A 45-year-old man with known human immunodeficiency virus infection presented with a 5-day history of dyspnea. When his dyspnea had become symptomatic, he had restarted his home dapsone prophylaxis, but his dyspnea had progressively worsened, and his urine became dark.

Based on these test results, the patient’s dapsone was stopped and replaced with atovaquone. Intravenous infusion of methylene blue was started, with subsequent improvement of the hypoxia and cyanosis (Figure 1). His urine became green, but it returned to a normal color in a matter of hours. He was ultimately diagnosed with P jirovecii pneumonia and completed a course of atovaquone with total resolution of his symptoms.

THE MECHANISMS BEHIND METHEMOGLOBINEMIA

Heme iron is normally in the ferrous state (Fe²⁺), which allows for hemoglobin to carry oxygen and release it to tissues.¹ Exposure to an oxidative stress can lead to methemoglobinemia from an increase in abnormal hemoglobin that contains iron in a ferric state (Fe³⁺).^1,2

Methemoglobin reduces oxygen-carrying capacity in two ways: it is unable to carry oxygen, and its presence shifts the oxy­gen dissociation curve to the left, causing any remaining normal hemoglobin to be unable to release oxygen to the tissues.^1,2

Causes of acquired methemoglobinemia include topical anesthetics (eg, benzocaine, lidocaine) and antibiotics (eg, dapsone).^2,3 Signs and symptoms include cyanosis, headache, fatigue, dyspnea, lethargy, respiratory distress, and dark-colored urine.^1,2

MANAGEMENT

Treatment consists of intravenous methylene blue, which reduces the hemoglobin from a ferric state to a ferrous state.^1–4 Methylene blue is a water-soluble dye excreted primarily in the urine, and common side effects include dizziness, nausea, and green urine.^5–7 The blue pigments from methylene blue combine with urobilin (a yellow pigment in the urine), producing a green color.⁷ This is not pathological and requires no treatment, as the urine returns to normal color after the body fully excretes the dye.^5–7

If intravenous methylene blue fails to produce a response, other treatments to consider include hemodialysis, blood transfusion, exchange transfusion, and hyperbaric oxygen therapy.²

A 45-year-old man with known human immunodeficiency virus infection presented with a 5-day history of dyspnea. When his dyspnea had become symptomatic, he had restarted his home dapsone prophylaxis, but his dyspnea had progressively worsened, and his urine became dark.

Based on these test results, the patient’s dapsone was stopped and replaced with atovaquone. Intravenous infusion of methylene blue was started, with subsequent improvement of the hypoxia and cyanosis (Figure 1). His urine became green, but it returned to a normal color in a matter of hours. He was ultimately diagnosed with P jirovecii pneumonia and completed a course of atovaquone with total resolution of his symptoms.

THE MECHANISMS BEHIND METHEMOGLOBINEMIA

Heme iron is normally in the ferrous state (Fe²⁺), which allows for hemoglobin to carry oxygen and release it to tissues.¹ Exposure to an oxidative stress can lead to methemoglobinemia from an increase in abnormal hemoglobin that contains iron in a ferric state (Fe³⁺).^1,2

Methemoglobin reduces oxygen-carrying capacity in two ways: it is unable to carry oxygen, and its presence shifts the oxy­gen dissociation curve to the left, causing any remaining normal hemoglobin to be unable to release oxygen to the tissues.^1,2

Causes of acquired methemoglobinemia include topical anesthetics (eg, benzocaine, lidocaine) and antibiotics (eg, dapsone).^2,3 Signs and symptoms include cyanosis, headache, fatigue, dyspnea, lethargy, respiratory distress, and dark-colored urine.^1,2

MANAGEMENT

Treatment consists of intravenous methylene blue, which reduces the hemoglobin from a ferric state to a ferrous state.^1–4 Methylene blue is a water-soluble dye excreted primarily in the urine, and common side effects include dizziness, nausea, and green urine.^5–7 The blue pigments from methylene blue combine with urobilin (a yellow pigment in the urine), producing a green color.⁷ This is not pathological and requires no treatment, as the urine returns to normal color after the body fully excretes the dye.^5–7

If intravenous methylene blue fails to produce a response, other treatments to consider include hemodialysis, blood transfusion, exchange transfusion, and hyperbaric oxygen therapy.²

A 45-year-old man with known human immunodeficiency virus infection presented with a 5-day history of dyspnea. When his dyspnea had become symptomatic, he had restarted his home dapsone prophylaxis, but his dyspnea had progressively worsened, and his urine became dark.

Based on these test results, the patient’s dapsone was stopped and replaced with atovaquone. Intravenous infusion of methylene blue was started, with subsequent improvement of the hypoxia and cyanosis (Figure 1). His urine became green, but it returned to a normal color in a matter of hours. He was ultimately diagnosed with P jirovecii pneumonia and completed a course of atovaquone with total resolution of his symptoms.

THE MECHANISMS BEHIND METHEMOGLOBINEMIA

Heme iron is normally in the ferrous state (Fe²⁺), which allows for hemoglobin to carry oxygen and release it to tissues.¹ Exposure to an oxidative stress can lead to methemoglobinemia from an increase in abnormal hemoglobin that contains iron in a ferric state (Fe³⁺).^1,2

Methemoglobin reduces oxygen-carrying capacity in two ways: it is unable to carry oxygen, and its presence shifts the oxy­gen dissociation curve to the left, causing any remaining normal hemoglobin to be unable to release oxygen to the tissues.^1,2

Causes of acquired methemoglobinemia include topical anesthetics (eg, benzocaine, lidocaine) and antibiotics (eg, dapsone).^2,3 Signs and symptoms include cyanosis, headache, fatigue, dyspnea, lethargy, respiratory distress, and dark-colored urine.^1,2

MANAGEMENT

Treatment consists of intravenous methylene blue, which reduces the hemoglobin from a ferric state to a ferrous state.^1–4 Methylene blue is a water-soluble dye excreted primarily in the urine, and common side effects include dizziness, nausea, and green urine.^5–7 The blue pigments from methylene blue combine with urobilin (a yellow pigment in the urine), producing a green color.⁷ This is not pathological and requires no treatment, as the urine returns to normal color after the body fully excretes the dye.^5–7

If intravenous methylene blue fails to produce a response, other treatments to consider include hemodialysis, blood transfusion, exchange transfusion, and hyperbaric oxygen therapy.²

Chronic pelvic pain is a common clinical problem in women, as prevalent in primary care as asthma or back pain.^1,2 It is often associated with lost work days and decreased productivity, increased healthcare spending, mood disorders, and negative effects on personal relationships.^1–3

While specialty care referral may eventually be indicated, primary care doctors can take steps to diagnose and effectively manage the condition.

COMPREHENSIVE MANAGEMENT LED BY PRIMARY CARE

Chronic pelvic pain is defined as pain in the lower abdomen persisting for 3 to 6 months and of sufficient severity to require medical care or cause a functional disability.³ It is often detrimental to a woman’s personal life and overall health, making a comprehensive assessment and multidisciplinary approach to management especially important.

The ideal care-delivery model is the patient-centered medical home, whereby a primary care physician coordinates comprehensive care with the help of an interdisciplinary team.^4,5 For complex cases, referral may be needed to other specialties (eg, obstetrics and gynecology, pain medicine) to help manage care.

TARGETED EVALUATION

Chronic pelvic pain often coexists with other systemic pain syndromes or psychiatric conditions common in primary care. Table 1 lists common causes and associated findings.

Detailed history is critical

The history is of utmost importance. Clinicians should query patients about the characteristics of the pain as well as their medical and surgical history. Particular attention should be given to obtaining a complete gynecologic history, including pregnancy, delivery complications, dyspareunia, sexual assault, and trauma. A detailed review of systems should focus on the reproductive, gastroenterologic, musculoskeletal, urologic, and neuropsychiatric systems.

As with many pain syndromes, allowing the patient to “tell her story” helps to establish rapport and obtain a more complete assessment. Chronic pelvic pain has been associated with physical or sexual abuse as a child or adult, so is essential to foster the doctor-patient relationship and create a safe and open space for disclosure.^3,6 It is important to screen women for safety at home as well as for satisfaction or dissatisfaction with their relationships with their spouse or partner and family.

Physical examination

The physical examination should be directed by the history but should always include abdominal and pelvic examinations. These should be conducted slowly and gently, assessing for areas of tenderness, masses, and other abnormalities. Clinicians should aim to pinpoint the exact anatomic locations of tenderness if possible. Ongoing dialogue facilitates this process by inquiring about pain at each point of the examination.

The pelvic examination should begin with visual inspection for redness, discharge, lesions, fissures, excoriations, and other abnormalities. A moistened cotton swab may be used to evaluate the vulva and vestibule for localized tenderness. The manual portion of the pelvic examination should begin with a single digit, noting any introital tenderness or spasm. Next, the levator ani muscles should be directly palpated for tone and tenderness. The pelvic floor should be evaluated with attention to tenderness of the bladder or musculoskeletal structures (Figure 1). A bimanual examination assessing uterine size and tenderness, nodularity, or a fixed, immobile uterus should be conducted.

Because the differential diagnosis of chronic pelvic pain is broad, the diagnostic workup and testing should be based on findings of the history and physical examination. In general, extensive laboratory testing is of limited use for evaluating women with chronic pelvic pain.^3,7

Urinalysis should be obtained for symptoms suggesting bladder involvement such as interstitial cystitis.

Pelvic ultrasonography can help identify pelvic masses palpated during the physical examination, but routine use of imaging is not recommended.^3,7 If pelvic congestion syndrome is suspected, starting with pelvic ultrasonography is reasonable before incurring the risk or cost of computed tomography or magnetic resonance imaging.⁸

GENERAL TREATMENT

Medical therapy

The main goals of medical therapy are to improve function and quality of life while minimizing adverse effects. General treatments include the following:

Analgesics. Nonsteroidal anti-inflammatory drugs and acetaminophen may provide pain relief, although there is weak evidence for their efficacy in treating chronic pelvic pain.⁹

Neuropathic agents. One of several available neuropathic agents commonly used in the treatment of chronic pain can be tried on patients who fail to respond to analgesics. Tricyclic antidepressants such as amitriptyline and imipramine decrease pain, reduce symptoms of depression, and improve sleep.¹⁰ The results of a small randomized controlled trial suggest that gabapentin is more effective than amitriptyline for reducing chronic pelvic pain.^11,12 Published guidelines currently list both amitriptyline and gabapentin as first-line agents; nortriptyline and pregabalin are considered acceptable initial alternatives.⁹

Venlafaxine and duloxetine may help chronic pelvic pain, although specific evidence is lacking. Duloxetine may be an appropriate choice for women with chronic pelvic pain who also experience depression and urinary stress incontinence.⁹

Opioids. Opioid therapy should be considered only when all other reasonable therapies have failed.¹⁰ Patients may develop tolerance or dependence, as well as opioid-induced adverse effects such as hyperalgesia.^9,10 Guidelines recommend that primary care providers consult with a pain management specialist before prescribing opioids, and that patients be thoroughly counseled about the risks and side effects.⁹

Nerve block and neuromodulation. There is weak evidence for the use of these modalities for treating chronic pelvic pain.⁹ If used, they should be part of a broader treatment plan and should be performed by providers who specialize in management of chronic pain.

DISEASE-SPECIFIC TREATMENT

Endometriosis: Hormonal therapy

Pelvic pain that significantly fluctuates with the menstrual cycle may be caused by endometriosis, the most common gynecologic cause of chronic pelvic pain. Women with cyclic chronic pelvic pain should be empirically treated with hormonal therapy for at least 3 to 6 months before diagnostic laparoscopy is performed.¹³

Oral contraceptives, gonadotropin-releasing hormone (GnRH) analogues, progestogens, and danazol have proven efficacy, although side-effect profiles differ significantly. In a comparative trial, patients treated with GnRH analogues had more improvement in pain scores compared with those treated with oral contraceptives, but they experienced a significant decrease in bone mineral density.¹¹ The effects on bone mineral density associated with GnRH analogue therapy can be mitigated by “add-back” low-dose hormonal therapy (norethindrone, low-dose estrogen, or a combination of estrogen and progesterone), which may also provide symptomatic relief for associated hot flashes and vaginal symptoms.¹¹

Interstitial cystitis often accompanies endometriosis

Recognizing that chronic pelvic pain may have more than one cause is important when developing a comprehensive care plan. Interstitial cystitis coexists with endometriosis in up to 60% of patients.¹⁴ Initial treatment is pentosan polysulfate sodium, an oral treatment approved by the US Food and Drug Administration for interstitial cystitis that works by restoring the protective glycosaminoglycan layer in the bladder.^14,15 Amitriptyline may also be used to treat interstitial cystitis-associated nocturia.

Myofascial pain: Neuromuscular blockers

According to a recent systematic review of therapies for chronic pelvic pain, patients with symptoms related to myofascial pain may benefit from neuromuscular blockade.¹² One randomized controlled trial of the effectiveness of botulinum toxin A vs saline for the treatment of chronic pelvic pain secondary to pelvic floor spasm found that after 6 months of observation, women who received botulinum toxin had significantly lower pain scores than those who received saline.¹²

Pelvic congestion syndrome may be treated with hormonal, radiologic, or surgical therapy.¹⁶ A randomized controlled trial involving patients with chronic pelvic pain secondary to pelvic congestion demonstrated that treatment with medroxyprogesterone acetate or a GnRH agonist (goserelin) improved pelvic symptoms.¹⁷

A Cochrane review of nonsurgical interventions for chronic pelvic pain included women with a diagnosis of pelvic congestion syndrome or adhesions. It found that patients treated with medroxyprogesterone acetate were more likely to have 50% pain reduction lasting up to 9 months compared with patients taking placebo.¹² In comparative studies, GnRH analogues were more effective in relieving pelvic pain than progestogen therapy.

Radiologic embolization therapy is as effective as hysterectomy for the relief of chronic pelvic pain related to pelvic congestion syndrome, and it can be performed in the outpatient setting.

Irritable bowel syndrome: Try dietary changes

Symptoms of chronic pelvic pain that are associated with changes in stool consistency and frequency suggest irritable bowel syndrome. Symptoms may improve with dietary changes and fiber supplementation. Antispasmodic agents are frequently used but their anticholinergic effects may worsen constipation.¹⁴

PELVIC PHYSICAL THERAPY

Pelvic physical therapy targets the musculoskeletal components of bowel, bladder, and sexual function to restore strength, flexibility, balance, and coordination to the pelvic floor and surrounding lumbopelvic muscles. Patients with dyspareunia, pain with activity, or a significant musculoskeletal abnormality (eg, vaginismus or point tenderness on examination) are particularly good candidates for this therapy. It is done by a physical therapist with special training in techniques to manipulate the pelvic floor to address pelvic pain.

Educating the patient

Informing the patient before the initial physical therapy visit is essential for success. Referring clinicians should emphasize to patients that treatment response can help to guide further physician intervention. Patients should be counseled that pelvic physical therapy includes a pelvic examination and an expectation to participate in a home program. Although noticeable improvement takes time, encouragement provided by the entire team, including medical providers, can help a patient maintain her care plan.

Therapists typically see a patient once a week for 8 to 12 visits initially. Insurance usually covers pelvic physical therapy through the same policy as routine physical therapy.

During the initial evaluation, the patient receives an external and internal pelvic examination assessing muscle length, strength, and coordination of the back, hip, and internal pelvic floor. Internal evaluation can be done vaginally or rectally, with one gloved finger, without the need for speculum or stirrups. Biofeedback and surface electromyography (using either perianal or internal electrode placement) are used to evaluate muscle activity and to assist the patient in developing appropriate motor control during strengthening or relaxation.¹⁸

Up-training (or strengthening) aims to improve pelvic floor endurance. It can improve pelvic instability and symptoms of heaviness and discomfort from prolapse. Patients learn to appropriately utilize the pelvic floor in isolation. If a patient is too weak to contract on her own, neuromuscular electrical stimulation is used with an internal electrode to provide an assisted contraction.

Down-training (or relaxation) focuses on reducing tone in overactive pelvic muscles. It can improve symptoms of chronic pelvic pain, sexual pain, vulvodynia, and pudendal neuralgias. Patients are made aware of chronic holding patterns that lead to excess tone in the pelvic floor and learn how to release them through stretching, cardiovascular activity, meditation, and manual release of the involved muscle groups internally and externally. Internal musculature can be manipulated by a therapist in clinic or by the patient’s trained partner; the patient can also reach necessary areas with a vaginal dilator.

Functional coordination of the pelvic floor is needed for comfortable vaginal penetration and defecation. Training with biofeedback improves a patient’s ability to relax and open the pelvic floor.¹⁸ Vaginal dilators with surface electromyography are used to treat vaginismus to eliminate reflexive pelvic floor spasm during penetration. Perineal and vaginal compliance can be improved through manual release techniques with hands or vaginal dilators to restore normal mobility of tissues. This can reduce pain from postsurgical changes, postpartum sequelae, atrophic vaginal changes, shortened muscles from chronic holding, and adhesions.

PSYCHOSOCIAL INTERVENTIONS

Pelvic pain is not only a biomedical difficulty; psychosocial factors can contribute to and be affected by pelvic pain. Patients with pelvic pain often experience lower quality of life, higher rates of anxiety and depression, and increased stress compared with others.^19,20 People with pain also have more relationship stress, and patients’ partners often experience emotional distress, isolation, and feelings of powerlessness in the relationship.²¹

Psychosocial interventions, provided along with biomedical treatment, can help to reduce pain, anxiety, and depression and improve relational well-being.^22,23 In addition to attending to pain-related symptoms, comprehensive care involves recognizing and treating coexisting anxiety, depression, stress, and relationship conflict. Interventions for these difficulties are many, and a comprehensive list of interventions is beyond the focus of this section.¹⁹

Cognitive behavioral therapy is based on the idea that maladaptive cognitions can lead to problematic behaviors and emotional distress.²⁴ Interventions are carried out by a provider with specialized training in its use (eg, therapist, pain psychologist, psychiatrist).

Meta-analyses of studies that investigated the efficacy of cognitive behavioral therapy for chronic pain found consistent small to medium improvement in pain-related symptoms.²⁴ Studies that used cognitive behavioral therapy for pelvic pain found reduced overall pain severity and pain during intercourse, increased sexual satisfaction, enhanced sexual function, and less-exaggerated responses to pain.^25–27

Although cognitive behavioral therapy and mindfulness-based interventions produce positive outcomes, research on these interventions typically includes treatment carried out over a span of weeks. Common barriers to such care include lack of patient motivation, financial limitations, transportation problems, and time constraints.

The following psychosocial interventions have been chosen because they can be delivered in a short amount of time and integrated into a patient’s medical care by a medical or behavioral health provider. Because of the brevity and simplicity of these interventions, more patients with pelvic pain can receive psychosocial care as part of their usual medical encounters.

Behavioral activation

People experiencing depressive symptoms tend to isolate themselves and stop participating in activities they enjoy, including spending time with family and friends. Behavioral activation interventions that address such isolating behaviors have been shown to be effective in improving depressive symptoms.^28–30

A simple, brief intervention can be administered during routine medical care,²⁸ involving the following steps:

• Determine activities that the patient might implement that would decrease depressive symptoms. Questions such as, “When do you feel less depressed?” or “What brings you some happiness in your life?” can generate possible activities.
• Ask the patient to identify people in her life who have been supportive and with whom she could engage.
• Create with the patient a list of possible activities and social interactions that may enhance well-being.
• Make a schedule for participating in activities, possibly with rewards for completing them. Patients should be encouraged to follow the prescribed schedule of activities rather than make decisions based on mood or other factors. 

Relaxation strategies

Relaxation can help patients reduce stress and anxiety, and can also help reduce pain.^31–33

Diaphragmatic or “belly breathing” is a deep-breathing technique in which participants are asked to take in air through the nose and fully fill the lungs and lower belly. This technique allows the body to take in more oxygen, helping to lower blood pressure and slow the heartbeat. In addition to physiologic benefits, concentrating on deep breathing can help slow down or stop intrusive thoughts and distressing physical sensations.³⁴

Progressive muscle relaxation involves the systematic tensing and relaxing of each large muscle group in the body.³⁵ The goal is to eliminate physical and emotional stress through focusing on the sensations of tension and relaxation.

Scripts and audio and video resources for belly breathing and progressive muscle relaxation can be found on the Internet. The techniques can be taught during the medical appointment or offered as resources for home practice.

Couple-based care

Targeting couples is more effective for improving well-being than focusing solely on a patient’s psychosocial difficulties, so each of the above interventions may be more effective if tailored to include the patient’s partner.³⁶ If the partner is with the patient during medical visits or is included in long-term psychosocial treatment, he or she can be directly involved in learning and practicing interventions with the patient. If the partner is not present, the patient can be asked to practice newly learned well-being-enhancing strategies with her partner outside the appointment time. Couples therapy can improve psychosocial well-being for both partners.

Setting goals

Chronic pelvic pain is a common clinical problem in women, as prevalent in primary care as asthma or back pain.^1,2 It is often associated with lost work days and decreased productivity, increased healthcare spending, mood disorders, and negative effects on personal relationships.^1–3

While specialty care referral may eventually be indicated, primary care doctors can take steps to diagnose and effectively manage the condition.

COMPREHENSIVE MANAGEMENT LED BY PRIMARY CARE

Chronic pelvic pain is defined as pain in the lower abdomen persisting for 3 to 6 months and of sufficient severity to require medical care or cause a functional disability.³ It is often detrimental to a woman’s personal life and overall health, making a comprehensive assessment and multidisciplinary approach to management especially important.

The ideal care-delivery model is the patient-centered medical home, whereby a primary care physician coordinates comprehensive care with the help of an interdisciplinary team.^4,5 For complex cases, referral may be needed to other specialties (eg, obstetrics and gynecology, pain medicine) to help manage care.

TARGETED EVALUATION

Chronic pelvic pain often coexists with other systemic pain syndromes or psychiatric conditions common in primary care. Table 1 lists common causes and associated findings.

Detailed history is critical

The history is of utmost importance. Clinicians should query patients about the characteristics of the pain as well as their medical and surgical history. Particular attention should be given to obtaining a complete gynecologic history, including pregnancy, delivery complications, dyspareunia, sexual assault, and trauma. A detailed review of systems should focus on the reproductive, gastroenterologic, musculoskeletal, urologic, and neuropsychiatric systems.

As with many pain syndromes, allowing the patient to “tell her story” helps to establish rapport and obtain a more complete assessment. Chronic pelvic pain has been associated with physical or sexual abuse as a child or adult, so is essential to foster the doctor-patient relationship and create a safe and open space for disclosure.^3,6 It is important to screen women for safety at home as well as for satisfaction or dissatisfaction with their relationships with their spouse or partner and family.

Physical examination

The physical examination should be directed by the history but should always include abdominal and pelvic examinations. These should be conducted slowly and gently, assessing for areas of tenderness, masses, and other abnormalities. Clinicians should aim to pinpoint the exact anatomic locations of tenderness if possible. Ongoing dialogue facilitates this process by inquiring about pain at each point of the examination.

The pelvic examination should begin with visual inspection for redness, discharge, lesions, fissures, excoriations, and other abnormalities. A moistened cotton swab may be used to evaluate the vulva and vestibule for localized tenderness. The manual portion of the pelvic examination should begin with a single digit, noting any introital tenderness or spasm. Next, the levator ani muscles should be directly palpated for tone and tenderness. The pelvic floor should be evaluated with attention to tenderness of the bladder or musculoskeletal structures (Figure 1). A bimanual examination assessing uterine size and tenderness, nodularity, or a fixed, immobile uterus should be conducted.

Because the differential diagnosis of chronic pelvic pain is broad, the diagnostic workup and testing should be based on findings of the history and physical examination. In general, extensive laboratory testing is of limited use for evaluating women with chronic pelvic pain.^3,7

Urinalysis should be obtained for symptoms suggesting bladder involvement such as interstitial cystitis.

Pelvic ultrasonography can help identify pelvic masses palpated during the physical examination, but routine use of imaging is not recommended.^3,7 If pelvic congestion syndrome is suspected, starting with pelvic ultrasonography is reasonable before incurring the risk or cost of computed tomography or magnetic resonance imaging.⁸

GENERAL TREATMENT

Medical therapy

The main goals of medical therapy are to improve function and quality of life while minimizing adverse effects. General treatments include the following:

Analgesics. Nonsteroidal anti-inflammatory drugs and acetaminophen may provide pain relief, although there is weak evidence for their efficacy in treating chronic pelvic pain.⁹

Neuropathic agents. One of several available neuropathic agents commonly used in the treatment of chronic pain can be tried on patients who fail to respond to analgesics. Tricyclic antidepressants such as amitriptyline and imipramine decrease pain, reduce symptoms of depression, and improve sleep.¹⁰ The results of a small randomized controlled trial suggest that gabapentin is more effective than amitriptyline for reducing chronic pelvic pain.^11,12 Published guidelines currently list both amitriptyline and gabapentin as first-line agents; nortriptyline and pregabalin are considered acceptable initial alternatives.⁹

Venlafaxine and duloxetine may help chronic pelvic pain, although specific evidence is lacking. Duloxetine may be an appropriate choice for women with chronic pelvic pain who also experience depression and urinary stress incontinence.⁹

Opioids. Opioid therapy should be considered only when all other reasonable therapies have failed.¹⁰ Patients may develop tolerance or dependence, as well as opioid-induced adverse effects such as hyperalgesia.^9,10 Guidelines recommend that primary care providers consult with a pain management specialist before prescribing opioids, and that patients be thoroughly counseled about the risks and side effects.⁹

Nerve block and neuromodulation. There is weak evidence for the use of these modalities for treating chronic pelvic pain.⁹ If used, they should be part of a broader treatment plan and should be performed by providers who specialize in management of chronic pain.

DISEASE-SPECIFIC TREATMENT

Endometriosis: Hormonal therapy

Pelvic pain that significantly fluctuates with the menstrual cycle may be caused by endometriosis, the most common gynecologic cause of chronic pelvic pain. Women with cyclic chronic pelvic pain should be empirically treated with hormonal therapy for at least 3 to 6 months before diagnostic laparoscopy is performed.¹³

Oral contraceptives, gonadotropin-releasing hormone (GnRH) analogues, progestogens, and danazol have proven efficacy, although side-effect profiles differ significantly. In a comparative trial, patients treated with GnRH analogues had more improvement in pain scores compared with those treated with oral contraceptives, but they experienced a significant decrease in bone mineral density.¹¹ The effects on bone mineral density associated with GnRH analogue therapy can be mitigated by “add-back” low-dose hormonal therapy (norethindrone, low-dose estrogen, or a combination of estrogen and progesterone), which may also provide symptomatic relief for associated hot flashes and vaginal symptoms.¹¹

Interstitial cystitis often accompanies endometriosis

Recognizing that chronic pelvic pain may have more than one cause is important when developing a comprehensive care plan. Interstitial cystitis coexists with endometriosis in up to 60% of patients.¹⁴ Initial treatment is pentosan polysulfate sodium, an oral treatment approved by the US Food and Drug Administration for interstitial cystitis that works by restoring the protective glycosaminoglycan layer in the bladder.^14,15 Amitriptyline may also be used to treat interstitial cystitis-associated nocturia.

Myofascial pain: Neuromuscular blockers

According to a recent systematic review of therapies for chronic pelvic pain, patients with symptoms related to myofascial pain may benefit from neuromuscular blockade.¹² One randomized controlled trial of the effectiveness of botulinum toxin A vs saline for the treatment of chronic pelvic pain secondary to pelvic floor spasm found that after 6 months of observation, women who received botulinum toxin had significantly lower pain scores than those who received saline.¹²

Pelvic congestion syndrome may be treated with hormonal, radiologic, or surgical therapy.¹⁶ A randomized controlled trial involving patients with chronic pelvic pain secondary to pelvic congestion demonstrated that treatment with medroxyprogesterone acetate or a GnRH agonist (goserelin) improved pelvic symptoms.¹⁷

A Cochrane review of nonsurgical interventions for chronic pelvic pain included women with a diagnosis of pelvic congestion syndrome or adhesions. It found that patients treated with medroxyprogesterone acetate were more likely to have 50% pain reduction lasting up to 9 months compared with patients taking placebo.¹² In comparative studies, GnRH analogues were more effective in relieving pelvic pain than progestogen therapy.

Radiologic embolization therapy is as effective as hysterectomy for the relief of chronic pelvic pain related to pelvic congestion syndrome, and it can be performed in the outpatient setting.

Irritable bowel syndrome: Try dietary changes

Symptoms of chronic pelvic pain that are associated with changes in stool consistency and frequency suggest irritable bowel syndrome. Symptoms may improve with dietary changes and fiber supplementation. Antispasmodic agents are frequently used but their anticholinergic effects may worsen constipation.¹⁴

PELVIC PHYSICAL THERAPY

Pelvic physical therapy targets the musculoskeletal components of bowel, bladder, and sexual function to restore strength, flexibility, balance, and coordination to the pelvic floor and surrounding lumbopelvic muscles. Patients with dyspareunia, pain with activity, or a significant musculoskeletal abnormality (eg, vaginismus or point tenderness on examination) are particularly good candidates for this therapy. It is done by a physical therapist with special training in techniques to manipulate the pelvic floor to address pelvic pain.

Educating the patient

Informing the patient before the initial physical therapy visit is essential for success. Referring clinicians should emphasize to patients that treatment response can help to guide further physician intervention. Patients should be counseled that pelvic physical therapy includes a pelvic examination and an expectation to participate in a home program. Although noticeable improvement takes time, encouragement provided by the entire team, including medical providers, can help a patient maintain her care plan.

Therapists typically see a patient once a week for 8 to 12 visits initially. Insurance usually covers pelvic physical therapy through the same policy as routine physical therapy.

During the initial evaluation, the patient receives an external and internal pelvic examination assessing muscle length, strength, and coordination of the back, hip, and internal pelvic floor. Internal evaluation can be done vaginally or rectally, with one gloved finger, without the need for speculum or stirrups. Biofeedback and surface electromyography (using either perianal or internal electrode placement) are used to evaluate muscle activity and to assist the patient in developing appropriate motor control during strengthening or relaxation.¹⁸

Up-training (or strengthening) aims to improve pelvic floor endurance. It can improve pelvic instability and symptoms of heaviness and discomfort from prolapse. Patients learn to appropriately utilize the pelvic floor in isolation. If a patient is too weak to contract on her own, neuromuscular electrical stimulation is used with an internal electrode to provide an assisted contraction.

Down-training (or relaxation) focuses on reducing tone in overactive pelvic muscles. It can improve symptoms of chronic pelvic pain, sexual pain, vulvodynia, and pudendal neuralgias. Patients are made aware of chronic holding patterns that lead to excess tone in the pelvic floor and learn how to release them through stretching, cardiovascular activity, meditation, and manual release of the involved muscle groups internally and externally. Internal musculature can be manipulated by a therapist in clinic or by the patient’s trained partner; the patient can also reach necessary areas with a vaginal dilator.

Functional coordination of the pelvic floor is needed for comfortable vaginal penetration and defecation. Training with biofeedback improves a patient’s ability to relax and open the pelvic floor.¹⁸ Vaginal dilators with surface electromyography are used to treat vaginismus to eliminate reflexive pelvic floor spasm during penetration. Perineal and vaginal compliance can be improved through manual release techniques with hands or vaginal dilators to restore normal mobility of tissues. This can reduce pain from postsurgical changes, postpartum sequelae, atrophic vaginal changes, shortened muscles from chronic holding, and adhesions.

PSYCHOSOCIAL INTERVENTIONS

Pelvic pain is not only a biomedical difficulty; psychosocial factors can contribute to and be affected by pelvic pain. Patients with pelvic pain often experience lower quality of life, higher rates of anxiety and depression, and increased stress compared with others.^19,20 People with pain also have more relationship stress, and patients’ partners often experience emotional distress, isolation, and feelings of powerlessness in the relationship.²¹

Psychosocial interventions, provided along with biomedical treatment, can help to reduce pain, anxiety, and depression and improve relational well-being.^22,23 In addition to attending to pain-related symptoms, comprehensive care involves recognizing and treating coexisting anxiety, depression, stress, and relationship conflict. Interventions for these difficulties are many, and a comprehensive list of interventions is beyond the focus of this section.¹⁹

Cognitive behavioral therapy is based on the idea that maladaptive cognitions can lead to problematic behaviors and emotional distress.²⁴ Interventions are carried out by a provider with specialized training in its use (eg, therapist, pain psychologist, psychiatrist).

Meta-analyses of studies that investigated the efficacy of cognitive behavioral therapy for chronic pain found consistent small to medium improvement in pain-related symptoms.²⁴ Studies that used cognitive behavioral therapy for pelvic pain found reduced overall pain severity and pain during intercourse, increased sexual satisfaction, enhanced sexual function, and less-exaggerated responses to pain.^25–27

Although cognitive behavioral therapy and mindfulness-based interventions produce positive outcomes, research on these interventions typically includes treatment carried out over a span of weeks. Common barriers to such care include lack of patient motivation, financial limitations, transportation problems, and time constraints.

The following psychosocial interventions have been chosen because they can be delivered in a short amount of time and integrated into a patient’s medical care by a medical or behavioral health provider. Because of the brevity and simplicity of these interventions, more patients with pelvic pain can receive psychosocial care as part of their usual medical encounters.

Behavioral activation

People experiencing depressive symptoms tend to isolate themselves and stop participating in activities they enjoy, including spending time with family and friends. Behavioral activation interventions that address such isolating behaviors have been shown to be effective in improving depressive symptoms.^28–30

A simple, brief intervention can be administered during routine medical care,²⁸ involving the following steps:

• Determine activities that the patient might implement that would decrease depressive symptoms. Questions such as, “When do you feel less depressed?” or “What brings you some happiness in your life?” can generate possible activities.
• Ask the patient to identify people in her life who have been supportive and with whom she could engage.
• Create with the patient a list of possible activities and social interactions that may enhance well-being.
• Make a schedule for participating in activities, possibly with rewards for completing them. Patients should be encouraged to follow the prescribed schedule of activities rather than make decisions based on mood or other factors. 

Relaxation strategies

Relaxation can help patients reduce stress and anxiety, and can also help reduce pain.^31–33

Diaphragmatic or “belly breathing” is a deep-breathing technique in which participants are asked to take in air through the nose and fully fill the lungs and lower belly. This technique allows the body to take in more oxygen, helping to lower blood pressure and slow the heartbeat. In addition to physiologic benefits, concentrating on deep breathing can help slow down or stop intrusive thoughts and distressing physical sensations.³⁴

Progressive muscle relaxation involves the systematic tensing and relaxing of each large muscle group in the body.³⁵ The goal is to eliminate physical and emotional stress through focusing on the sensations of tension and relaxation.

Scripts and audio and video resources for belly breathing and progressive muscle relaxation can be found on the Internet. The techniques can be taught during the medical appointment or offered as resources for home practice.

Couple-based care

Targeting couples is more effective for improving well-being than focusing solely on a patient’s psychosocial difficulties, so each of the above interventions may be more effective if tailored to include the patient’s partner.³⁶ If the partner is with the patient during medical visits or is included in long-term psychosocial treatment, he or she can be directly involved in learning and practicing interventions with the patient. If the partner is not present, the patient can be asked to practice newly learned well-being-enhancing strategies with her partner outside the appointment time. Couples therapy can improve psychosocial well-being for both partners.

Setting goals

Chronic pelvic pain is a common clinical problem in women, as prevalent in primary care as asthma or back pain.^1,2 It is often associated with lost work days and decreased productivity, increased healthcare spending, mood disorders, and negative effects on personal relationships.^1–3

While specialty care referral may eventually be indicated, primary care doctors can take steps to diagnose and effectively manage the condition.

COMPREHENSIVE MANAGEMENT LED BY PRIMARY CARE

Chronic pelvic pain is defined as pain in the lower abdomen persisting for 3 to 6 months and of sufficient severity to require medical care or cause a functional disability.³ It is often detrimental to a woman’s personal life and overall health, making a comprehensive assessment and multidisciplinary approach to management especially important.

The ideal care-delivery model is the patient-centered medical home, whereby a primary care physician coordinates comprehensive care with the help of an interdisciplinary team.^4,5 For complex cases, referral may be needed to other specialties (eg, obstetrics and gynecology, pain medicine) to help manage care.

TARGETED EVALUATION

Chronic pelvic pain often coexists with other systemic pain syndromes or psychiatric conditions common in primary care. Table 1 lists common causes and associated findings.

Detailed history is critical

The history is of utmost importance. Clinicians should query patients about the characteristics of the pain as well as their medical and surgical history. Particular attention should be given to obtaining a complete gynecologic history, including pregnancy, delivery complications, dyspareunia, sexual assault, and trauma. A detailed review of systems should focus on the reproductive, gastroenterologic, musculoskeletal, urologic, and neuropsychiatric systems.

As with many pain syndromes, allowing the patient to “tell her story” helps to establish rapport and obtain a more complete assessment. Chronic pelvic pain has been associated with physical or sexual abuse as a child or adult, so is essential to foster the doctor-patient relationship and create a safe and open space for disclosure.^3,6 It is important to screen women for safety at home as well as for satisfaction or dissatisfaction with their relationships with their spouse or partner and family.

Physical examination

The physical examination should be directed by the history but should always include abdominal and pelvic examinations. These should be conducted slowly and gently, assessing for areas of tenderness, masses, and other abnormalities. Clinicians should aim to pinpoint the exact anatomic locations of tenderness if possible. Ongoing dialogue facilitates this process by inquiring about pain at each point of the examination.

The pelvic examination should begin with visual inspection for redness, discharge, lesions, fissures, excoriations, and other abnormalities. A moistened cotton swab may be used to evaluate the vulva and vestibule for localized tenderness. The manual portion of the pelvic examination should begin with a single digit, noting any introital tenderness or spasm. Next, the levator ani muscles should be directly palpated for tone and tenderness. The pelvic floor should be evaluated with attention to tenderness of the bladder or musculoskeletal structures (Figure 1). A bimanual examination assessing uterine size and tenderness, nodularity, or a fixed, immobile uterus should be conducted.

Because the differential diagnosis of chronic pelvic pain is broad, the diagnostic workup and testing should be based on findings of the history and physical examination. In general, extensive laboratory testing is of limited use for evaluating women with chronic pelvic pain.^3,7

Urinalysis should be obtained for symptoms suggesting bladder involvement such as interstitial cystitis.

Pelvic ultrasonography can help identify pelvic masses palpated during the physical examination, but routine use of imaging is not recommended.^3,7 If pelvic congestion syndrome is suspected, starting with pelvic ultrasonography is reasonable before incurring the risk or cost of computed tomography or magnetic resonance imaging.⁸

GENERAL TREATMENT

Medical therapy

The main goals of medical therapy are to improve function and quality of life while minimizing adverse effects. General treatments include the following:

Analgesics. Nonsteroidal anti-inflammatory drugs and acetaminophen may provide pain relief, although there is weak evidence for their efficacy in treating chronic pelvic pain.⁹

Neuropathic agents. One of several available neuropathic agents commonly used in the treatment of chronic pain can be tried on patients who fail to respond to analgesics. Tricyclic antidepressants such as amitriptyline and imipramine decrease pain, reduce symptoms of depression, and improve sleep.¹⁰ The results of a small randomized controlled trial suggest that gabapentin is more effective than amitriptyline for reducing chronic pelvic pain.^11,12 Published guidelines currently list both amitriptyline and gabapentin as first-line agents; nortriptyline and pregabalin are considered acceptable initial alternatives.⁹

Venlafaxine and duloxetine may help chronic pelvic pain, although specific evidence is lacking. Duloxetine may be an appropriate choice for women with chronic pelvic pain who also experience depression and urinary stress incontinence.⁹

Opioids. Opioid therapy should be considered only when all other reasonable therapies have failed.¹⁰ Patients may develop tolerance or dependence, as well as opioid-induced adverse effects such as hyperalgesia.^9,10 Guidelines recommend that primary care providers consult with a pain management specialist before prescribing opioids, and that patients be thoroughly counseled about the risks and side effects.⁹

Nerve block and neuromodulation. There is weak evidence for the use of these modalities for treating chronic pelvic pain.⁹ If used, they should be part of a broader treatment plan and should be performed by providers who specialize in management of chronic pain.

DISEASE-SPECIFIC TREATMENT

Endometriosis: Hormonal therapy

Pelvic pain that significantly fluctuates with the menstrual cycle may be caused by endometriosis, the most common gynecologic cause of chronic pelvic pain. Women with cyclic chronic pelvic pain should be empirically treated with hormonal therapy for at least 3 to 6 months before diagnostic laparoscopy is performed.¹³

Oral contraceptives, gonadotropin-releasing hormone (GnRH) analogues, progestogens, and danazol have proven efficacy, although side-effect profiles differ significantly. In a comparative trial, patients treated with GnRH analogues had more improvement in pain scores compared with those treated with oral contraceptives, but they experienced a significant decrease in bone mineral density.¹¹ The effects on bone mineral density associated with GnRH analogue therapy can be mitigated by “add-back” low-dose hormonal therapy (norethindrone, low-dose estrogen, or a combination of estrogen and progesterone), which may also provide symptomatic relief for associated hot flashes and vaginal symptoms.¹¹

Interstitial cystitis often accompanies endometriosis

Recognizing that chronic pelvic pain may have more than one cause is important when developing a comprehensive care plan. Interstitial cystitis coexists with endometriosis in up to 60% of patients.¹⁴ Initial treatment is pentosan polysulfate sodium, an oral treatment approved by the US Food and Drug Administration for interstitial cystitis that works by restoring the protective glycosaminoglycan layer in the bladder.^14,15 Amitriptyline may also be used to treat interstitial cystitis-associated nocturia.

Myofascial pain: Neuromuscular blockers

According to a recent systematic review of therapies for chronic pelvic pain, patients with symptoms related to myofascial pain may benefit from neuromuscular blockade.¹² One randomized controlled trial of the effectiveness of botulinum toxin A vs saline for the treatment of chronic pelvic pain secondary to pelvic floor spasm found that after 6 months of observation, women who received botulinum toxin had significantly lower pain scores than those who received saline.¹²

Pelvic congestion syndrome may be treated with hormonal, radiologic, or surgical therapy.¹⁶ A randomized controlled trial involving patients with chronic pelvic pain secondary to pelvic congestion demonstrated that treatment with medroxyprogesterone acetate or a GnRH agonist (goserelin) improved pelvic symptoms.¹⁷

A Cochrane review of nonsurgical interventions for chronic pelvic pain included women with a diagnosis of pelvic congestion syndrome or adhesions. It found that patients treated with medroxyprogesterone acetate were more likely to have 50% pain reduction lasting up to 9 months compared with patients taking placebo.¹² In comparative studies, GnRH analogues were more effective in relieving pelvic pain than progestogen therapy.

Radiologic embolization therapy is as effective as hysterectomy for the relief of chronic pelvic pain related to pelvic congestion syndrome, and it can be performed in the outpatient setting.

Irritable bowel syndrome: Try dietary changes

Symptoms of chronic pelvic pain that are associated with changes in stool consistency and frequency suggest irritable bowel syndrome. Symptoms may improve with dietary changes and fiber supplementation. Antispasmodic agents are frequently used but their anticholinergic effects may worsen constipation.¹⁴

PELVIC PHYSICAL THERAPY

Pelvic physical therapy targets the musculoskeletal components of bowel, bladder, and sexual function to restore strength, flexibility, balance, and coordination to the pelvic floor and surrounding lumbopelvic muscles. Patients with dyspareunia, pain with activity, or a significant musculoskeletal abnormality (eg, vaginismus or point tenderness on examination) are particularly good candidates for this therapy. It is done by a physical therapist with special training in techniques to manipulate the pelvic floor to address pelvic pain.

Educating the patient

Informing the patient before the initial physical therapy visit is essential for success. Referring clinicians should emphasize to patients that treatment response can help to guide further physician intervention. Patients should be counseled that pelvic physical therapy includes a pelvic examination and an expectation to participate in a home program. Although noticeable improvement takes time, encouragement provided by the entire team, including medical providers, can help a patient maintain her care plan.

Therapists typically see a patient once a week for 8 to 12 visits initially. Insurance usually covers pelvic physical therapy through the same policy as routine physical therapy.

During the initial evaluation, the patient receives an external and internal pelvic examination assessing muscle length, strength, and coordination of the back, hip, and internal pelvic floor. Internal evaluation can be done vaginally or rectally, with one gloved finger, without the need for speculum or stirrups. Biofeedback and surface electromyography (using either perianal or internal electrode placement) are used to evaluate muscle activity and to assist the patient in developing appropriate motor control during strengthening or relaxation.¹⁸

Up-training (or strengthening) aims to improve pelvic floor endurance. It can improve pelvic instability and symptoms of heaviness and discomfort from prolapse. Patients learn to appropriately utilize the pelvic floor in isolation. If a patient is too weak to contract on her own, neuromuscular electrical stimulation is used with an internal electrode to provide an assisted contraction.

Down-training (or relaxation) focuses on reducing tone in overactive pelvic muscles. It can improve symptoms of chronic pelvic pain, sexual pain, vulvodynia, and pudendal neuralgias. Patients are made aware of chronic holding patterns that lead to excess tone in the pelvic floor and learn how to release them through stretching, cardiovascular activity, meditation, and manual release of the involved muscle groups internally and externally. Internal musculature can be manipulated by a therapist in clinic or by the patient’s trained partner; the patient can also reach necessary areas with a vaginal dilator.

Functional coordination of the pelvic floor is needed for comfortable vaginal penetration and defecation. Training with biofeedback improves a patient’s ability to relax and open the pelvic floor.¹⁸ Vaginal dilators with surface electromyography are used to treat vaginismus to eliminate reflexive pelvic floor spasm during penetration. Perineal and vaginal compliance can be improved through manual release techniques with hands or vaginal dilators to restore normal mobility of tissues. This can reduce pain from postsurgical changes, postpartum sequelae, atrophic vaginal changes, shortened muscles from chronic holding, and adhesions.

PSYCHOSOCIAL INTERVENTIONS

Pelvic pain is not only a biomedical difficulty; psychosocial factors can contribute to and be affected by pelvic pain. Patients with pelvic pain often experience lower quality of life, higher rates of anxiety and depression, and increased stress compared with others.^19,20 People with pain also have more relationship stress, and patients’ partners often experience emotional distress, isolation, and feelings of powerlessness in the relationship.²¹

Psychosocial interventions, provided along with biomedical treatment, can help to reduce pain, anxiety, and depression and improve relational well-being.^22,23 In addition to attending to pain-related symptoms, comprehensive care involves recognizing and treating coexisting anxiety, depression, stress, and relationship conflict. Interventions for these difficulties are many, and a comprehensive list of interventions is beyond the focus of this section.¹⁹

Cognitive behavioral therapy is based on the idea that maladaptive cognitions can lead to problematic behaviors and emotional distress.²⁴ Interventions are carried out by a provider with specialized training in its use (eg, therapist, pain psychologist, psychiatrist).

Meta-analyses of studies that investigated the efficacy of cognitive behavioral therapy for chronic pain found consistent small to medium improvement in pain-related symptoms.²⁴ Studies that used cognitive behavioral therapy for pelvic pain found reduced overall pain severity and pain during intercourse, increased sexual satisfaction, enhanced sexual function, and less-exaggerated responses to pain.^25–27

Although cognitive behavioral therapy and mindfulness-based interventions produce positive outcomes, research on these interventions typically includes treatment carried out over a span of weeks. Common barriers to such care include lack of patient motivation, financial limitations, transportation problems, and time constraints.

The following psychosocial interventions have been chosen because they can be delivered in a short amount of time and integrated into a patient’s medical care by a medical or behavioral health provider. Because of the brevity and simplicity of these interventions, more patients with pelvic pain can receive psychosocial care as part of their usual medical encounters.

Behavioral activation

People experiencing depressive symptoms tend to isolate themselves and stop participating in activities they enjoy, including spending time with family and friends. Behavioral activation interventions that address such isolating behaviors have been shown to be effective in improving depressive symptoms.^28–30

A simple, brief intervention can be administered during routine medical care,²⁸ involving the following steps:

• Determine activities that the patient might implement that would decrease depressive symptoms. Questions such as, “When do you feel less depressed?” or “What brings you some happiness in your life?” can generate possible activities.
• Ask the patient to identify people in her life who have been supportive and with whom she could engage.
• Create with the patient a list of possible activities and social interactions that may enhance well-being.
• Make a schedule for participating in activities, possibly with rewards for completing them. Patients should be encouraged to follow the prescribed schedule of activities rather than make decisions based on mood or other factors. 

Relaxation strategies

Relaxation can help patients reduce stress and anxiety, and can also help reduce pain.^31–33

Diaphragmatic or “belly breathing” is a deep-breathing technique in which participants are asked to take in air through the nose and fully fill the lungs and lower belly. This technique allows the body to take in more oxygen, helping to lower blood pressure and slow the heartbeat. In addition to physiologic benefits, concentrating on deep breathing can help slow down or stop intrusive thoughts and distressing physical sensations.³⁴

Progressive muscle relaxation involves the systematic tensing and relaxing of each large muscle group in the body.³⁵ The goal is to eliminate physical and emotional stress through focusing on the sensations of tension and relaxation.

Scripts and audio and video resources for belly breathing and progressive muscle relaxation can be found on the Internet. The techniques can be taught during the medical appointment or offered as resources for home practice.

Couple-based care

Targeting couples is more effective for improving well-being than focusing solely on a patient’s psychosocial difficulties, so each of the above interventions may be more effective if tailored to include the patient’s partner.³⁶ If the partner is with the patient during medical visits or is included in long-term psychosocial treatment, he or she can be directly involved in learning and practicing interventions with the patient. If the partner is not present, the patient can be asked to practice newly learned well-being-enhancing strategies with her partner outside the appointment time. Couples therapy can improve psychosocial well-being for both partners.

Setting goals

Sometimes the answer is straightforward—the pills were started to reduce knee pain, but the pain is still there. But sometimes if I suggest stopping a drug, I get surprising pushback from the patient: “But the pain may be worse without those pills.” And it can be hard to assess whether a medication has attained its therapeutic goal, such as when a drug is given to prevent or reduce the occurrence of intermittent events (eg, hydroxychloroquine to reduce flares in lupus, aspirin to prevent transient ischemic attacks). Unless a medication has been given sufficient time to have its effect and has clearly failed, we often have to trust its efficacy because those events might be more frequent if the drug were stopped.

In this issue of the Journal, Kim and Factora discuss a difficult scenario—discontinuing cognitive-enhancing therapy in patients with Alzheimer dementia. The stakes, hopes, and anxiety are high for the patient and caregivers. These drugs have only modest efficacy, and it is often difficult to know if they are working. To complicate matters, dementia is progressive, but the rate of progression differs among individuals, making it harder to be convinced that the drugs have lost their efficacy and that discontinuation is warranted in order to reduce the side effects, cost, and pill burden. Similar challenges arise for similar reasons when considering discontinuation of antipsychotics or other drugs given for behavioral reasons to elderly patients with dementia.¹

The issues surrounding downsizing medication lists—or deprescribing—extend far beyond patients with Alzheimer dementia. A disease may have progressed beyond the point where the drug can make a significant impact. Patients often develop tachyphylaxis to the newer protein drugs (biologics for rheumatoid arthritis, inflammatory bowel disease, psoriasis, or gout) due to the generation of neutralizing antidrug antibodies. At some point the patient’s life expectancy becomes a factor when considering medications directed at preventing long-term complications of a disease and the increased likelihood of significant adverse effects in patients as they age (eg, from aggressively prescribed antihypertensive and antidiabetic drugs). For drugs such as bisphosphonates, alkylating agents, and metoclopramide, complications of cumulative dosing over time should be considered a reason to discontinue therapy.

The take-home message from this article is to create opportunities to periodically revisit the rationale for all of a patient’s prescriptions, and to make sure patients are comfortable knowing why they should keep taking each of their medications. While revisiting a patient’s prescriptions may indeed reduce the medication burden, I believe it also enhances adherence to the remaining prescribed medications. The medication reconciliation process requires more than simply checking off the box in the EMR to indicate that the medications were “reviewed.”

Sometimes the answer is straightforward—the pills were started to reduce knee pain, but the pain is still there. But sometimes if I suggest stopping a drug, I get surprising pushback from the patient: “But the pain may be worse without those pills.” And it can be hard to assess whether a medication has attained its therapeutic goal, such as when a drug is given to prevent or reduce the occurrence of intermittent events (eg, hydroxychloroquine to reduce flares in lupus, aspirin to prevent transient ischemic attacks). Unless a medication has been given sufficient time to have its effect and has clearly failed, we often have to trust its efficacy because those events might be more frequent if the drug were stopped.

In this issue of the Journal, Kim and Factora discuss a difficult scenario—discontinuing cognitive-enhancing therapy in patients with Alzheimer dementia. The stakes, hopes, and anxiety are high for the patient and caregivers. These drugs have only modest efficacy, and it is often difficult to know if they are working. To complicate matters, dementia is progressive, but the rate of progression differs among individuals, making it harder to be convinced that the drugs have lost their efficacy and that discontinuation is warranted in order to reduce the side effects, cost, and pill burden. Similar challenges arise for similar reasons when considering discontinuation of antipsychotics or other drugs given for behavioral reasons to elderly patients with dementia.¹

The issues surrounding downsizing medication lists—or deprescribing—extend far beyond patients with Alzheimer dementia. A disease may have progressed beyond the point where the drug can make a significant impact. Patients often develop tachyphylaxis to the newer protein drugs (biologics for rheumatoid arthritis, inflammatory bowel disease, psoriasis, or gout) due to the generation of neutralizing antidrug antibodies. At some point the patient’s life expectancy becomes a factor when considering medications directed at preventing long-term complications of a disease and the increased likelihood of significant adverse effects in patients as they age (eg, from aggressively prescribed antihypertensive and antidiabetic drugs). For drugs such as bisphosphonates, alkylating agents, and metoclopramide, complications of cumulative dosing over time should be considered a reason to discontinue therapy.

The take-home message from this article is to create opportunities to periodically revisit the rationale for all of a patient’s prescriptions, and to make sure patients are comfortable knowing why they should keep taking each of their medications. While revisiting a patient’s prescriptions may indeed reduce the medication burden, I believe it also enhances adherence to the remaining prescribed medications. The medication reconciliation process requires more than simply checking off the box in the EMR to indicate that the medications were “reviewed.”

Sometimes the answer is straightforward—the pills were started to reduce knee pain, but the pain is still there. But sometimes if I suggest stopping a drug, I get surprising pushback from the patient: “But the pain may be worse without those pills.” And it can be hard to assess whether a medication has attained its therapeutic goal, such as when a drug is given to prevent or reduce the occurrence of intermittent events (eg, hydroxychloroquine to reduce flares in lupus, aspirin to prevent transient ischemic attacks). Unless a medication has been given sufficient time to have its effect and has clearly failed, we often have to trust its efficacy because those events might be more frequent if the drug were stopped.

In this issue of the Journal, Kim and Factora discuss a difficult scenario—discontinuing cognitive-enhancing therapy in patients with Alzheimer dementia. The stakes, hopes, and anxiety are high for the patient and caregivers. These drugs have only modest efficacy, and it is often difficult to know if they are working. To complicate matters, dementia is progressive, but the rate of progression differs among individuals, making it harder to be convinced that the drugs have lost their efficacy and that discontinuation is warranted in order to reduce the side effects, cost, and pill burden. Similar challenges arise for similar reasons when considering discontinuation of antipsychotics or other drugs given for behavioral reasons to elderly patients with dementia.¹

The issues surrounding downsizing medication lists—or deprescribing—extend far beyond patients with Alzheimer dementia. A disease may have progressed beyond the point where the drug can make a significant impact. Patients often develop tachyphylaxis to the newer protein drugs (biologics for rheumatoid arthritis, inflammatory bowel disease, psoriasis, or gout) due to the generation of neutralizing antidrug antibodies. At some point the patient’s life expectancy becomes a factor when considering medications directed at preventing long-term complications of a disease and the increased likelihood of significant adverse effects in patients as they age (eg, from aggressively prescribed antihypertensive and antidiabetic drugs). For drugs such as bisphosphonates, alkylating agents, and metoclopramide, complications of cumulative dosing over time should be considered a reason to discontinue therapy.

The take-home message from this article is to create opportunities to periodically revisit the rationale for all of a patient’s prescriptions, and to make sure patients are comfortable knowing why they should keep taking each of their medications. While revisiting a patient’s prescriptions may indeed reduce the medication burden, I believe it also enhances adherence to the remaining prescribed medications. The medication reconciliation process requires more than simply checking off the box in the EMR to indicate that the medications were “reviewed.”

In the article, “Update on the management of venous thromboembolism” (Bartholomew JR, Cleve Clin J Med 2017; 84[suppl 3]:39–46), 2 sentences in the text regarding dose reduction for body weight have errors. The corrected sentences follow:

On page 42, left column, the last 5 lines should read: “The recommended dose should be reduced to 2.5 mg twice daily in patients that meet 2 of the following criteria: age 80 or older; body weight of 60 kg or less; or with a serum creatinine 1.5 mg/dL or greater.”

And on page 42, right column, the sentence 10 lines from the top should read: “Edoxaban is given orally at 60 mg once daily but reduced to 30 mg once daily if the CrCL is 30 mL/min to 50 mL/min, if body weight is 60 kg or less, or with use of certain P-glycoprotein inhibitors.”

In the article, “Update on the management of venous thromboembolism” (Bartholomew JR, Cleve Clin J Med 2017; 84[suppl 3]:39–46), 2 sentences in the text regarding dose reduction for body weight have errors. The corrected sentences follow:

On page 42, left column, the last 5 lines should read: “The recommended dose should be reduced to 2.5 mg twice daily in patients that meet 2 of the following criteria: age 80 or older; body weight of 60 kg or less; or with a serum creatinine 1.5 mg/dL or greater.”

And on page 42, right column, the sentence 10 lines from the top should read: “Edoxaban is given orally at 60 mg once daily but reduced to 30 mg once daily if the CrCL is 30 mL/min to 50 mL/min, if body weight is 60 kg or less, or with use of certain P-glycoprotein inhibitors.”

In the article, “Update on the management of venous thromboembolism” (Bartholomew JR, Cleve Clin J Med 2017; 84[suppl 3]:39–46), 2 sentences in the text regarding dose reduction for body weight have errors. The corrected sentences follow:

On page 42, left column, the last 5 lines should read: “The recommended dose should be reduced to 2.5 mg twice daily in patients that meet 2 of the following criteria: age 80 or older; body weight of 60 kg or less; or with a serum creatinine 1.5 mg/dL or greater.”

And on page 42, right column, the sentence 10 lines from the top should read: “Edoxaban is given orally at 60 mg once daily but reduced to 30 mg once daily if the CrCL is 30 mL/min to 50 mL/min, if body weight is 60 kg or less, or with use of certain P-glycoprotein inhibitors.”

Medical students remain protected by DACA – for now. The AIDS epidemic’s skin villains are back, there’s a new leading cause of liver cancer, and how storage of firearms at home affects suicidal teens.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

Medical students remain protected by DACA – for now. The AIDS epidemic’s skin villains are back, there’s a new leading cause of liver cancer, and how storage of firearms at home affects suicidal teens.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

Medical students remain protected by DACA – for now. The AIDS epidemic’s skin villains are back, there’s a new leading cause of liver cancer, and how storage of firearms at home affects suicidal teens.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

Click here to access the March 2018 Digital Edition.

Table of Contents

• A Nationwide Survey and Needs Assessment of Colonoscopy Quality Assurance Programs
• Incidence and Management of Asymptomatic Hypertensive Urgency at a VA Emergency Department
• Gabapentin Use in Acute Alcohol Withdrawal Management
• Medical Marijuana Redux
• Choice Program Expansion Jeopardizes High-Quality VHA Mental Health Services
• Brigadier General Carl Rogers Darnall: Saving Lives on a Massive Scale

Click here to access the March 2018 Digital Edition.

Table of Contents

• A Nationwide Survey and Needs Assessment of Colonoscopy Quality Assurance Programs
• Incidence and Management of Asymptomatic Hypertensive Urgency at a VA Emergency Department
• Gabapentin Use in Acute Alcohol Withdrawal Management
• Medical Marijuana Redux
• Choice Program Expansion Jeopardizes High-Quality VHA Mental Health Services
• Brigadier General Carl Rogers Darnall: Saving Lives on a Massive Scale

Click here to access the March 2018 Digital Edition.

Table of Contents

• A Nationwide Survey and Needs Assessment of Colonoscopy Quality Assurance Programs
• Incidence and Management of Asymptomatic Hypertensive Urgency at a VA Emergency Department
• Gabapentin Use in Acute Alcohol Withdrawal Management
• Medical Marijuana Redux
• Choice Program Expansion Jeopardizes High-Quality VHA Mental Health Services
• Brigadier General Carl Rogers Darnall: Saving Lives on a Massive Scale

Click here to access Combating Public Pathogens in Federal Health Care Systems

Table of Contents

• Current State of Hepatitis C Care in the VA
• Integrating Care for Patients With Chronic Liver Disease and Mental Health and Substance Use Disorders
• Hepatitis A Virus Prevention and Vaccination Within and Outside the VHA in Light of Recent Outbreaks
• Accessibility and Uptake of Pre-Exposure Prophylaxis for HIV Prevention in the VHA
• Achieving Excellence in Hepatitis B Virus Care for Veterans in the VHA

Click here to access Combating Public Pathogens in Federal Health Care Systems

Table of Contents

• Current State of Hepatitis C Care in the VA
• Integrating Care for Patients With Chronic Liver Disease and Mental Health and Substance Use Disorders
• Hepatitis A Virus Prevention and Vaccination Within and Outside the VHA in Light of Recent Outbreaks
• Accessibility and Uptake of Pre-Exposure Prophylaxis for HIV Prevention in the VHA
• Achieving Excellence in Hepatitis B Virus Care for Veterans in the VHA

Click here to access Combating Public Pathogens in Federal Health Care Systems

Table of Contents

• Current State of Hepatitis C Care in the VA
• Integrating Care for Patients With Chronic Liver Disease and Mental Health and Substance Use Disorders
• Hepatitis A Virus Prevention and Vaccination Within and Outside the VHA in Light of Recent Outbreaks
• Accessibility and Uptake of Pre-Exposure Prophylaxis for HIV Prevention in the VHA
• Achieving Excellence in Hepatitis B Virus Care for Veterans in the VHA

The lesions on this 41-year-old African-American woman’s skin have waxed and waned over the years—but they’re always on her mind. They are most prominent on her arms and trunk but crop up almost anywhere on her body.

When they manifest—for no apparent reason—they itch, creating an irresistible urge for the patient to pick at them. This provides some relief, both from the itching and from her feeling that there is “something in there” that she needs to remove. Fairly often, her digging (with fingernails) results in “finding” white bumps at the ends of tiny hairs.

As these small excoriations heal, the wounds itch—compelling her to pick the site open again. She knows she is caught in a vicious cycle but doesn’t know how to stop. Selective serotonin reuptake inhibitors have been tried, with little to no effect.

EXAMINATION
The patient’s type IV skin is covered with dark brown, maculopapular lesions that are so numerous and large (average diameter, 2 to 3 cm) that they are impossible to ignore. Her palms, soles, face, and midback are spared.

Only a few of the newer lesions are palpable, showing faint signs of central excoriation. Previous biopsies failed to show significant pathology.

The patient appears ill at ease during history-taking. She admits to picking her skin for many years but doesn’t believe she is inhabited by any kind of bug. The skin on her wrists and between her fingers is clear. Her 3-year-old daughter’s skin is free of notable changes.

What is the diagnosis?

While it has been posited as a form of obsessive compulsive disorder (OCD), dermatillomania responds poorly, if at all, to standard OCD treatments. It is considered by others to more closely resemble addiction because, despite knowing its harm, patients persistently pick at the skin and often report a subsequent sense of relief.

This patient’s type IV skin lent itself to postinflammatory hyperpigmentation upon injury. Although she knew this, she still felt that she could somehow pick the darkness away.

Bloodwork was done to rule out other conditions, such as porphyria, hematologic disease, and renal or liver disease. Had a recent biopsy not been performed, this would have been included to rule out systemic disease.

The patient was given a topical steroid cream to put on any itchy lesions and counseled to avoid picking or scratching them, since this was the only way her skin could ever clear.

TAKE-HOME LEARNING POINTS

• One common term for this patient’s disorder is dermatillomania, though the DSM-5 and ICD-10 refer to it as skin-picking disorder.
• This patient experienced postinflammatory hyperpigmentation, which caused her considerable embarrassment.
• Many affected patients have unresolved underlying psychologic issues that contribute to their problem.
• The solution (which may require extensive counseling): Stop picking, and the dark lesions will eventually resolve.

The lesions on this 41-year-old African-American woman’s skin have waxed and waned over the years—but they’re always on her mind. They are most prominent on her arms and trunk but crop up almost anywhere on her body.

When they manifest—for no apparent reason—they itch, creating an irresistible urge for the patient to pick at them. This provides some relief, both from the itching and from her feeling that there is “something in there” that she needs to remove. Fairly often, her digging (with fingernails) results in “finding” white bumps at the ends of tiny hairs.

As these small excoriations heal, the wounds itch—compelling her to pick the site open again. She knows she is caught in a vicious cycle but doesn’t know how to stop. Selective serotonin reuptake inhibitors have been tried, with little to no effect.

EXAMINATION
The patient’s type IV skin is covered with dark brown, maculopapular lesions that are so numerous and large (average diameter, 2 to 3 cm) that they are impossible to ignore. Her palms, soles, face, and midback are spared.

Only a few of the newer lesions are palpable, showing faint signs of central excoriation. Previous biopsies failed to show significant pathology.

The patient appears ill at ease during history-taking. She admits to picking her skin for many years but doesn’t believe she is inhabited by any kind of bug. The skin on her wrists and between her fingers is clear. Her 3-year-old daughter’s skin is free of notable changes.

What is the diagnosis?

While it has been posited as a form of obsessive compulsive disorder (OCD), dermatillomania responds poorly, if at all, to standard OCD treatments. It is considered by others to more closely resemble addiction because, despite knowing its harm, patients persistently pick at the skin and often report a subsequent sense of relief.

This patient’s type IV skin lent itself to postinflammatory hyperpigmentation upon injury. Although she knew this, she still felt that she could somehow pick the darkness away.

Bloodwork was done to rule out other conditions, such as porphyria, hematologic disease, and renal or liver disease. Had a recent biopsy not been performed, this would have been included to rule out systemic disease.

The patient was given a topical steroid cream to put on any itchy lesions and counseled to avoid picking or scratching them, since this was the only way her skin could ever clear.

TAKE-HOME LEARNING POINTS

• One common term for this patient’s disorder is dermatillomania, though the DSM-5 and ICD-10 refer to it as skin-picking disorder.
• This patient experienced postinflammatory hyperpigmentation, which caused her considerable embarrassment.
• Many affected patients have unresolved underlying psychologic issues that contribute to their problem.
• The solution (which may require extensive counseling): Stop picking, and the dark lesions will eventually resolve.

The lesions on this 41-year-old African-American woman’s skin have waxed and waned over the years—but they’re always on her mind. They are most prominent on her arms and trunk but crop up almost anywhere on her body.

When they manifest—for no apparent reason—they itch, creating an irresistible urge for the patient to pick at them. This provides some relief, both from the itching and from her feeling that there is “something in there” that she needs to remove. Fairly often, her digging (with fingernails) results in “finding” white bumps at the ends of tiny hairs.

As these small excoriations heal, the wounds itch—compelling her to pick the site open again. She knows she is caught in a vicious cycle but doesn’t know how to stop. Selective serotonin reuptake inhibitors have been tried, with little to no effect.

EXAMINATION
The patient’s type IV skin is covered with dark brown, maculopapular lesions that are so numerous and large (average diameter, 2 to 3 cm) that they are impossible to ignore. Her palms, soles, face, and midback are spared.

Only a few of the newer lesions are palpable, showing faint signs of central excoriation. Previous biopsies failed to show significant pathology.

The patient appears ill at ease during history-taking. She admits to picking her skin for many years but doesn’t believe she is inhabited by any kind of bug. The skin on her wrists and between her fingers is clear. Her 3-year-old daughter’s skin is free of notable changes.

What is the diagnosis?

While it has been posited as a form of obsessive compulsive disorder (OCD), dermatillomania responds poorly, if at all, to standard OCD treatments. It is considered by others to more closely resemble addiction because, despite knowing its harm, patients persistently pick at the skin and often report a subsequent sense of relief.

This patient’s type IV skin lent itself to postinflammatory hyperpigmentation upon injury. Although she knew this, she still felt that she could somehow pick the darkness away.

Bloodwork was done to rule out other conditions, such as porphyria, hematologic disease, and renal or liver disease. Had a recent biopsy not been performed, this would have been included to rule out systemic disease.

The patient was given a topical steroid cream to put on any itchy lesions and counseled to avoid picking or scratching them, since this was the only way her skin could ever clear.

TAKE-HOME LEARNING POINTS

• One common term for this patient’s disorder is dermatillomania, though the DSM-5 and ICD-10 refer to it as skin-picking disorder.
• This patient experienced postinflammatory hyperpigmentation, which caused her considerable embarrassment.
• Many affected patients have unresolved underlying psychologic issues that contribute to their problem.
• The solution (which may require extensive counseling): Stop picking, and the dark lesions will eventually resolve.

Recently, exciting clinical progress has been made in the study of hepatotropic pathogens in the context of liver-dependent infectious diseases. Tissue engineering has been applied to authentically recapitulate human liver biology, facilitating the study of host-pathogen interactions during the entire pathogen life cycle. This is crucial for the development and validation of therapeutic interventions, such as drug and vaccine candidates that may act on the liver cells. The engineered models range from two-dimensional (2-D) cultures of primary human hepatocytes (HH) and stem cell–derived progeny to three-dimensional (3-D) organoid cultures and humanized rodent models. A review by Nil Gural and colleagues, published in Cellular and Molecular Gastroenterology and Hepatology, described these unique models. Furthermore, the progress made in combining individual approaches and pairing the most appropriate model system and readout modality was discussed.

The major human hepatotropic pathogens include hepatitis C virus (HCV), hepatitis B virus (HBV), and the protozoan parasites Plasmodium falciparum and P. vivax. While HBV and HCV can cause chronic liver diseases such as cirrhosis and hepatocellular carcinoma, Plasmodium parasites cause malaria. The use of cancer cell lines and animal models to study host-pathogen interactions is limited by uncontrolled proliferation, abnormal liver-specific functions, and stringent host dependency of the hepatotropic pathogens. HHs are thus the only ideal system to study these pathogens, however, maintaining these cells ex vivo is challenging.

For instance, 2D monolayers of human hepatoma-derived cell lines (such as HepG2-A16 and HepaRG) are easier to maintain, to amplify for scaling up, and to use for drug screening, thus representing a renewable alternative to primary hepatocytes. These model systems have been useful to study short-term infections of human Plasmodium parasites (P. vivax and P. falciparum); other hepatotropic pathogens such as Ebola, Lassa, human cytomegalovirus, and dengue viruses; and to generate virion stocks (HCV, HBV). For long-term scientific analyses and cultures, as well as clinical isolates of pathogens that do not infect hepatoma cells, immortalized cell lines have been engineered to differentiate and maintain HH functions for a longer duration. Additionally, cocultivation of primary hepatocytes with nonparenchymal cells or hepatocytes with mouse fibroblasts preserves hepatocyte phenotype. The latter is a self-assembling coculture system that could potentially maintain an infection for over 30 days and be used for testing anti-HBV drugs. A micropatterned coculture system, in which hepatocytes are positioned in “islands” via photolithographic patterning of collagen, surrounded by mouse embryonic fibroblasts, can maintain hepatocyte phenotypes for 4-6 weeks, and remain permissive to P. falciparum, P. vivax, HBV, and HCV infections. Furthermore, micropatterned coculture systems support full developmental liver stages of both P. falciparum and P. vivax, with the release of merozoites from hepatocytes and their subsequent infection of overlaid human red blood cells.

Alternatively, embryonic stem cells and induced pluripotent stem cells of human origin can be differentiated into hepatocytelike cells that enable investigation of host genetics within the context of host-pathogen interactions, and can also be used for target identification for drug development. However, stem cell cultures require significant culture expertise and may not represent a fully differentiated adult hepatocyte phenotype.

Recently, exciting clinical progress has been made in the study of hepatotropic pathogens in the context of liver-dependent infectious diseases. Tissue engineering has been applied to authentically recapitulate human liver biology, facilitating the study of host-pathogen interactions during the entire pathogen life cycle. This is crucial for the development and validation of therapeutic interventions, such as drug and vaccine candidates that may act on the liver cells. The engineered models range from two-dimensional (2-D) cultures of primary human hepatocytes (HH) and stem cell–derived progeny to three-dimensional (3-D) organoid cultures and humanized rodent models. A review by Nil Gural and colleagues, published in Cellular and Molecular Gastroenterology and Hepatology, described these unique models. Furthermore, the progress made in combining individual approaches and pairing the most appropriate model system and readout modality was discussed.

The major human hepatotropic pathogens include hepatitis C virus (HCV), hepatitis B virus (HBV), and the protozoan parasites Plasmodium falciparum and P. vivax. While HBV and HCV can cause chronic liver diseases such as cirrhosis and hepatocellular carcinoma, Plasmodium parasites cause malaria. The use of cancer cell lines and animal models to study host-pathogen interactions is limited by uncontrolled proliferation, abnormal liver-specific functions, and stringent host dependency of the hepatotropic pathogens. HHs are thus the only ideal system to study these pathogens, however, maintaining these cells ex vivo is challenging.

For instance, 2D monolayers of human hepatoma-derived cell lines (such as HepG2-A16 and HepaRG) are easier to maintain, to amplify for scaling up, and to use for drug screening, thus representing a renewable alternative to primary hepatocytes. These model systems have been useful to study short-term infections of human Plasmodium parasites (P. vivax and P. falciparum); other hepatotropic pathogens such as Ebola, Lassa, human cytomegalovirus, and dengue viruses; and to generate virion stocks (HCV, HBV). For long-term scientific analyses and cultures, as well as clinical isolates of pathogens that do not infect hepatoma cells, immortalized cell lines have been engineered to differentiate and maintain HH functions for a longer duration. Additionally, cocultivation of primary hepatocytes with nonparenchymal cells or hepatocytes with mouse fibroblasts preserves hepatocyte phenotype. The latter is a self-assembling coculture system that could potentially maintain an infection for over 30 days and be used for testing anti-HBV drugs. A micropatterned coculture system, in which hepatocytes are positioned in “islands” via photolithographic patterning of collagen, surrounded by mouse embryonic fibroblasts, can maintain hepatocyte phenotypes for 4-6 weeks, and remain permissive to P. falciparum, P. vivax, HBV, and HCV infections. Furthermore, micropatterned coculture systems support full developmental liver stages of both P. falciparum and P. vivax, with the release of merozoites from hepatocytes and their subsequent infection of overlaid human red blood cells.

Alternatively, embryonic stem cells and induced pluripotent stem cells of human origin can be differentiated into hepatocytelike cells that enable investigation of host genetics within the context of host-pathogen interactions, and can also be used for target identification for drug development. However, stem cell cultures require significant culture expertise and may not represent a fully differentiated adult hepatocyte phenotype.

Recently, exciting clinical progress has been made in the study of hepatotropic pathogens in the context of liver-dependent infectious diseases. Tissue engineering has been applied to authentically recapitulate human liver biology, facilitating the study of host-pathogen interactions during the entire pathogen life cycle. This is crucial for the development and validation of therapeutic interventions, such as drug and vaccine candidates that may act on the liver cells. The engineered models range from two-dimensional (2-D) cultures of primary human hepatocytes (HH) and stem cell–derived progeny to three-dimensional (3-D) organoid cultures and humanized rodent models. A review by Nil Gural and colleagues, published in Cellular and Molecular Gastroenterology and Hepatology, described these unique models. Furthermore, the progress made in combining individual approaches and pairing the most appropriate model system and readout modality was discussed.

The major human hepatotropic pathogens include hepatitis C virus (HCV), hepatitis B virus (HBV), and the protozoan parasites Plasmodium falciparum and P. vivax. While HBV and HCV can cause chronic liver diseases such as cirrhosis and hepatocellular carcinoma, Plasmodium parasites cause malaria. The use of cancer cell lines and animal models to study host-pathogen interactions is limited by uncontrolled proliferation, abnormal liver-specific functions, and stringent host dependency of the hepatotropic pathogens. HHs are thus the only ideal system to study these pathogens, however, maintaining these cells ex vivo is challenging.

For instance, 2D monolayers of human hepatoma-derived cell lines (such as HepG2-A16 and HepaRG) are easier to maintain, to amplify for scaling up, and to use for drug screening, thus representing a renewable alternative to primary hepatocytes. These model systems have been useful to study short-term infections of human Plasmodium parasites (P. vivax and P. falciparum); other hepatotropic pathogens such as Ebola, Lassa, human cytomegalovirus, and dengue viruses; and to generate virion stocks (HCV, HBV). For long-term scientific analyses and cultures, as well as clinical isolates of pathogens that do not infect hepatoma cells, immortalized cell lines have been engineered to differentiate and maintain HH functions for a longer duration. Additionally, cocultivation of primary hepatocytes with nonparenchymal cells or hepatocytes with mouse fibroblasts preserves hepatocyte phenotype. The latter is a self-assembling coculture system that could potentially maintain an infection for over 30 days and be used for testing anti-HBV drugs. A micropatterned coculture system, in which hepatocytes are positioned in “islands” via photolithographic patterning of collagen, surrounded by mouse embryonic fibroblasts, can maintain hepatocyte phenotypes for 4-6 weeks, and remain permissive to P. falciparum, P. vivax, HBV, and HCV infections. Furthermore, micropatterned coculture systems support full developmental liver stages of both P. falciparum and P. vivax, with the release of merozoites from hepatocytes and their subsequent infection of overlaid human red blood cells.

Alternatively, embryonic stem cells and induced pluripotent stem cells of human origin can be differentiated into hepatocytelike cells that enable investigation of host genetics within the context of host-pathogen interactions, and can also be used for target identification for drug development. However, stem cell cultures require significant culture expertise and may not represent a fully differentiated adult hepatocyte phenotype.

Baby Boomers—a term used to refer to individuals born in the United States between 1946 and 1964—are now approaching old age. Surprisingly, these older adults are using illicit substances in a pattern not seen in prior generations of older adults, including developing substance use disorders (SUDs) at increasingly higher rates; in previous generations, the prevalence of such disorders typically lowered with advancing age.

This article discusses how to recognize and treat SUDs in older adults. Alcohol is the most commonly used substance among older adults,¹ and there is a largebody of literature describing the identification and treatment of alcohol-related disorders in these patients. Therefore, this article will instead focus on older adults’ use of illicit substances, including marijuana, cocaine, and heroin.

Epidemiology

Prior clinical data regarding substance abuse in older adults focused on alcohol, prescription drugs, nicotine, and caffeine.² In the past, compared with younger adults, older adults had lower rates of alcohol and other illicit drug use.^3,4 Baby Boomers appear to be defying this trend.

A 2013 Substance Abuse and Mental Health Services Administration survey found that the percentage of adults ages 50 to 64 who used illicit substances increased from 2.7% in 2002 to 6.0% in 2013.⁵ Specifically, during that time, past-month illicit substance use increased from 3.4% to 7.9% among those ages 50 to 54, from 1.9% to 5.7% among those ages 55 to 59, and from 2.5% to 3.9% among those ages 60 to 64.⁵

More recently, a 2014 study of geriatric patients found that of the 1,302 patients age ≥65 admitted to a Level 1 trauma center, 48.3% had a positive urine drug screen.⁶ Someresearchers have estimated that 5.7 million older adults will require treatment for a substance use disorder in 2020, which is roughly double the 2.8 million who had an SUD in 2002 to 2006.⁷

Risk factors and patterns of substance abuse

Individual, social, and familial factors can contribute to substance use and abuse in late life. The Table¹ outlines some of the potential risk factors for older adults associated with the use of illicit substances. Substance abuse among older adults can be divided into 2 broad categories: early onset (starting before age 50) and late onset (starting after age 50).⁸ While data are limited, in general, early-onset use is a more common pattern; late-onset use represents an estimated <10% of substance use among older adults. The factors that lead some adults to continue substance use in late life, or to begin substance use later in life, have not been thoroughly evaluated.

Although older adults may abuse a wide variety of illicit substances, here we describe their use of marijuana, cocaine, and heroin.

Marijuana use has changed substantially in the last decade. While marijuana is illegal under federal law, as of November 2017, 29 states had legalized marijuana for medicinal purposes and 7 states and the District of Columbia had legalized it for recreational use. The increased legal and social acceptance of marijuana has led to new businesses and methods of use beyond smoking. New types of marijuana products include edible substances, tinctures, and oils that can be vaporized and inhaled.

In addition to euphoria and relaxation, the effects of marijuana use include increased latency time and decreased ability to respond to stimuli.² Nonpsychiatric effects of marijuana include shallow breathing, weakened immune system, and increasing cardiac workload.² The latter effect is especially important for older adults, many of whom may have preexisting cardiac illness and may be more likely to experience an adverse cardiac event as a result of marijuana use.² Older adults who begin to use marijuana in late life may do so not primarily as a social activity, but more likely to experience the drug’s potentially beneficial effects on pain or appetite.² For more on theuse of marijuana for these reasons, see “Medical marijuana: Do the benefits outweigh the risks?” in Current Psychiatry, January 2018, p. 34-41.

Cocaine. Although cocaine is a CNS stimulant that causes a short-lived euphoria, its adverse effects impact many body systems.⁹ Myocardial infarction (MI) secondary to coronary artery vasospasms, stroke (hemorrhagic and ischemic), seizures, psychosis, aortic dissection, and acute renal injury are some of the most severe complications. Acute MI is the most frequent and severe cardiovascular complication seen among abusers.¹⁰ Cocaine use can cause dizziness, restlessness, headache, mydriasis, and anxiety.

In a pilot study, Kalapatapu et al¹¹ compared the effects of cocaine abuse in younger vs older users. They found that older users had similar patterns of cocaine abuse in terms of the amount of cocaine used and frequency of use.¹¹ They also found that specific cognitive functions, including psychomotor speed, attention, and short-term memory, are particularly sensitive to the combined effects of aging and cocaine abuse.¹¹

Heroin is an opioid and a CNS depressant. Common effects include slowed heart rate, decreased blood pressure, and decreased respiration rate. Chronic heroin users show an overall decrease in immune system functioning¹²; this deficit might be particularly pronounced in an older person whose immune system functioning has already begun to decline as a result of aging. In recent years, as is the case with younger substance users, prescription opioids have replaced heroin as the opioid of choice among older users. However, for some early-onset heroin users, the use of this particular drug becomes well entrenched and unlikely to change, even in late life. Each year of heroin use increases the likelihood of continued use the next year by approximately 3%.² Some research suggests that older heroin users do not decrease their use over time, and face many of the same risks as younger users, including poorer physical and mental health, severe physical disability, and mortality.¹³

There are no screening protocols in the clinical setting that are designed specifically for detecting illicit substance abuse among older adults. Furthermore, diagnosis can be easily overlooked because the signs and symptoms of illicit substance use can be mistaken for other illnesses. To complicate matters further, older adults often do not disclose their substance use, understate it, or even try to explain away their symptoms.¹ Many older adults live alone, which may increase their risk of receiving no treatment.¹⁴

Older adults generally experience reduced tolerance to the effects of illicit substances because of age-related physiologic changes, such as decreases in renal functioning, motor functioning, and cardiac output; altered liver metabolism of certain drugs; and elevated blood glucose levels.¹⁵ As a result, symptoms of illicit substance use could be mistaken for dementia or other forms of cognitive impairment.^1,16

Although not designed specifically for older adults, an evidence-based screening instrument, such as the CAGE Questionnaire Adapted to Include Drugs, may be helpful in identifying substance abuse in these patients. Urine and/or serum drug screening, along with obtaining a comprehensive history from a trustworthy source, is useful for diagnosis.

Pharmacologic treatments

Research evaluating the use of medication for treating substance abuse specifically in older adults is extremely limited; studies have focused primarily on younger patients or mixed-age populations. Treatments that have been shown to be effective for younger patients may or may not be effective for older adults.

Marijuana. There are no FDA-approved treatments for marijuana abuse. An open-label study found that N-acetylcysteine, 1,200 mg twice a day, resulted in a significant reduction in marijuana craving as measured by the 12-item version of the Marijuana Craving Questionnaire.¹⁷ In a double-blinded placebo-controlled study, adolescents who were dependent on marijuana who received N-acetylcysteine, 1,200 mg twice a day, were more than twice likely to stop marijuana use compared with those who received placebo.¹⁸ Some researchers have proposed that N-acetylcysteine may prevent continued use of marijuana via glutamate modulation in the nucleus accumbens. Animal models have demonstrated that chronic drug self-administration downregulates the cystine-glutamate exchanger in the nucleus accumbens, and that N-acetylcysteine upregulates this exchanger, which reduces reinstatement of drug seeking.Further studies are needed to verify this speculation.

Cocaine. There are no FDA-approved treatments for cocaine abuse. No specific treatment approach has been found to be consistently effective.

A potential “cocaine vaccine” called TA-CD, which is made from succinyl norcocaine conjugated to cholera toxin, is being evaluated. An initial study had promising results, finding a significant reduction in cocaine use among those who received TA-CD.¹⁹ A later double-blinded placebo-controlled study only partially replicated the efficacy found in the initial study.²⁰

Currently, other cocaine treatments are also being investigated. An enzyme to rapidly metabolize cocaine is being evaluated.²¹ So far, none of these treatments have targeted older adults, and there may be age-specific issues to consider if these approaches eventually receive FDA approval.

Heroin. Several FDA-approved medications are available for treating dependency to heroin and other opioids, including naltrexone, buprenorphine, and methadone, but none have been studied specifically in older adults. Some studies of transdermal buprenorphine for treating chronic pain in older adults have concluded that this formulation may offer advantages for older patients.^22,23 Compared with oral or sublingual buprenorphine, the transdermal formulation avoids the first-pass effect in the liver, thus greatly increasing bioavailability of the drug; avoids renal metabolism; and offers greater tolerability in patients with mild to moderate hepatic impairment.^22,23 However, transdermal buprenorphine has been approved only for the treatment of pain. These beneficial aspects of transdermal buprenorphine may be applicable to older opioid users, but no age-specific studies of buprenorphine for treating opioid abuse have been conducted.

Nonpharmacologic treatments

The same psychotherapeutic treatments used to treat younger patients with SUDs may be appropriate for older adults. Older patients may experience feelings of isolation and shame related to needing treatment for substance abuse. These factors in treatment of older patients often are overcome by group psychotherapy. Self-help programs, such as Narcotics Anonymous or Alcoholics Anonymous, and group therapy also may be options.

On the other hand, individual psychotherapy, such as cognitive-behavioral therapy (CBT), interpersonal therapy, and psychodynamic therapy, can provide a private and confidential environment for older adults who are less social.²⁴

The highly structured nature of CBT may be well suited to older adults who have memory difficulties.¹ A study of 110 older veterans with substance abuse problems found evidence for the effectiveness of group CBT among these patients.²⁵ All but 8 participants in this study were age ≥65. The intervention consisted of 16 weekly group sessions that began with analysis of substance use behavior to determine high-risk situations for use, followed by a series of modules to teach skills for coping with social pressure, being at home and alone, feelings of depression and loneliness, anxiety and tension, anger and frustration, cues for substance use, and other factors. Approximately 44% (49 of 110) completed treatment (≥13 sessions). Approximately 55% of those who completed the treatment were abstinent at 6-month follow-up.²⁵

Don’t assume your older patient is not using illicit substances

It is a myth that older adults do not use and abuse illicit substances. Illicit drug use among older adults is increasing. Older adults with SUDs may not present with the same symptoms as their younger counterparts, and thus it may be difficult to identify the problem. Maintain a high index of suspicion regarding the use of illicit substances in these patients.

Treatment options are generally limited and health care settings offer few interventions designed specifically for older adults. In general, proper identification of SUDs and targeted treatment can highly improve outcomes.

Baby Boomers—a term used to refer to individuals born in the United States between 1946 and 1964—are now approaching old age. Surprisingly, these older adults are using illicit substances in a pattern not seen in prior generations of older adults, including developing substance use disorders (SUDs) at increasingly higher rates; in previous generations, the prevalence of such disorders typically lowered with advancing age.

This article discusses how to recognize and treat SUDs in older adults. Alcohol is the most commonly used substance among older adults,¹ and there is a largebody of literature describing the identification and treatment of alcohol-related disorders in these patients. Therefore, this article will instead focus on older adults’ use of illicit substances, including marijuana, cocaine, and heroin.

Epidemiology

Prior clinical data regarding substance abuse in older adults focused on alcohol, prescription drugs, nicotine, and caffeine.² In the past, compared with younger adults, older adults had lower rates of alcohol and other illicit drug use.^3,4 Baby Boomers appear to be defying this trend.

A 2013 Substance Abuse and Mental Health Services Administration survey found that the percentage of adults ages 50 to 64 who used illicit substances increased from 2.7% in 2002 to 6.0% in 2013.⁵ Specifically, during that time, past-month illicit substance use increased from 3.4% to 7.9% among those ages 50 to 54, from 1.9% to 5.7% among those ages 55 to 59, and from 2.5% to 3.9% among those ages 60 to 64.⁵

More recently, a 2014 study of geriatric patients found that of the 1,302 patients age ≥65 admitted to a Level 1 trauma center, 48.3% had a positive urine drug screen.⁶ Someresearchers have estimated that 5.7 million older adults will require treatment for a substance use disorder in 2020, which is roughly double the 2.8 million who had an SUD in 2002 to 2006.⁷

Risk factors and patterns of substance abuse

Individual, social, and familial factors can contribute to substance use and abuse in late life. The Table¹ outlines some of the potential risk factors for older adults associated with the use of illicit substances. Substance abuse among older adults can be divided into 2 broad categories: early onset (starting before age 50) and late onset (starting after age 50).⁸ While data are limited, in general, early-onset use is a more common pattern; late-onset use represents an estimated <10% of substance use among older adults. The factors that lead some adults to continue substance use in late life, or to begin substance use later in life, have not been thoroughly evaluated.

Although older adults may abuse a wide variety of illicit substances, here we describe their use of marijuana, cocaine, and heroin.

Marijuana use has changed substantially in the last decade. While marijuana is illegal under federal law, as of November 2017, 29 states had legalized marijuana for medicinal purposes and 7 states and the District of Columbia had legalized it for recreational use. The increased legal and social acceptance of marijuana has led to new businesses and methods of use beyond smoking. New types of marijuana products include edible substances, tinctures, and oils that can be vaporized and inhaled.

In addition to euphoria and relaxation, the effects of marijuana use include increased latency time and decreased ability to respond to stimuli.² Nonpsychiatric effects of marijuana include shallow breathing, weakened immune system, and increasing cardiac workload.² The latter effect is especially important for older adults, many of whom may have preexisting cardiac illness and may be more likely to experience an adverse cardiac event as a result of marijuana use.² Older adults who begin to use marijuana in late life may do so not primarily as a social activity, but more likely to experience the drug’s potentially beneficial effects on pain or appetite.² For more on theuse of marijuana for these reasons, see “Medical marijuana: Do the benefits outweigh the risks?” in Current Psychiatry, January 2018, p. 34-41.

Cocaine. Although cocaine is a CNS stimulant that causes a short-lived euphoria, its adverse effects impact many body systems.⁹ Myocardial infarction (MI) secondary to coronary artery vasospasms, stroke (hemorrhagic and ischemic), seizures, psychosis, aortic dissection, and acute renal injury are some of the most severe complications. Acute MI is the most frequent and severe cardiovascular complication seen among abusers.¹⁰ Cocaine use can cause dizziness, restlessness, headache, mydriasis, and anxiety.

In a pilot study, Kalapatapu et al¹¹ compared the effects of cocaine abuse in younger vs older users. They found that older users had similar patterns of cocaine abuse in terms of the amount of cocaine used and frequency of use.¹¹ They also found that specific cognitive functions, including psychomotor speed, attention, and short-term memory, are particularly sensitive to the combined effects of aging and cocaine abuse.¹¹

Heroin is an opioid and a CNS depressant. Common effects include slowed heart rate, decreased blood pressure, and decreased respiration rate. Chronic heroin users show an overall decrease in immune system functioning¹²; this deficit might be particularly pronounced in an older person whose immune system functioning has already begun to decline as a result of aging. In recent years, as is the case with younger substance users, prescription opioids have replaced heroin as the opioid of choice among older users. However, for some early-onset heroin users, the use of this particular drug becomes well entrenched and unlikely to change, even in late life. Each year of heroin use increases the likelihood of continued use the next year by approximately 3%.² Some research suggests that older heroin users do not decrease their use over time, and face many of the same risks as younger users, including poorer physical and mental health, severe physical disability, and mortality.¹³

There are no screening protocols in the clinical setting that are designed specifically for detecting illicit substance abuse among older adults. Furthermore, diagnosis can be easily overlooked because the signs and symptoms of illicit substance use can be mistaken for other illnesses. To complicate matters further, older adults often do not disclose their substance use, understate it, or even try to explain away their symptoms.¹ Many older adults live alone, which may increase their risk of receiving no treatment.¹⁴

Older adults generally experience reduced tolerance to the effects of illicit substances because of age-related physiologic changes, such as decreases in renal functioning, motor functioning, and cardiac output; altered liver metabolism of certain drugs; and elevated blood glucose levels.¹⁵ As a result, symptoms of illicit substance use could be mistaken for dementia or other forms of cognitive impairment.^1,16

Although not designed specifically for older adults, an evidence-based screening instrument, such as the CAGE Questionnaire Adapted to Include Drugs, may be helpful in identifying substance abuse in these patients. Urine and/or serum drug screening, along with obtaining a comprehensive history from a trustworthy source, is useful for diagnosis.

Pharmacologic treatments

Research evaluating the use of medication for treating substance abuse specifically in older adults is extremely limited; studies have focused primarily on younger patients or mixed-age populations. Treatments that have been shown to be effective for younger patients may or may not be effective for older adults.

Marijuana. There are no FDA-approved treatments for marijuana abuse. An open-label study found that N-acetylcysteine, 1,200 mg twice a day, resulted in a significant reduction in marijuana craving as measured by the 12-item version of the Marijuana Craving Questionnaire.¹⁷ In a double-blinded placebo-controlled study, adolescents who were dependent on marijuana who received N-acetylcysteine, 1,200 mg twice a day, were more than twice likely to stop marijuana use compared with those who received placebo.¹⁸ Some researchers have proposed that N-acetylcysteine may prevent continued use of marijuana via glutamate modulation in the nucleus accumbens. Animal models have demonstrated that chronic drug self-administration downregulates the cystine-glutamate exchanger in the nucleus accumbens, and that N-acetylcysteine upregulates this exchanger, which reduces reinstatement of drug seeking.Further studies are needed to verify this speculation.

Cocaine. There are no FDA-approved treatments for cocaine abuse. No specific treatment approach has been found to be consistently effective.

A potential “cocaine vaccine” called TA-CD, which is made from succinyl norcocaine conjugated to cholera toxin, is being evaluated. An initial study had promising results, finding a significant reduction in cocaine use among those who received TA-CD.¹⁹ A later double-blinded placebo-controlled study only partially replicated the efficacy found in the initial study.²⁰

Currently, other cocaine treatments are also being investigated. An enzyme to rapidly metabolize cocaine is being evaluated.²¹ So far, none of these treatments have targeted older adults, and there may be age-specific issues to consider if these approaches eventually receive FDA approval.

Heroin. Several FDA-approved medications are available for treating dependency to heroin and other opioids, including naltrexone, buprenorphine, and methadone, but none have been studied specifically in older adults. Some studies of transdermal buprenorphine for treating chronic pain in older adults have concluded that this formulation may offer advantages for older patients.^22,23 Compared with oral or sublingual buprenorphine, the transdermal formulation avoids the first-pass effect in the liver, thus greatly increasing bioavailability of the drug; avoids renal metabolism; and offers greater tolerability in patients with mild to moderate hepatic impairment.^22,23 However, transdermal buprenorphine has been approved only for the treatment of pain. These beneficial aspects of transdermal buprenorphine may be applicable to older opioid users, but no age-specific studies of buprenorphine for treating opioid abuse have been conducted.

Nonpharmacologic treatments

The same psychotherapeutic treatments used to treat younger patients with SUDs may be appropriate for older adults. Older patients may experience feelings of isolation and shame related to needing treatment for substance abuse. These factors in treatment of older patients often are overcome by group psychotherapy. Self-help programs, such as Narcotics Anonymous or Alcoholics Anonymous, and group therapy also may be options.

On the other hand, individual psychotherapy, such as cognitive-behavioral therapy (CBT), interpersonal therapy, and psychodynamic therapy, can provide a private and confidential environment for older adults who are less social.²⁴

The highly structured nature of CBT may be well suited to older adults who have memory difficulties.¹ A study of 110 older veterans with substance abuse problems found evidence for the effectiveness of group CBT among these patients.²⁵ All but 8 participants in this study were age ≥65. The intervention consisted of 16 weekly group sessions that began with analysis of substance use behavior to determine high-risk situations for use, followed by a series of modules to teach skills for coping with social pressure, being at home and alone, feelings of depression and loneliness, anxiety and tension, anger and frustration, cues for substance use, and other factors. Approximately 44% (49 of 110) completed treatment (≥13 sessions). Approximately 55% of those who completed the treatment were abstinent at 6-month follow-up.²⁵

Don’t assume your older patient is not using illicit substances

It is a myth that older adults do not use and abuse illicit substances. Illicit drug use among older adults is increasing. Older adults with SUDs may not present with the same symptoms as their younger counterparts, and thus it may be difficult to identify the problem. Maintain a high index of suspicion regarding the use of illicit substances in these patients.

Treatment options are generally limited and health care settings offer few interventions designed specifically for older adults. In general, proper identification of SUDs and targeted treatment can highly improve outcomes.

Baby Boomers—a term used to refer to individuals born in the United States between 1946 and 1964—are now approaching old age. Surprisingly, these older adults are using illicit substances in a pattern not seen in prior generations of older adults, including developing substance use disorders (SUDs) at increasingly higher rates; in previous generations, the prevalence of such disorders typically lowered with advancing age.

This article discusses how to recognize and treat SUDs in older adults. Alcohol is the most commonly used substance among older adults,¹ and there is a largebody of literature describing the identification and treatment of alcohol-related disorders in these patients. Therefore, this article will instead focus on older adults’ use of illicit substances, including marijuana, cocaine, and heroin.

Epidemiology

Prior clinical data regarding substance abuse in older adults focused on alcohol, prescription drugs, nicotine, and caffeine.² In the past, compared with younger adults, older adults had lower rates of alcohol and other illicit drug use.^3,4 Baby Boomers appear to be defying this trend.

A 2013 Substance Abuse and Mental Health Services Administration survey found that the percentage of adults ages 50 to 64 who used illicit substances increased from 2.7% in 2002 to 6.0% in 2013.⁵ Specifically, during that time, past-month illicit substance use increased from 3.4% to 7.9% among those ages 50 to 54, from 1.9% to 5.7% among those ages 55 to 59, and from 2.5% to 3.9% among those ages 60 to 64.⁵

More recently, a 2014 study of geriatric patients found that of the 1,302 patients age ≥65 admitted to a Level 1 trauma center, 48.3% had a positive urine drug screen.⁶ Someresearchers have estimated that 5.7 million older adults will require treatment for a substance use disorder in 2020, which is roughly double the 2.8 million who had an SUD in 2002 to 2006.⁷

Risk factors and patterns of substance abuse

Individual, social, and familial factors can contribute to substance use and abuse in late life. The Table¹ outlines some of the potential risk factors for older adults associated with the use of illicit substances. Substance abuse among older adults can be divided into 2 broad categories: early onset (starting before age 50) and late onset (starting after age 50).⁸ While data are limited, in general, early-onset use is a more common pattern; late-onset use represents an estimated <10% of substance use among older adults. The factors that lead some adults to continue substance use in late life, or to begin substance use later in life, have not been thoroughly evaluated.

Although older adults may abuse a wide variety of illicit substances, here we describe their use of marijuana, cocaine, and heroin.

Marijuana use has changed substantially in the last decade. While marijuana is illegal under federal law, as of November 2017, 29 states had legalized marijuana for medicinal purposes and 7 states and the District of Columbia had legalized it for recreational use. The increased legal and social acceptance of marijuana has led to new businesses and methods of use beyond smoking. New types of marijuana products include edible substances, tinctures, and oils that can be vaporized and inhaled.

In addition to euphoria and relaxation, the effects of marijuana use include increased latency time and decreased ability to respond to stimuli.² Nonpsychiatric effects of marijuana include shallow breathing, weakened immune system, and increasing cardiac workload.² The latter effect is especially important for older adults, many of whom may have preexisting cardiac illness and may be more likely to experience an adverse cardiac event as a result of marijuana use.² Older adults who begin to use marijuana in late life may do so not primarily as a social activity, but more likely to experience the drug’s potentially beneficial effects on pain or appetite.² For more on theuse of marijuana for these reasons, see “Medical marijuana: Do the benefits outweigh the risks?” in Current Psychiatry, January 2018, p. 34-41.

Cocaine. Although cocaine is a CNS stimulant that causes a short-lived euphoria, its adverse effects impact many body systems.⁹ Myocardial infarction (MI) secondary to coronary artery vasospasms, stroke (hemorrhagic and ischemic), seizures, psychosis, aortic dissection, and acute renal injury are some of the most severe complications. Acute MI is the most frequent and severe cardiovascular complication seen among abusers.¹⁰ Cocaine use can cause dizziness, restlessness, headache, mydriasis, and anxiety.

In a pilot study, Kalapatapu et al¹¹ compared the effects of cocaine abuse in younger vs older users. They found that older users had similar patterns of cocaine abuse in terms of the amount of cocaine used and frequency of use.¹¹ They also found that specific cognitive functions, including psychomotor speed, attention, and short-term memory, are particularly sensitive to the combined effects of aging and cocaine abuse.¹¹

Heroin is an opioid and a CNS depressant. Common effects include slowed heart rate, decreased blood pressure, and decreased respiration rate. Chronic heroin users show an overall decrease in immune system functioning¹²; this deficit might be particularly pronounced in an older person whose immune system functioning has already begun to decline as a result of aging. In recent years, as is the case with younger substance users, prescription opioids have replaced heroin as the opioid of choice among older users. However, for some early-onset heroin users, the use of this particular drug becomes well entrenched and unlikely to change, even in late life. Each year of heroin use increases the likelihood of continued use the next year by approximately 3%.² Some research suggests that older heroin users do not decrease their use over time, and face many of the same risks as younger users, including poorer physical and mental health, severe physical disability, and mortality.¹³

There are no screening protocols in the clinical setting that are designed specifically for detecting illicit substance abuse among older adults. Furthermore, diagnosis can be easily overlooked because the signs and symptoms of illicit substance use can be mistaken for other illnesses. To complicate matters further, older adults often do not disclose their substance use, understate it, or even try to explain away their symptoms.¹ Many older adults live alone, which may increase their risk of receiving no treatment.¹⁴

Older adults generally experience reduced tolerance to the effects of illicit substances because of age-related physiologic changes, such as decreases in renal functioning, motor functioning, and cardiac output; altered liver metabolism of certain drugs; and elevated blood glucose levels.¹⁵ As a result, symptoms of illicit substance use could be mistaken for dementia or other forms of cognitive impairment.^1,16

Although not designed specifically for older adults, an evidence-based screening instrument, such as the CAGE Questionnaire Adapted to Include Drugs, may be helpful in identifying substance abuse in these patients. Urine and/or serum drug screening, along with obtaining a comprehensive history from a trustworthy source, is useful for diagnosis.

Pharmacologic treatments

Research evaluating the use of medication for treating substance abuse specifically in older adults is extremely limited; studies have focused primarily on younger patients or mixed-age populations. Treatments that have been shown to be effective for younger patients may or may not be effective for older adults.

Marijuana. There are no FDA-approved treatments for marijuana abuse. An open-label study found that N-acetylcysteine, 1,200 mg twice a day, resulted in a significant reduction in marijuana craving as measured by the 12-item version of the Marijuana Craving Questionnaire.¹⁷ In a double-blinded placebo-controlled study, adolescents who were dependent on marijuana who received N-acetylcysteine, 1,200 mg twice a day, were more than twice likely to stop marijuana use compared with those who received placebo.¹⁸ Some researchers have proposed that N-acetylcysteine may prevent continued use of marijuana via glutamate modulation in the nucleus accumbens. Animal models have demonstrated that chronic drug self-administration downregulates the cystine-glutamate exchanger in the nucleus accumbens, and that N-acetylcysteine upregulates this exchanger, which reduces reinstatement of drug seeking.Further studies are needed to verify this speculation.

Cocaine. There are no FDA-approved treatments for cocaine abuse. No specific treatment approach has been found to be consistently effective.

A potential “cocaine vaccine” called TA-CD, which is made from succinyl norcocaine conjugated to cholera toxin, is being evaluated. An initial study had promising results, finding a significant reduction in cocaine use among those who received TA-CD.¹⁹ A later double-blinded placebo-controlled study only partially replicated the efficacy found in the initial study.²⁰

Currently, other cocaine treatments are also being investigated. An enzyme to rapidly metabolize cocaine is being evaluated.²¹ So far, none of these treatments have targeted older adults, and there may be age-specific issues to consider if these approaches eventually receive FDA approval.

Heroin. Several FDA-approved medications are available for treating dependency to heroin and other opioids, including naltrexone, buprenorphine, and methadone, but none have been studied specifically in older adults. Some studies of transdermal buprenorphine for treating chronic pain in older adults have concluded that this formulation may offer advantages for older patients.^22,23 Compared with oral or sublingual buprenorphine, the transdermal formulation avoids the first-pass effect in the liver, thus greatly increasing bioavailability of the drug; avoids renal metabolism; and offers greater tolerability in patients with mild to moderate hepatic impairment.^22,23 However, transdermal buprenorphine has been approved only for the treatment of pain. These beneficial aspects of transdermal buprenorphine may be applicable to older opioid users, but no age-specific studies of buprenorphine for treating opioid abuse have been conducted.

Nonpharmacologic treatments

The same psychotherapeutic treatments used to treat younger patients with SUDs may be appropriate for older adults. Older patients may experience feelings of isolation and shame related to needing treatment for substance abuse. These factors in treatment of older patients often are overcome by group psychotherapy. Self-help programs, such as Narcotics Anonymous or Alcoholics Anonymous, and group therapy also may be options.

On the other hand, individual psychotherapy, such as cognitive-behavioral therapy (CBT), interpersonal therapy, and psychodynamic therapy, can provide a private and confidential environment for older adults who are less social.²⁴

The highly structured nature of CBT may be well suited to older adults who have memory difficulties.¹ A study of 110 older veterans with substance abuse problems found evidence for the effectiveness of group CBT among these patients.²⁵ All but 8 participants in this study were age ≥65. The intervention consisted of 16 weekly group sessions that began with analysis of substance use behavior to determine high-risk situations for use, followed by a series of modules to teach skills for coping with social pressure, being at home and alone, feelings of depression and loneliness, anxiety and tension, anger and frustration, cues for substance use, and other factors. Approximately 44% (49 of 110) completed treatment (≥13 sessions). Approximately 55% of those who completed the treatment were abstinent at 6-month follow-up.²⁵

Don’t assume your older patient is not using illicit substances

It is a myth that older adults do not use and abuse illicit substances. Illicit drug use among older adults is increasing. Older adults with SUDs may not present with the same symptoms as their younger counterparts, and thus it may be difficult to identify the problem. Maintain a high index of suspicion regarding the use of illicit substances in these patients.

Treatment options are generally limited and health care settings offer few interventions designed specifically for older adults. In general, proper identification of SUDs and targeted treatment can highly improve outcomes.