, if a high-volume solution is used, extending the duration over which the preparation is consumed.⁵ In addition, it is recommended that patients consume sugar-free drinks and liquids to avoid dumping syndrome from high sugar content.⁶

The use of split-dose regimens is also strongly recommended for elective colonoscopy by the US Multi-Society Task Force on Colorectal Cancer.⁵

Our clinical experience has been in line with the above recommendations.

We routinely use low-volume (2-L) polyethylene glycol electrolyte preparations such as Moviprep and Miralax in split-dose regimens, in which patients drink half of the preparation the day before the procedure and the other half the day of the procedure. In our experience, these are well tolerated by patients with a history of bariatric surgery and provide adequate colon cleansing before colonoscopy.

RATIONALE

Adequate bowel preparation by the ingestion of a cleansing agent is extremely important before colonoscopy: the quality of colon preparation affects the diagnostic accuracy and safety of the procedure, as inadequate bowel preparation has been associated with failure to detect polyps and with a higher rate of adverse events during the procedure.^1–3

The most commonly used bowel preparations can be divided into high-volume (which require drinking at least 4 L of a cathartic solution) and low-volume (which require drinking about 2 L).⁴ Polyethylene glycol electrolyte solutions are among the most commonly used and are available in both high-volume (eg, Golytely, Nulytely) and low-volume (eg, Moviprep, Miralax) forms.

Other low-volume preparations include sodium picosulfate (Prepopik), magnesium citrate, and sodium phosphate tablets. However, these should be avoided in patients with renal insufficiency.⁴

Prices for bowel preparations vary. For example, the average reported wholesale price of Golytely is $24.56, Moviprep $81.17, and Miralax $10.08.⁴ However, the final cost depends on the patient’s insurance coverage. Generic formulations are available for some preparations.

After bariatric surgery, patients have a smaller stomach

After bariatric surgery, patients have significantly reduced stomach volume, due either to resection of a part of the stomach (such as in partial gastrectomy) or to diversion of the gastrointestinal (GI) tract to bypass most of the stomach (such as in Roux-en-Y gastric bypass). This causes early satiety with smaller amounts of food and leads to weight loss. However, this restriction in stomach volume also makes it more difficult for the patient to tolerate the intake of large volumes of fluids for bowel cleansing before colonoscopy.

Bariatric surgery patients may require colonoscopy for indications such as colorectal cancer screening, chronic diarrhea, or GI bleeding, all of which are commonly encountered during routine clinical practice.

Guidelines are available

Currently, there are no published data available to support the use of one preparation over another in patients with a history of bariatric surgery. However, for patients who have had bariatric surgery, guidelines from the US Multi-Society Task Force on Colorectal Cancer—endorsed by the three major American gastroenterology societies, ie, the American Gastroenterological Association, the American College of Gastroenterology, and the American Society for Gastrointestinal Endoscopy—recommend either a low-volume solution or, if a high-volume solution is used, extending the duration over which the preparation is consumed.⁵ In addition, it is recommended that patients consume sugar-free drinks and liquids to avoid dumping syndrome from high sugar content.⁶

The use of split-dose regimens is also strongly recommended for elective colonoscopy by the US Multi-Society Task Force on Colorectal Cancer.⁵

Our clinical experience has been in line with the above recommendations.

We routinely use low-volume (2-L) polyethylene glycol electrolyte preparations such as Moviprep and Miralax in split-dose regimens, in which patients drink half of the preparation the day before the procedure and the other half the day of the procedure. In our experience, these are well tolerated by patients with a history of bariatric surgery and provide adequate colon cleansing before colonoscopy.

RATIONALE

Adequate bowel preparation by the ingestion of a cleansing agent is extremely important before colonoscopy: the quality of colon preparation affects the diagnostic accuracy and safety of the procedure, as inadequate bowel preparation has been associated with failure to detect polyps and with a higher rate of adverse events during the procedure.^1–3

The most commonly used bowel preparations can be divided into high-volume (which require drinking at least 4 L of a cathartic solution) and low-volume (which require drinking about 2 L).⁴ Polyethylene glycol electrolyte solutions are among the most commonly used and are available in both high-volume (eg, Golytely, Nulytely) and low-volume (eg, Moviprep, Miralax) forms.

Other low-volume preparations include sodium picosulfate (Prepopik), magnesium citrate, and sodium phosphate tablets. However, these should be avoided in patients with renal insufficiency.⁴

Prices for bowel preparations vary. For example, the average reported wholesale price of Golytely is $24.56, Moviprep $81.17, and Miralax $10.08.⁴ However, the final cost depends on the patient’s insurance coverage. Generic formulations are available for some preparations.

After bariatric surgery, patients have a smaller stomach

After bariatric surgery, patients have significantly reduced stomach volume, due either to resection of a part of the stomach (such as in partial gastrectomy) or to diversion of the gastrointestinal (GI) tract to bypass most of the stomach (such as in Roux-en-Y gastric bypass). This causes early satiety with smaller amounts of food and leads to weight loss. However, this restriction in stomach volume also makes it more difficult for the patient to tolerate the intake of large volumes of fluids for bowel cleansing before colonoscopy.

Bariatric surgery patients may require colonoscopy for indications such as colorectal cancer screening, chronic diarrhea, or GI bleeding, all of which are commonly encountered during routine clinical practice.

Guidelines are available

Currently, there are no published data available to support the use of one preparation over another in patients with a history of bariatric surgery. However, for patients who have had bariatric surgery, guidelines from the US Multi-Society Task Force on Colorectal Cancer—endorsed by the three major American gastroenterology societies, ie, the American Gastroenterological Association, the American College of Gastroenterology, and the American Society for Gastrointestinal Endoscopy—recommend either a low-volume solution or, if a high-volume solution is used, extending the duration over which the preparation is consumed.⁵ In addition, it is recommended that patients consume sugar-free drinks and liquids to avoid dumping syndrome from high sugar content.⁶

The use of split-dose regimens is also strongly recommended for elective colonoscopy by the US Multi-Society Task Force on Colorectal Cancer.⁵

Our clinical experience has been in line with the above recommendations.

A 48-year-old Nicaraguan man underwent mag netic resonance imaging (MRI) 3 days after admission to a South Florida hospital for treatment of cellulitis of the right thigh with vancomycin. MRI had been ordered to evaluate for a possible drainable source of infection, as the clinical picture and duration of illness was worsening and longer than expected for typical uncomplicated cellulitis despite intravenous antibiotic therapy. The MRI showed multiple enlarged inguinal lymph nodes and cellulitis of the superficial soft tissues of the thigh without discrete drainable collections.

After the procedure, the patient was noted to have a bullous lesion on each thigh, each lesion roughly 1 cm in diameter and filled with clear serous fluid (Figure 1). He reported that his legs had been pressed together before entering the MRI machine and that he had felt a burning sensation in both thighs during the test. Examination confirmed that the lesions indeed aligned with each other when he pressed his thighs together.

Study of a biopsy of one of the lesions revealed subepidermal cell blisters with focal epidermal necrosis and coagulative changes in the superficial dermis, consistent with a thermal injury (Figure 2).

HOW BURNS CAN OCCUR DURING MRI

Thermal burns are a potential cause of injury during MRI. Most have been observed in patients connected to external metal-containing monitoring devices, such as electrocardiogram leads and pulse oximeters.^1,2 Thermal burns  in patients unconnected to external devices have occurred when the patient’s body was touching radiofrequency coils³ or, as with our patient, when skin touches skin.^2,4,5 Skin-to-skin contact during MRI can cause the scanner to emit high-power electromagnetic radiofrequency pulses that are conducted through the body, creating heat. Tissue loops are created at points of skin-to-skin contact, thus forming a closed conducting circuit. The current flowing through this circuit can produce second-degree burns.⁴

We believe that during placement in the scanner, our patient inadvertently moved his thighs together, forming a closed loop conduction circuit and resulting in a thermal burn.

This case illustrates the importance of correct positioning during MRI. The MRI technicians had taken standard precautions, placing a sheet over the patient and ensuring no direct contact with the radiofrequency transmitter receiver (MR unit). However, precautions against skin-to-skin contact were not taken, and the patient’s legs were not separated.

LESSONS LEARNED

Appropriate positioning prevents closed skin-to-skin loops, but this may be more challenging in a larger patient.⁶ While the patient is in the scanner, a “squeeze ball” alert system allows the patient to signal the technologist should unexpected distress or heating occur.^6,7 A patient’s inability to utilize the squeeze ball contributes to the risk of a severe injury. Further, in this instance, there may have been a language barrier. Also, proximity of the anatomic skin-to-skin loop to the imaged body part (and therefore the center of the MRI coil) may have conferred risk related to field strength in this patient.

The MRI technologist, under supervision of a radiologist, is primarily responsible for positioning the patient to decrease the risk of this complication and for following institutional MRI safety protocols and professional guidelines.^6–8 MRI technologist certification training highlights all aspects of safety, including skin-to-skin conducting loop prevention.^7,8

A 48-year-old Nicaraguan man underwent mag netic resonance imaging (MRI) 3 days after admission to a South Florida hospital for treatment of cellulitis of the right thigh with vancomycin. MRI had been ordered to evaluate for a possible drainable source of infection, as the clinical picture and duration of illness was worsening and longer than expected for typical uncomplicated cellulitis despite intravenous antibiotic therapy. The MRI showed multiple enlarged inguinal lymph nodes and cellulitis of the superficial soft tissues of the thigh without discrete drainable collections.

After the procedure, the patient was noted to have a bullous lesion on each thigh, each lesion roughly 1 cm in diameter and filled with clear serous fluid (Figure 1). He reported that his legs had been pressed together before entering the MRI machine and that he had felt a burning sensation in both thighs during the test. Examination confirmed that the lesions indeed aligned with each other when he pressed his thighs together.

Study of a biopsy of one of the lesions revealed subepidermal cell blisters with focal epidermal necrosis and coagulative changes in the superficial dermis, consistent with a thermal injury (Figure 2).

HOW BURNS CAN OCCUR DURING MRI

Thermal burns are a potential cause of injury during MRI. Most have been observed in patients connected to external metal-containing monitoring devices, such as electrocardiogram leads and pulse oximeters.^1,2 Thermal burns  in patients unconnected to external devices have occurred when the patient’s body was touching radiofrequency coils³ or, as with our patient, when skin touches skin.^2,4,5 Skin-to-skin contact during MRI can cause the scanner to emit high-power electromagnetic radiofrequency pulses that are conducted through the body, creating heat. Tissue loops are created at points of skin-to-skin contact, thus forming a closed conducting circuit. The current flowing through this circuit can produce second-degree burns.⁴

We believe that during placement in the scanner, our patient inadvertently moved his thighs together, forming a closed loop conduction circuit and resulting in a thermal burn.

This case illustrates the importance of correct positioning during MRI. The MRI technicians had taken standard precautions, placing a sheet over the patient and ensuring no direct contact with the radiofrequency transmitter receiver (MR unit). However, precautions against skin-to-skin contact were not taken, and the patient’s legs were not separated.

LESSONS LEARNED

Appropriate positioning prevents closed skin-to-skin loops, but this may be more challenging in a larger patient.⁶ While the patient is in the scanner, a “squeeze ball” alert system allows the patient to signal the technologist should unexpected distress or heating occur.^6,7 A patient’s inability to utilize the squeeze ball contributes to the risk of a severe injury. Further, in this instance, there may have been a language barrier. Also, proximity of the anatomic skin-to-skin loop to the imaged body part (and therefore the center of the MRI coil) may have conferred risk related to field strength in this patient.

The MRI technologist, under supervision of a radiologist, is primarily responsible for positioning the patient to decrease the risk of this complication and for following institutional MRI safety protocols and professional guidelines.^6–8 MRI technologist certification training highlights all aspects of safety, including skin-to-skin conducting loop prevention.^7,8

A 48-year-old Nicaraguan man underwent mag netic resonance imaging (MRI) 3 days after admission to a South Florida hospital for treatment of cellulitis of the right thigh with vancomycin. MRI had been ordered to evaluate for a possible drainable source of infection, as the clinical picture and duration of illness was worsening and longer than expected for typical uncomplicated cellulitis despite intravenous antibiotic therapy. The MRI showed multiple enlarged inguinal lymph nodes and cellulitis of the superficial soft tissues of the thigh without discrete drainable collections.

After the procedure, the patient was noted to have a bullous lesion on each thigh, each lesion roughly 1 cm in diameter and filled with clear serous fluid (Figure 1). He reported that his legs had been pressed together before entering the MRI machine and that he had felt a burning sensation in both thighs during the test. Examination confirmed that the lesions indeed aligned with each other when he pressed his thighs together.

Study of a biopsy of one of the lesions revealed subepidermal cell blisters with focal epidermal necrosis and coagulative changes in the superficial dermis, consistent with a thermal injury (Figure 2).

HOW BURNS CAN OCCUR DURING MRI

Thermal burns are a potential cause of injury during MRI. Most have been observed in patients connected to external metal-containing monitoring devices, such as electrocardiogram leads and pulse oximeters.^1,2 Thermal burns  in patients unconnected to external devices have occurred when the patient’s body was touching radiofrequency coils³ or, as with our patient, when skin touches skin.^2,4,5 Skin-to-skin contact during MRI can cause the scanner to emit high-power electromagnetic radiofrequency pulses that are conducted through the body, creating heat. Tissue loops are created at points of skin-to-skin contact, thus forming a closed conducting circuit. The current flowing through this circuit can produce second-degree burns.⁴

We believe that during placement in the scanner, our patient inadvertently moved his thighs together, forming a closed loop conduction circuit and resulting in a thermal burn.

This case illustrates the importance of correct positioning during MRI. The MRI technicians had taken standard precautions, placing a sheet over the patient and ensuring no direct contact with the radiofrequency transmitter receiver (MR unit). However, precautions against skin-to-skin contact were not taken, and the patient’s legs were not separated.

LESSONS LEARNED

Appropriate positioning prevents closed skin-to-skin loops, but this may be more challenging in a larger patient.⁶ While the patient is in the scanner, a “squeeze ball” alert system allows the patient to signal the technologist should unexpected distress or heating occur.^6,7 A patient’s inability to utilize the squeeze ball contributes to the risk of a severe injury. Further, in this instance, there may have been a language barrier. Also, proximity of the anatomic skin-to-skin loop to the imaged body part (and therefore the center of the MRI coil) may have conferred risk related to field strength in this patient.

The MRI technologist, under supervision of a radiologist, is primarily responsible for positioning the patient to decrease the risk of this complication and for following institutional MRI safety protocols and professional guidelines.^6–8 MRI technologist certification training highlights all aspects of safety, including skin-to-skin conducting loop prevention.^7,8

To the Editor: I enjoyed the article “Serotonin syndrome: Preventing, recognizing, and treating it.”¹ I am a relatively new internal medicine physician, out of residency only 1 year, and sadly I felt that the psychiatric training I received was minimal at best. Therefore, I was very excited to read more about serotonin syndrome since such a large percentage of my patients are on selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors.

Could you speak to the time frame it takes for serotonin syndrome to develop? For instance, if someone is taking an SSRI and develops a terrible yeast infection, would 3 doses of fluconazole be enough to tip the scales? Or as-needed sumatriptan, with some ondansetron for migraine? The problem I have is that patients often require short doses of many medications that can interact, and I routinely sigh, briefly explain the possibility of serotonin syndrome, and then click through the flashing red warning signs on the electronic medical record and send patients out with their meds—though in honesty I do not know the likelihood of developing even mild symptoms of serotonin syndrome with short courses of interacting medications.

To the Editor: I enjoyed the article “Serotonin syndrome: Preventing, recognizing, and treating it.”¹ I am a relatively new internal medicine physician, out of residency only 1 year, and sadly I felt that the psychiatric training I received was minimal at best. Therefore, I was very excited to read more about serotonin syndrome since such a large percentage of my patients are on selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors.

Could you speak to the time frame it takes for serotonin syndrome to develop? For instance, if someone is taking an SSRI and develops a terrible yeast infection, would 3 doses of fluconazole be enough to tip the scales? Or as-needed sumatriptan, with some ondansetron for migraine? The problem I have is that patients often require short doses of many medications that can interact, and I routinely sigh, briefly explain the possibility of serotonin syndrome, and then click through the flashing red warning signs on the electronic medical record and send patients out with their meds—though in honesty I do not know the likelihood of developing even mild symptoms of serotonin syndrome with short courses of interacting medications.

To the Editor: I enjoyed the article “Serotonin syndrome: Preventing, recognizing, and treating it.”¹ I am a relatively new internal medicine physician, out of residency only 1 year, and sadly I felt that the psychiatric training I received was minimal at best. Therefore, I was very excited to read more about serotonin syndrome since such a large percentage of my patients are on selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors.

Could you speak to the time frame it takes for serotonin syndrome to develop? For instance, if someone is taking an SSRI and develops a terrible yeast infection, would 3 doses of fluconazole be enough to tip the scales? Or as-needed sumatriptan, with some ondansetron for migraine? The problem I have is that patients often require short doses of many medications that can interact, and I routinely sigh, briefly explain the possibility of serotonin syndrome, and then click through the flashing red warning signs on the electronic medical record and send patients out with their meds—though in honesty I do not know the likelihood of developing even mild symptoms of serotonin syndrome with short courses of interacting medications.

In Reply: The questions posed by Dr. Rose reflect critical issues primary care physicians encounter when prescribing medications for patients who are taking serotonergic agents. “Switching strategies” have been described for starting or discontinuing serotonergic antidepressants.¹ Options range from conservative exchanges requiring 5 half-lives between discontinuation of 1 antidepressant and initiation of another vs a direct cross-taper exchange. Decisions regarding specific patients should take into account previous adverse effects from serotonergic medications and half-lives of discontinued antidepressants. To our knowledge, switching strategies have not been validated and are based on expert opinion. Scenarios are complicated further if patients have already been prescribed 2 or more antidepressants and 1 medication is exchanged or dose-adjusted while another is added. With this degree of complexity, we recommend referral to a psychiatrist.

Dr. Rose’s questions on prescribing nonpsychiatric serotonergic drugs concurrently with antidepressants broaches a topic with even less evidence. Some data exist about nonpsychiatric serotonergic drugs given in combination with triptans. Soldin et al² reviewed the US Food and Drug Administration’s Adverse Event Reporting System and discovered 38 cases of serotonin syndrome in patients using triptans. Eleven of these patients were using triptans without concomitant antidepressants. Though definitive evidence is lacking for safe prescribing practice with triptans, the authors noted that most cases of triptan-induced serotonin toxicity occur within hours of triptan ingestion.²

The evidence on the risk of serotonin syndrome with other medications is limited to case reports. In regard to linezolid, a review suggested that when linezolid was administered to a patient on long-term citalopram, a prolonged serotonin syndrome was precipitated, which is not an issue with other antidepressants.³ The World Health Organization has issued warnings for serotonin toxicity with ondansetron and other 5-HT3 receptor antagonists based on case reports.^4,5 No data are available for the appropriate prescribing of 5-HT3 antagonists with antidepressants. A review of cases suggests a link between fluconazole and severe serotonin toxicity in patients taking citalopram; however, no prescribing guidelines have been established for fluconazole either.⁶

Dr. Rose asks important clinical questions, but evidence-based answers are not available.  We can only recommend that patients be advised to report symptoms immediately after starting any medication associated with serotonin syndrome. For patients on multiple antidepressants, psychiatric assistance is advised. An observational cohort study of patients using antidepressants while exposed to other suspect drugs may better delineate effects of several pharmaceuticals on the serotonergic axis. Only then may safe prescribing practices be validated with evidence.

In Reply: The questions posed by Dr. Rose reflect critical issues primary care physicians encounter when prescribing medications for patients who are taking serotonergic agents. “Switching strategies” have been described for starting or discontinuing serotonergic antidepressants.¹ Options range from conservative exchanges requiring 5 half-lives between discontinuation of 1 antidepressant and initiation of another vs a direct cross-taper exchange. Decisions regarding specific patients should take into account previous adverse effects from serotonergic medications and half-lives of discontinued antidepressants. To our knowledge, switching strategies have not been validated and are based on expert opinion. Scenarios are complicated further if patients have already been prescribed 2 or more antidepressants and 1 medication is exchanged or dose-adjusted while another is added. With this degree of complexity, we recommend referral to a psychiatrist.

Dr. Rose’s questions on prescribing nonpsychiatric serotonergic drugs concurrently with antidepressants broaches a topic with even less evidence. Some data exist about nonpsychiatric serotonergic drugs given in combination with triptans. Soldin et al² reviewed the US Food and Drug Administration’s Adverse Event Reporting System and discovered 38 cases of serotonin syndrome in patients using triptans. Eleven of these patients were using triptans without concomitant antidepressants. Though definitive evidence is lacking for safe prescribing practice with triptans, the authors noted that most cases of triptan-induced serotonin toxicity occur within hours of triptan ingestion.²

The evidence on the risk of serotonin syndrome with other medications is limited to case reports. In regard to linezolid, a review suggested that when linezolid was administered to a patient on long-term citalopram, a prolonged serotonin syndrome was precipitated, which is not an issue with other antidepressants.³ The World Health Organization has issued warnings for serotonin toxicity with ondansetron and other 5-HT3 receptor antagonists based on case reports.^4,5 No data are available for the appropriate prescribing of 5-HT3 antagonists with antidepressants. A review of cases suggests a link between fluconazole and severe serotonin toxicity in patients taking citalopram; however, no prescribing guidelines have been established for fluconazole either.⁶

Dr. Rose asks important clinical questions, but evidence-based answers are not available.  We can only recommend that patients be advised to report symptoms immediately after starting any medication associated with serotonin syndrome. For patients on multiple antidepressants, psychiatric assistance is advised. An observational cohort study of patients using antidepressants while exposed to other suspect drugs may better delineate effects of several pharmaceuticals on the serotonergic axis. Only then may safe prescribing practices be validated with evidence.

In Reply: The questions posed by Dr. Rose reflect critical issues primary care physicians encounter when prescribing medications for patients who are taking serotonergic agents. “Switching strategies” have been described for starting or discontinuing serotonergic antidepressants.¹ Options range from conservative exchanges requiring 5 half-lives between discontinuation of 1 antidepressant and initiation of another vs a direct cross-taper exchange. Decisions regarding specific patients should take into account previous adverse effects from serotonergic medications and half-lives of discontinued antidepressants. To our knowledge, switching strategies have not been validated and are based on expert opinion. Scenarios are complicated further if patients have already been prescribed 2 or more antidepressants and 1 medication is exchanged or dose-adjusted while another is added. With this degree of complexity, we recommend referral to a psychiatrist.

Dr. Rose’s questions on prescribing nonpsychiatric serotonergic drugs concurrently with antidepressants broaches a topic with even less evidence. Some data exist about nonpsychiatric serotonergic drugs given in combination with triptans. Soldin et al² reviewed the US Food and Drug Administration’s Adverse Event Reporting System and discovered 38 cases of serotonin syndrome in patients using triptans. Eleven of these patients were using triptans without concomitant antidepressants. Though definitive evidence is lacking for safe prescribing practice with triptans, the authors noted that most cases of triptan-induced serotonin toxicity occur within hours of triptan ingestion.²

The evidence on the risk of serotonin syndrome with other medications is limited to case reports. In regard to linezolid, a review suggested that when linezolid was administered to a patient on long-term citalopram, a prolonged serotonin syndrome was precipitated, which is not an issue with other antidepressants.³ The World Health Organization has issued warnings for serotonin toxicity with ondansetron and other 5-HT3 receptor antagonists based on case reports.^4,5 No data are available for the appropriate prescribing of 5-HT3 antagonists with antidepressants. A review of cases suggests a link between fluconazole and severe serotonin toxicity in patients taking citalopram; however, no prescribing guidelines have been established for fluconazole either.⁶

Dr. Rose asks important clinical questions, but evidence-based answers are not available.  We can only recommend that patients be advised to report symptoms immediately after starting any medication associated with serotonin syndrome. For patients on multiple antidepressants, psychiatric assistance is advised. An observational cohort study of patients using antidepressants while exposed to other suspect drugs may better delineate effects of several pharmaceuticals on the serotonergic axis. Only then may safe prescribing practices be validated with evidence.

Click here to access the May 2017 Digital Edition.

Table of Contents

• Providing Mental Health Care to All Veterans Regardless of Discharge Status
• Need for Mental Health Providers in Progressive Tinnitus Management
• Blood Loss and Need for Blood Transfusions in Total Knee and Total Hip Arthroplasty
• Peripheral Exudative Hemorrhagic Chorioretinopathy in Patients With Nonexudative Age-Related Macular Degeneration
• The Personal Health Inventory: Current Use, Perceived Barriers, and Benefits
• Dependence of Elevated Eosinophil Levels on Geographic Location
• The Design and Implementation of a Home-Based Cardiac Rehabilitation Program
• FRAX Prediction With and Without Bone Mineral Density Testing
• Improved Access to Drug Safety Labeling Changes Information
• Defining Pharmacy Leadership in the VA
• VA Nurses Advocate for Best Care

Click here to access the May 2017 Digital Edition.

Table of Contents

• Providing Mental Health Care to All Veterans Regardless of Discharge Status
• Need for Mental Health Providers in Progressive Tinnitus Management
• Blood Loss and Need for Blood Transfusions in Total Knee and Total Hip Arthroplasty
• Peripheral Exudative Hemorrhagic Chorioretinopathy in Patients With Nonexudative Age-Related Macular Degeneration
• The Personal Health Inventory: Current Use, Perceived Barriers, and Benefits
• Dependence of Elevated Eosinophil Levels on Geographic Location
• The Design and Implementation of a Home-Based Cardiac Rehabilitation Program
• FRAX Prediction With and Without Bone Mineral Density Testing
• Improved Access to Drug Safety Labeling Changes Information
• Defining Pharmacy Leadership in the VA
• VA Nurses Advocate for Best Care

Click here to access the May 2017 Digital Edition.

Table of Contents

• Providing Mental Health Care to All Veterans Regardless of Discharge Status
• Need for Mental Health Providers in Progressive Tinnitus Management
• Blood Loss and Need for Blood Transfusions in Total Knee and Total Hip Arthroplasty
• Peripheral Exudative Hemorrhagic Chorioretinopathy in Patients With Nonexudative Age-Related Macular Degeneration
• The Personal Health Inventory: Current Use, Perceived Barriers, and Benefits
• Dependence of Elevated Eosinophil Levels on Geographic Location
• The Design and Implementation of a Home-Based Cardiac Rehabilitation Program
• FRAX Prediction With and Without Bone Mineral Density Testing
• Improved Access to Drug Safety Labeling Changes Information
• Defining Pharmacy Leadership in the VA
• VA Nurses Advocate for Best Care

Many individuals read about the health benefits of certain foods, such as coffee, grapefruit, and red wine, but psychiatrists might neglect to inform their patients that these common foods could interact with drugs, thereby preventing certain psychotropics from achieving maximum benefit or causing toxicity. Educate your patients about food–drug interactions and to refrain from alcohol and specific foods when taking psychotropics. Although far from comprehensive, we present a discussion of the most frequently encountered and preventable food/nutrient–drug interactions.

Grapefruit juice may alter bioavailability of many psychotropics by inhibiting cytochrome P450 (CYP) 3A4 and 1A2 isoforms, interfering with prehepatic metabolism, and enteric absorption. Common medications affected by this interaction include alprazolam, buspirone, sertraline, carbamazepine, and methadone.¹ Patients should be advised about eating grapefruit or drinking grapefruit juice as it could require dose adjustment to avoid drug toxicity.

Table salt. Lithium is a salt, and less table salt intake could cause lithium levels to rise and vice versa. Lithium and other salts compete for absorption and secretion in the renal tubules, which are responsible for this interaction. Therefore, it is advisable to keep a stable salt intake throughout treatment. Patients should be cautioned about eating salty foods during the summer because excessive sweating could lead to lithium intoxication.

Caffeine is a widely used stimulant; however, it can decrease blood lithium levels and block clozapine clearance via inhibition of the CYP1A2 enzyme. Excessive caffeine intake can lead to clozapine toxicity.²

Beef liver, aged sausage and cheese, and wine contain tyramine. Tyramine is broken down by monoamine oxidase (MAO) enzymes in the body, which are inhibited by MAO inhibitors (MAOI) such as phenelzine and selegiline. A patient taking a MAOI cannot catabolize tyramine and other amines. These exogenous amines could cause a life-threatening hyperadrenergic crisis. Physicians should educate their patients about the MAOI diet and monitor adherence to the food avoidance list.

St. John’s wort is a herb commonly used for treating mild depression. It is a strong inducer of the CYP3A4 enzyme and reduces plasma concentrations and could decrease clinical effectiveness of aripiprazole, quetia­pine, alprazolam, and oxycodone.³ It could interact with serotonin reuptake inhibitors causing serotonin syndrome.

Full vs empty stomach. Food is known to affect bioavailability and enteral absorption of different psychotropics. Some medications are best taken on a full stomach and some on an empty one. For example, the antipsychotic ziprasidone should be taken with meals of at least 500 calories for optimal and consistent bioavailability. Benzodiazepines are rapidly absorbed when taken on an empty stomach.

Discuss dietary habits with patients to encourage a healthy lifestyle and provide valuable direction about potential food/nutrient–drug interactions.

Many individuals read about the health benefits of certain foods, such as coffee, grapefruit, and red wine, but psychiatrists might neglect to inform their patients that these common foods could interact with drugs, thereby preventing certain psychotropics from achieving maximum benefit or causing toxicity. Educate your patients about food–drug interactions and to refrain from alcohol and specific foods when taking psychotropics. Although far from comprehensive, we present a discussion of the most frequently encountered and preventable food/nutrient–drug interactions.

Grapefruit juice may alter bioavailability of many psychotropics by inhibiting cytochrome P450 (CYP) 3A4 and 1A2 isoforms, interfering with prehepatic metabolism, and enteric absorption. Common medications affected by this interaction include alprazolam, buspirone, sertraline, carbamazepine, and methadone.¹ Patients should be advised about eating grapefruit or drinking grapefruit juice as it could require dose adjustment to avoid drug toxicity.

Table salt. Lithium is a salt, and less table salt intake could cause lithium levels to rise and vice versa. Lithium and other salts compete for absorption and secretion in the renal tubules, which are responsible for this interaction. Therefore, it is advisable to keep a stable salt intake throughout treatment. Patients should be cautioned about eating salty foods during the summer because excessive sweating could lead to lithium intoxication.

Caffeine is a widely used stimulant; however, it can decrease blood lithium levels and block clozapine clearance via inhibition of the CYP1A2 enzyme. Excessive caffeine intake can lead to clozapine toxicity.²

Beef liver, aged sausage and cheese, and wine contain tyramine. Tyramine is broken down by monoamine oxidase (MAO) enzymes in the body, which are inhibited by MAO inhibitors (MAOI) such as phenelzine and selegiline. A patient taking a MAOI cannot catabolize tyramine and other amines. These exogenous amines could cause a life-threatening hyperadrenergic crisis. Physicians should educate their patients about the MAOI diet and monitor adherence to the food avoidance list.

St. John’s wort is a herb commonly used for treating mild depression. It is a strong inducer of the CYP3A4 enzyme and reduces plasma concentrations and could decrease clinical effectiveness of aripiprazole, quetia­pine, alprazolam, and oxycodone.³ It could interact with serotonin reuptake inhibitors causing serotonin syndrome.

Full vs empty stomach. Food is known to affect bioavailability and enteral absorption of different psychotropics. Some medications are best taken on a full stomach and some on an empty one. For example, the antipsychotic ziprasidone should be taken with meals of at least 500 calories for optimal and consistent bioavailability. Benzodiazepines are rapidly absorbed when taken on an empty stomach.

Discuss dietary habits with patients to encourage a healthy lifestyle and provide valuable direction about potential food/nutrient–drug interactions.

Many individuals read about the health benefits of certain foods, such as coffee, grapefruit, and red wine, but psychiatrists might neglect to inform their patients that these common foods could interact with drugs, thereby preventing certain psychotropics from achieving maximum benefit or causing toxicity. Educate your patients about food–drug interactions and to refrain from alcohol and specific foods when taking psychotropics. Although far from comprehensive, we present a discussion of the most frequently encountered and preventable food/nutrient–drug interactions.

Grapefruit juice may alter bioavailability of many psychotropics by inhibiting cytochrome P450 (CYP) 3A4 and 1A2 isoforms, interfering with prehepatic metabolism, and enteric absorption. Common medications affected by this interaction include alprazolam, buspirone, sertraline, carbamazepine, and methadone.¹ Patients should be advised about eating grapefruit or drinking grapefruit juice as it could require dose adjustment to avoid drug toxicity.

Table salt. Lithium is a salt, and less table salt intake could cause lithium levels to rise and vice versa. Lithium and other salts compete for absorption and secretion in the renal tubules, which are responsible for this interaction. Therefore, it is advisable to keep a stable salt intake throughout treatment. Patients should be cautioned about eating salty foods during the summer because excessive sweating could lead to lithium intoxication.

Caffeine is a widely used stimulant; however, it can decrease blood lithium levels and block clozapine clearance via inhibition of the CYP1A2 enzyme. Excessive caffeine intake can lead to clozapine toxicity.²

Beef liver, aged sausage and cheese, and wine contain tyramine. Tyramine is broken down by monoamine oxidase (MAO) enzymes in the body, which are inhibited by MAO inhibitors (MAOI) such as phenelzine and selegiline. A patient taking a MAOI cannot catabolize tyramine and other amines. These exogenous amines could cause a life-threatening hyperadrenergic crisis. Physicians should educate their patients about the MAOI diet and monitor adherence to the food avoidance list.

St. John’s wort is a herb commonly used for treating mild depression. It is a strong inducer of the CYP3A4 enzyme and reduces plasma concentrations and could decrease clinical effectiveness of aripiprazole, quetia­pine, alprazolam, and oxycodone.³ It could interact with serotonin reuptake inhibitors causing serotonin syndrome.

Full vs empty stomach. Food is known to affect bioavailability and enteral absorption of different psychotropics. Some medications are best taken on a full stomach and some on an empty one. For example, the antipsychotic ziprasidone should be taken with meals of at least 500 calories for optimal and consistent bioavailability. Benzodiazepines are rapidly absorbed when taken on an empty stomach.

Discuss dietary habits with patients to encourage a healthy lifestyle and provide valuable direction about potential food/nutrient–drug interactions.