Pain

Ms. G, a 36-year-old woman, presented to the emergency department (ED) requesting a neurologic evaluation. She told clinicians she had “NMDA receptor encephalitis.”

Ms. G reported successful self-treatment of “life-long” body pain that was precipitated by multiple external stimuli (food, social encounters, interpersonal conflict, etc.). Through her own research, she had learned that both ketamine and magnesium could alter nociception in rats through N-methyl-d-aspartic acid (NMDA) receptor antagonism, and so she decided to try treating her pain with Delsym, an over-the-counter cough syrup containing dextromethorphan polistirex (DXM), which at high doses acts as an NMDA receptor antagonist. She said she was taking Delsym, 120 mg/d, and magnesium oxide, 600 mg/d.

In the ED, Ms. G had a labile affect, pressured speech, and flight of ideas. She denied any history of psychiatric treatment, suicide attempts, or substance abuse. Ms. G’s family reported she had been unusually social, talkative, and impulsive. She was admitted to the inpatient psychiatric unit with a diagnosis of mania.

On psychiatric evaluation, Ms. G was grandiose, irritable, and perseverative about her aberrant symptoms. She felt she did not experience the world as other people did, but found relief from her chronic pain after taking Delsym. She was not taking other medications. Ms. G did not report a family history of bipolar disorder or psychosis. Her laboratory results, including a comprehensive metabolic panel, complete blood count, lipid panel, thyroid studies, urine drug screening, and urinalysis, were unremarkable. Her blood pressure was mildly elevated (141/82 mm Hg).

Ms. G’s eventual diagnosis was substance-induced mania (DXM). The DXM-containing cough syrup and magnesium were discontinued in the hospital. She was stabilized on lithium extended-release, 900 mg/d (blood level 0.8 mmol/L), and olanzapine, 10 mg/d at bedtime. However, after discharge, Ms. G resumed using Delsym, which resulted in 3 subsequent psychiatric hospitalizations for mania during the next year.

I first treated Ms. G as an outpatient after her second hospitalization. At that point, she was stable. Her mental status was calm and cooperative, and she had a linear thought process. At her baseline, in the absence of mania, she had a blunted affect. She understood that DXM caused her to have manic symptoms, but she continued to believe that Delsym and magnesium cured her physical suffering and social inhibition. I noticed Ms. G would use figurative language inappropriately. I later learned she had sensitivities to food textures and a specialized interest in electronics. Because of this, I suspected Ms. G was on the autism spectrum; she met several DSM-5 criteria for autism spectrum disorder (ASD), particularly deficits in social-emotional reciprocity, highly restricted interests, and hyperreactivity to sensory input.

Upon routine lab screening, Ms. G was found to have hypothyroidism, with a thyroid-stimulating hormone level of 6.67 mcIU/mL. This resolved after discontinuing lithium. Olanzapine caused adverse metabolic effects and also was discontinued. Ms. G remained euthymic without any mood-stabilizing medication, except during periods when she abused DXM, when she would again become manic. Eventually, her motivation to avoid hospitalization would promote her abstinence.

Continue to: Implications of NMDA receptor antagonism

Implications of NMDA receptor antagonism

The use of ketamine as an NMDA receptor antagonist for treating depression and other psychiatric illnesses has gained momentum. Esketamine, the S-enantiomer of racemic ketamine, is now available as an FDA-approved intranasal formulation for treatment-resistant depression. Ketamine stops afferent nociception to the brain and is used as an analgesic (at low concentrations) and anesthetic (at high concentrations).¹

Dextromethorphan is abused as a recreational drug because at high doses it works similarly to both ketamine and phencyclidine. Individuals who abuse DXM can develop psychosis, motor/cognitive impairment, agitation, fevers, hypertension, tachycardia, and death.² In patients with ASD, researchers have identified genetic variations of NMDA receptors that are linked to dysfunction of these receptors.³ In animal models, as well as in humans, researchers have found that suppression or excitation of the NMDA receptor can ameliorate ASD symptoms, including social withdrawal and repetitive behaviors.³

Many individuals with ASD suffer from sensory abnormalities, including a reduced sensitivity to pain or a crippling sensitivity to various stimuli. Patients with ASD may have difficulty describing these abnormalities, and as a result, they may be misdiagnosed. One case report described a 15-year-old girl diagnosed with social anxiety and chronic generalized pain when in social situations.⁴ Pediatric rheumatologists had diagnosed her with “amplified pain syndrome.” When she presented to a mental health clinic for a neurodevelopmental evaluation, she explained to clinicians how she simply “did not ‘get’ people; they are just empty shells” and subsequently was given a diagnosis of ASD.⁴

In psychiatric patients who have comorbid substance use disorders, it is vital for clinicians to not only detect the presence of substance misuse, but also to understand what drives the patient toward abuse. Ms. G’s case, with its combination of substance abuse and ASD, illustrates the importance of listening to our patients for more precise diagnostic formulations, which then shape our treatment recommendations.

Ms. G, a 36-year-old woman, presented to the emergency department (ED) requesting a neurologic evaluation. She told clinicians she had “NMDA receptor encephalitis.”

Ms. G reported successful self-treatment of “life-long” body pain that was precipitated by multiple external stimuli (food, social encounters, interpersonal conflict, etc.). Through her own research, she had learned that both ketamine and magnesium could alter nociception in rats through N-methyl-d-aspartic acid (NMDA) receptor antagonism, and so she decided to try treating her pain with Delsym, an over-the-counter cough syrup containing dextromethorphan polistirex (DXM), which at high doses acts as an NMDA receptor antagonist. She said she was taking Delsym, 120 mg/d, and magnesium oxide, 600 mg/d.

In the ED, Ms. G had a labile affect, pressured speech, and flight of ideas. She denied any history of psychiatric treatment, suicide attempts, or substance abuse. Ms. G’s family reported she had been unusually social, talkative, and impulsive. She was admitted to the inpatient psychiatric unit with a diagnosis of mania.

On psychiatric evaluation, Ms. G was grandiose, irritable, and perseverative about her aberrant symptoms. She felt she did not experience the world as other people did, but found relief from her chronic pain after taking Delsym. She was not taking other medications. Ms. G did not report a family history of bipolar disorder or psychosis. Her laboratory results, including a comprehensive metabolic panel, complete blood count, lipid panel, thyroid studies, urine drug screening, and urinalysis, were unremarkable. Her blood pressure was mildly elevated (141/82 mm Hg).

Ms. G’s eventual diagnosis was substance-induced mania (DXM). The DXM-containing cough syrup and magnesium were discontinued in the hospital. She was stabilized on lithium extended-release, 900 mg/d (blood level 0.8 mmol/L), and olanzapine, 10 mg/d at bedtime. However, after discharge, Ms. G resumed using Delsym, which resulted in 3 subsequent psychiatric hospitalizations for mania during the next year.

I first treated Ms. G as an outpatient after her second hospitalization. At that point, she was stable. Her mental status was calm and cooperative, and she had a linear thought process. At her baseline, in the absence of mania, she had a blunted affect. She understood that DXM caused her to have manic symptoms, but she continued to believe that Delsym and magnesium cured her physical suffering and social inhibition. I noticed Ms. G would use figurative language inappropriately. I later learned she had sensitivities to food textures and a specialized interest in electronics. Because of this, I suspected Ms. G was on the autism spectrum; she met several DSM-5 criteria for autism spectrum disorder (ASD), particularly deficits in social-emotional reciprocity, highly restricted interests, and hyperreactivity to sensory input.

Upon routine lab screening, Ms. G was found to have hypothyroidism, with a thyroid-stimulating hormone level of 6.67 mcIU/mL. This resolved after discontinuing lithium. Olanzapine caused adverse metabolic effects and also was discontinued. Ms. G remained euthymic without any mood-stabilizing medication, except during periods when she abused DXM, when she would again become manic. Eventually, her motivation to avoid hospitalization would promote her abstinence.

Continue to: Implications of NMDA receptor antagonism

Implications of NMDA receptor antagonism

The use of ketamine as an NMDA receptor antagonist for treating depression and other psychiatric illnesses has gained momentum. Esketamine, the S-enantiomer of racemic ketamine, is now available as an FDA-approved intranasal formulation for treatment-resistant depression. Ketamine stops afferent nociception to the brain and is used as an analgesic (at low concentrations) and anesthetic (at high concentrations).¹

Dextromethorphan is abused as a recreational drug because at high doses it works similarly to both ketamine and phencyclidine. Individuals who abuse DXM can develop psychosis, motor/cognitive impairment, agitation, fevers, hypertension, tachycardia, and death.² In patients with ASD, researchers have identified genetic variations of NMDA receptors that are linked to dysfunction of these receptors.³ In animal models, as well as in humans, researchers have found that suppression or excitation of the NMDA receptor can ameliorate ASD symptoms, including social withdrawal and repetitive behaviors.³

Many individuals with ASD suffer from sensory abnormalities, including a reduced sensitivity to pain or a crippling sensitivity to various stimuli. Patients with ASD may have difficulty describing these abnormalities, and as a result, they may be misdiagnosed. One case report described a 15-year-old girl diagnosed with social anxiety and chronic generalized pain when in social situations.⁴ Pediatric rheumatologists had diagnosed her with “amplified pain syndrome.” When she presented to a mental health clinic for a neurodevelopmental evaluation, she explained to clinicians how she simply “did not ‘get’ people; they are just empty shells” and subsequently was given a diagnosis of ASD.⁴

In psychiatric patients who have comorbid substance use disorders, it is vital for clinicians to not only detect the presence of substance misuse, but also to understand what drives the patient toward abuse. Ms. G’s case, with its combination of substance abuse and ASD, illustrates the importance of listening to our patients for more precise diagnostic formulations, which then shape our treatment recommendations.

Ms. G, a 36-year-old woman, presented to the emergency department (ED) requesting a neurologic evaluation. She told clinicians she had “NMDA receptor encephalitis.”

Ms. G reported successful self-treatment of “life-long” body pain that was precipitated by multiple external stimuli (food, social encounters, interpersonal conflict, etc.). Through her own research, she had learned that both ketamine and magnesium could alter nociception in rats through N-methyl-d-aspartic acid (NMDA) receptor antagonism, and so she decided to try treating her pain with Delsym, an over-the-counter cough syrup containing dextromethorphan polistirex (DXM), which at high doses acts as an NMDA receptor antagonist. She said she was taking Delsym, 120 mg/d, and magnesium oxide, 600 mg/d.

In the ED, Ms. G had a labile affect, pressured speech, and flight of ideas. She denied any history of psychiatric treatment, suicide attempts, or substance abuse. Ms. G’s family reported she had been unusually social, talkative, and impulsive. She was admitted to the inpatient psychiatric unit with a diagnosis of mania.

On psychiatric evaluation, Ms. G was grandiose, irritable, and perseverative about her aberrant symptoms. She felt she did not experience the world as other people did, but found relief from her chronic pain after taking Delsym. She was not taking other medications. Ms. G did not report a family history of bipolar disorder or psychosis. Her laboratory results, including a comprehensive metabolic panel, complete blood count, lipid panel, thyroid studies, urine drug screening, and urinalysis, were unremarkable. Her blood pressure was mildly elevated (141/82 mm Hg).

Ms. G’s eventual diagnosis was substance-induced mania (DXM). The DXM-containing cough syrup and magnesium were discontinued in the hospital. She was stabilized on lithium extended-release, 900 mg/d (blood level 0.8 mmol/L), and olanzapine, 10 mg/d at bedtime. However, after discharge, Ms. G resumed using Delsym, which resulted in 3 subsequent psychiatric hospitalizations for mania during the next year.

I first treated Ms. G as an outpatient after her second hospitalization. At that point, she was stable. Her mental status was calm and cooperative, and she had a linear thought process. At her baseline, in the absence of mania, she had a blunted affect. She understood that DXM caused her to have manic symptoms, but she continued to believe that Delsym and magnesium cured her physical suffering and social inhibition. I noticed Ms. G would use figurative language inappropriately. I later learned she had sensitivities to food textures and a specialized interest in electronics. Because of this, I suspected Ms. G was on the autism spectrum; she met several DSM-5 criteria for autism spectrum disorder (ASD), particularly deficits in social-emotional reciprocity, highly restricted interests, and hyperreactivity to sensory input.

Upon routine lab screening, Ms. G was found to have hypothyroidism, with a thyroid-stimulating hormone level of 6.67 mcIU/mL. This resolved after discontinuing lithium. Olanzapine caused adverse metabolic effects and also was discontinued. Ms. G remained euthymic without any mood-stabilizing medication, except during periods when she abused DXM, when she would again become manic. Eventually, her motivation to avoid hospitalization would promote her abstinence.

Continue to: Implications of NMDA receptor antagonism

Implications of NMDA receptor antagonism

The use of ketamine as an NMDA receptor antagonist for treating depression and other psychiatric illnesses has gained momentum. Esketamine, the S-enantiomer of racemic ketamine, is now available as an FDA-approved intranasal formulation for treatment-resistant depression. Ketamine stops afferent nociception to the brain and is used as an analgesic (at low concentrations) and anesthetic (at high concentrations).¹

Dextromethorphan is abused as a recreational drug because at high doses it works similarly to both ketamine and phencyclidine. Individuals who abuse DXM can develop psychosis, motor/cognitive impairment, agitation, fevers, hypertension, tachycardia, and death.² In patients with ASD, researchers have identified genetic variations of NMDA receptors that are linked to dysfunction of these receptors.³ In animal models, as well as in humans, researchers have found that suppression or excitation of the NMDA receptor can ameliorate ASD symptoms, including social withdrawal and repetitive behaviors.³

Many individuals with ASD suffer from sensory abnormalities, including a reduced sensitivity to pain or a crippling sensitivity to various stimuli. Patients with ASD may have difficulty describing these abnormalities, and as a result, they may be misdiagnosed. One case report described a 15-year-old girl diagnosed with social anxiety and chronic generalized pain when in social situations.⁴ Pediatric rheumatologists had diagnosed her with “amplified pain syndrome.” When she presented to a mental health clinic for a neurodevelopmental evaluation, she explained to clinicians how she simply “did not ‘get’ people; they are just empty shells” and subsequently was given a diagnosis of ASD.⁴

In psychiatric patients who have comorbid substance use disorders, it is vital for clinicians to not only detect the presence of substance misuse, but also to understand what drives the patient toward abuse. Ms. G’s case, with its combination of substance abuse and ASD, illustrates the importance of listening to our patients for more precise diagnostic formulations, which then shape our treatment recommendations.

A 54-year-old pharmacist with a history of gout, hypertension, and conjunctivitis presents for evaluation of pink eye in the summer. The morning before coming into the office, he noticed that his right eye was red and inflamed. He self-treated with saline washes and eye drops, but upon awakening the next day, he found his right eye to be crusted shut with surrounding yellow discharge. He has not had any changes to his vision but endorses a somewhat uncomfortable, “gritty” sensation. He reports no recent cough, nasal congestion, or allergies, and he has not been around any sick contacts. His blood pressure is 102/58 mm Hg, pulse is 76 bpm, and body mass index is 27.3 kg/m². His eye exam reveals unilateral conjunctival injections but no hyperemia of the conjunctiva adjacent to the cornea. Mucopurulent discharge was neither found on the undersurface of the eyelid nor emerging from the eye. Which of the following is the best treatment for this patient’s condition?

A) Erythromycin 5 mg/gram ophthalmic ointment.

B) Ofloxacin 0.3% ophthalmic drops.

C) Antihistamine drops.

D) Eye lubricant drops.

E) No treatment necessary.

This patient is an adult presenting with presumed conjunctivitis. Because he is presenting in the summer without observed purulent discharge, his condition is unlikely to be bacterial. This patient does not need treatment, although eye lubricant drops could reduce his discomfort.

Nearly 1% of primary care office visits¹ and 300 million in annual costs² are spent evaluating and treating “pink eye.” After ruling out serious eye disease, clinicians need to determine which cases of suspected conjunctivitis are most likely to be bacterial to allow for judicious use of antibiotic eye drops. This is an important undertaking as most patients assume that antibiotics are needed.

How do we know which history and clinical exam findings to lean on when attempting to categorize conjunctivitis as bacterial or not? If a patient reports purulent discharge, doesn’t that mean it is bacterial? Surprisingly, a systematic review published in 2016 by Narayana and McGee found that a patient’s self-report of “purulent drainage” is diagnostically unhelpful, but if a clinician finds it on exam, the likelihood of a bacterial etiology increases.³

Narayana and McGee analyzed three studies that enrolled a total of 281 patients with presumed conjunctivitis who underwent bacterial cultures. They then determined which findings increased the probability of positive bacterial culture. From strongest to weakest, the best indicators of a bacterial cause were found to be: complete redness of the conjunctival membrane obscuring tarsal vessels (the vessels visible on the inside of everted upper or lower eyelids) (likelihood ratio, 4.6), observed purulent discharge (LR, 3.9), matting of both eyes in the morning (LR, 3.6), and presence during winter/spring months (LR, 1.9). On the other hand, failure to observe a red eye at 20 feet (LR, 0.2), absence of morning gluing of either eye (LR, 0.3), and presentation during summer months (LR, 0.4) all decreased the probability of a bacterial cause. This review and different study by Stenson et al. unfortunately have conflicting evidence regarding whether the following findings are diagnostically helpful: qualities of eye discomfort (such as burning or itching), preauricular adenopathy, conjunctival follicles, and conjunctival papillae.^3,4 Rietveld and colleagues found that a history of conjunctivitis decreased the likelihood of bacterial conjunctivitis.⁵

Pearl: The best indicators of a bacterial cause in patients with presumed conjunctivitis are complete redness of the conjunctival membrane obscuring tarsal vessels, observed purulent discharge, and matting of both eyes in the morning. Presentation during the summer months and having a history of conjunctivitis decreases the likelihood of bacterial conjunctivitis.

Ms. Momany is a fourth-year medical student at University of Washington, Seattle. Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington and serves as third-year medical student clerkship director at that university. Contact Dr. Paauw at [email protected].

References

1. Azari AA and Barney NP. JAMA. 2013 Oct 23; 310(16):1721-9.

2. Smith AF and Waycaster C. BMC Ophthalmol. 2009 Nov 25. doi: 10.1186/1471-2415-9-13.

3) Narayana S and McGee S. Am J Med. 2015;128(11):1220-4.e1.

4) Stenson S et al. Arch Ophthalmol. 1982;100(8):1275-7.

5) Rietveld RP et al. BMJ. 2004 Jul 24;329(7459):206-10.

A 54-year-old pharmacist with a history of gout, hypertension, and conjunctivitis presents for evaluation of pink eye in the summer. The morning before coming into the office, he noticed that his right eye was red and inflamed. He self-treated with saline washes and eye drops, but upon awakening the next day, he found his right eye to be crusted shut with surrounding yellow discharge. He has not had any changes to his vision but endorses a somewhat uncomfortable, “gritty” sensation. He reports no recent cough, nasal congestion, or allergies, and he has not been around any sick contacts. His blood pressure is 102/58 mm Hg, pulse is 76 bpm, and body mass index is 27.3 kg/m². His eye exam reveals unilateral conjunctival injections but no hyperemia of the conjunctiva adjacent to the cornea. Mucopurulent discharge was neither found on the undersurface of the eyelid nor emerging from the eye. Which of the following is the best treatment for this patient’s condition?

A) Erythromycin 5 mg/gram ophthalmic ointment.

B) Ofloxacin 0.3% ophthalmic drops.

C) Antihistamine drops.

D) Eye lubricant drops.

E) No treatment necessary.

This patient is an adult presenting with presumed conjunctivitis. Because he is presenting in the summer without observed purulent discharge, his condition is unlikely to be bacterial. This patient does not need treatment, although eye lubricant drops could reduce his discomfort.

Nearly 1% of primary care office visits¹ and 300 million in annual costs² are spent evaluating and treating “pink eye.” After ruling out serious eye disease, clinicians need to determine which cases of suspected conjunctivitis are most likely to be bacterial to allow for judicious use of antibiotic eye drops. This is an important undertaking as most patients assume that antibiotics are needed.

How do we know which history and clinical exam findings to lean on when attempting to categorize conjunctivitis as bacterial or not? If a patient reports purulent discharge, doesn’t that mean it is bacterial? Surprisingly, a systematic review published in 2016 by Narayana and McGee found that a patient’s self-report of “purulent drainage” is diagnostically unhelpful, but if a clinician finds it on exam, the likelihood of a bacterial etiology increases.³

Narayana and McGee analyzed three studies that enrolled a total of 281 patients with presumed conjunctivitis who underwent bacterial cultures. They then determined which findings increased the probability of positive bacterial culture. From strongest to weakest, the best indicators of a bacterial cause were found to be: complete redness of the conjunctival membrane obscuring tarsal vessels (the vessels visible on the inside of everted upper or lower eyelids) (likelihood ratio, 4.6), observed purulent discharge (LR, 3.9), matting of both eyes in the morning (LR, 3.6), and presence during winter/spring months (LR, 1.9). On the other hand, failure to observe a red eye at 20 feet (LR, 0.2), absence of morning gluing of either eye (LR, 0.3), and presentation during summer months (LR, 0.4) all decreased the probability of a bacterial cause. This review and different study by Stenson et al. unfortunately have conflicting evidence regarding whether the following findings are diagnostically helpful: qualities of eye discomfort (such as burning or itching), preauricular adenopathy, conjunctival follicles, and conjunctival papillae.^3,4 Rietveld and colleagues found that a history of conjunctivitis decreased the likelihood of bacterial conjunctivitis.⁵

Pearl: The best indicators of a bacterial cause in patients with presumed conjunctivitis are complete redness of the conjunctival membrane obscuring tarsal vessels, observed purulent discharge, and matting of both eyes in the morning. Presentation during the summer months and having a history of conjunctivitis decreases the likelihood of bacterial conjunctivitis.

Ms. Momany is a fourth-year medical student at University of Washington, Seattle. Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington and serves as third-year medical student clerkship director at that university. Contact Dr. Paauw at [email protected].

References

1. Azari AA and Barney NP. JAMA. 2013 Oct 23; 310(16):1721-9.

2. Smith AF and Waycaster C. BMC Ophthalmol. 2009 Nov 25. doi: 10.1186/1471-2415-9-13.

3) Narayana S and McGee S. Am J Med. 2015;128(11):1220-4.e1.

4) Stenson S et al. Arch Ophthalmol. 1982;100(8):1275-7.

5) Rietveld RP et al. BMJ. 2004 Jul 24;329(7459):206-10.

A 54-year-old pharmacist with a history of gout, hypertension, and conjunctivitis presents for evaluation of pink eye in the summer. The morning before coming into the office, he noticed that his right eye was red and inflamed. He self-treated with saline washes and eye drops, but upon awakening the next day, he found his right eye to be crusted shut with surrounding yellow discharge. He has not had any changes to his vision but endorses a somewhat uncomfortable, “gritty” sensation. He reports no recent cough, nasal congestion, or allergies, and he has not been around any sick contacts. His blood pressure is 102/58 mm Hg, pulse is 76 bpm, and body mass index is 27.3 kg/m². His eye exam reveals unilateral conjunctival injections but no hyperemia of the conjunctiva adjacent to the cornea. Mucopurulent discharge was neither found on the undersurface of the eyelid nor emerging from the eye. Which of the following is the best treatment for this patient’s condition?

A) Erythromycin 5 mg/gram ophthalmic ointment.

B) Ofloxacin 0.3% ophthalmic drops.

C) Antihistamine drops.

D) Eye lubricant drops.

E) No treatment necessary.

This patient is an adult presenting with presumed conjunctivitis. Because he is presenting in the summer without observed purulent discharge, his condition is unlikely to be bacterial. This patient does not need treatment, although eye lubricant drops could reduce his discomfort.

Nearly 1% of primary care office visits¹ and 300 million in annual costs² are spent evaluating and treating “pink eye.” After ruling out serious eye disease, clinicians need to determine which cases of suspected conjunctivitis are most likely to be bacterial to allow for judicious use of antibiotic eye drops. This is an important undertaking as most patients assume that antibiotics are needed.

How do we know which history and clinical exam findings to lean on when attempting to categorize conjunctivitis as bacterial or not? If a patient reports purulent discharge, doesn’t that mean it is bacterial? Surprisingly, a systematic review published in 2016 by Narayana and McGee found that a patient’s self-report of “purulent drainage” is diagnostically unhelpful, but if a clinician finds it on exam, the likelihood of a bacterial etiology increases.³

Narayana and McGee analyzed three studies that enrolled a total of 281 patients with presumed conjunctivitis who underwent bacterial cultures. They then determined which findings increased the probability of positive bacterial culture. From strongest to weakest, the best indicators of a bacterial cause were found to be: complete redness of the conjunctival membrane obscuring tarsal vessels (the vessels visible on the inside of everted upper or lower eyelids) (likelihood ratio, 4.6), observed purulent discharge (LR, 3.9), matting of both eyes in the morning (LR, 3.6), and presence during winter/spring months (LR, 1.9). On the other hand, failure to observe a red eye at 20 feet (LR, 0.2), absence of morning gluing of either eye (LR, 0.3), and presentation during summer months (LR, 0.4) all decreased the probability of a bacterial cause. This review and different study by Stenson et al. unfortunately have conflicting evidence regarding whether the following findings are diagnostically helpful: qualities of eye discomfort (such as burning or itching), preauricular adenopathy, conjunctival follicles, and conjunctival papillae.^3,4 Rietveld and colleagues found that a history of conjunctivitis decreased the likelihood of bacterial conjunctivitis.⁵

Pearl: The best indicators of a bacterial cause in patients with presumed conjunctivitis are complete redness of the conjunctival membrane obscuring tarsal vessels, observed purulent discharge, and matting of both eyes in the morning. Presentation during the summer months and having a history of conjunctivitis decreases the likelihood of bacterial conjunctivitis.

Ms. Momany is a fourth-year medical student at University of Washington, Seattle. Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington and serves as third-year medical student clerkship director at that university. Contact Dr. Paauw at [email protected].

References

1. Azari AA and Barney NP. JAMA. 2013 Oct 23; 310(16):1721-9.

2. Smith AF and Waycaster C. BMC Ophthalmol. 2009 Nov 25. doi: 10.1186/1471-2415-9-13.

3) Narayana S and McGee S. Am J Med. 2015;128(11):1220-4.e1.

4) Stenson S et al. Arch Ophthalmol. 1982;100(8):1275-7.

5) Rietveld RP et al. BMJ. 2004 Jul 24;329(7459):206-10.

The FP suspected cutaneous vasculitis of the ear caused by levamisole-adulterated cocaine.

Levamisole is an antihelminthic drug approved for veterinary purposes. In the past, the drug had been used as an immune modulator in autoimmune disorders, but no longer is considered safe for human use, as it can cause agranulocytosis. Sellers around the world often lace cocaine with levamisole because it boosts the profits and potentiates the psychoactive effects of the cocaine. Cutaneous vasculitis secondary to levamisole-adulterated cocaine has been reported many times in the literature.

Levamisole-associated vasculitis presents with ear purpura, retiform (like a net) purpura of the trunk or extremities, and neutropenia. Patients will test positive for perinuclear antineutrophil cytoplasmic antibody (pANCA). This cutaneous vasculitis also may present on the nose or face. There are reports of cocaine/levamisole-associated autoimmune syndrome involving agranulocytosis and cutaneous vasculitis.

The patient tested positive for pANCA, as was expected. The FP told her to discontinue her cocaine use, as she ran the risk of worse manifestations. She refused any treatment for her drug use and stated she could stop it on her own. The FP referred the patient to Dermatology, but the vasculitis was barely visible by the time she was seen. Convincing the patient not to use cocaine again remained the only treatment.

‌

Photo courtesy of Jon Karnes, MD, and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Mayeaux EJ, Usatine R, Martin N, et al. Vasculitis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1169-1173.

To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the 3rd edition of the Color Atlas and Synopsis of Family Medicine as an app by clicking on this link: https://usatinemedia.com/app/color-atlas-of-family-medicine/

The FP suspected cutaneous vasculitis of the ear caused by levamisole-adulterated cocaine.

Levamisole is an antihelminthic drug approved for veterinary purposes. In the past, the drug had been used as an immune modulator in autoimmune disorders, but no longer is considered safe for human use, as it can cause agranulocytosis. Sellers around the world often lace cocaine with levamisole because it boosts the profits and potentiates the psychoactive effects of the cocaine. Cutaneous vasculitis secondary to levamisole-adulterated cocaine has been reported many times in the literature.

Levamisole-associated vasculitis presents with ear purpura, retiform (like a net) purpura of the trunk or extremities, and neutropenia. Patients will test positive for perinuclear antineutrophil cytoplasmic antibody (pANCA). This cutaneous vasculitis also may present on the nose or face. There are reports of cocaine/levamisole-associated autoimmune syndrome involving agranulocytosis and cutaneous vasculitis.

The patient tested positive for pANCA, as was expected. The FP told her to discontinue her cocaine use, as she ran the risk of worse manifestations. She refused any treatment for her drug use and stated she could stop it on her own. The FP referred the patient to Dermatology, but the vasculitis was barely visible by the time she was seen. Convincing the patient not to use cocaine again remained the only treatment.

‌

Photo courtesy of Jon Karnes, MD, and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Mayeaux EJ, Usatine R, Martin N, et al. Vasculitis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1169-1173.

To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the 3rd edition of the Color Atlas and Synopsis of Family Medicine as an app by clicking on this link: https://usatinemedia.com/app/color-atlas-of-family-medicine/

The FP suspected cutaneous vasculitis of the ear caused by levamisole-adulterated cocaine.

Levamisole is an antihelminthic drug approved for veterinary purposes. In the past, the drug had been used as an immune modulator in autoimmune disorders, but no longer is considered safe for human use, as it can cause agranulocytosis. Sellers around the world often lace cocaine with levamisole because it boosts the profits and potentiates the psychoactive effects of the cocaine. Cutaneous vasculitis secondary to levamisole-adulterated cocaine has been reported many times in the literature.

Levamisole-associated vasculitis presents with ear purpura, retiform (like a net) purpura of the trunk or extremities, and neutropenia. Patients will test positive for perinuclear antineutrophil cytoplasmic antibody (pANCA). This cutaneous vasculitis also may present on the nose or face. There are reports of cocaine/levamisole-associated autoimmune syndrome involving agranulocytosis and cutaneous vasculitis.

The patient tested positive for pANCA, as was expected. The FP told her to discontinue her cocaine use, as she ran the risk of worse manifestations. She refused any treatment for her drug use and stated she could stop it on her own. The FP referred the patient to Dermatology, but the vasculitis was barely visible by the time she was seen. Convincing the patient not to use cocaine again remained the only treatment.

‌

Photo courtesy of Jon Karnes, MD, and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Mayeaux EJ, Usatine R, Martin N, et al. Vasculitis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1169-1173.

To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/

You can get the 3rd edition of the Color Atlas and Synopsis of Family Medicine as an app by clicking on this link: https://usatinemedia.com/app/color-atlas-of-family-medicine/

A prosthetic leg that elicits the sensation of knee motion and the feeling of the sole of the foot touching the ground may improve walking performance and reduce phantom limb pain, according to a proof-of-concept study with two patients.

Huntstock/thinkstockphotos

With the bionic leg system, the patients performed better during clinically important tests indoors and outdoors, study author Stanisa Raspopovic, PhD, explained during a press briefing about the research. The findings were published in Nature Medicine.

The results indicate that the use of sensory feedback “could be common practice” in prosthetic devices in the future, he said. Dr. Raspopovic is a researcher at Swiss Federal Institute of Technology Zürich and a founder of SensArs Neuroprosthetics, which is based in Lausanne, Switzerland.

Neural prosthetics allow the nervous system and external devices to interact. These brain-machine interfaces may improve quality of life for patients with brain or spinal cord injuries, degenerative disease, or loss of limbs.

“Conventional leg prostheses do not convey sensory information about motion or interaction with the ground to above-knee amputees, thereby reducing confidence and walking speed in the users,” the study authors wrote. Users may also have high levels of mental and physical fatigue, and the lack of physiologic feedback from the extremity to the brain may contribute to the generation of phantom limb pain.

To evaluate whether neural sensory feedback restoration could address these issues, investigators conducted a study with two patients who had undergone transfemoral amputations as a result of traumatic events. The patients were implanted with four intraneural stimulation electrodes in the remaining tibial nerve. The prosthetic leg device included sensors to represent foot touch and pressure and knee joint angle. The sensors transmitted sensory signals to the nervous system through the stimulation electrodes in the tibial nerve.

When the patients walked outdoors over a path traced in the sand, “participants’ speeds were significantly higher when sensory feedback was provided,” the authors wrote. One participant walked 3.56 m/min faster, and the other walked 5.68 m/min faster.

The participants also rated their confidence in the prosthesis on a scale from 0 to 10. For patient 1, self-rated confidence improved from 4.85 to 7.71 with the device. Patient 2 reported a confidence level that climbed from 2.7 to 5.55.

When tested indoors, both patients reached a 0.5 km/hour higher speed on the treadmill when stimulation was provided and both had a lower mean rate of oxygen uptake during the sensory feedback trials, the study authors reported.

Levels of phantom limb pain also decreased significantly after 10-minute stimulation sessions, but not during control sessions.

Longer studies with more patients are required, and fully implantable devices without transcutaneous cables need to be developed, the authors wrote.

Grants from the European Research Council, European Commission, and Swiss National Science Foundation funded the research. Dr. Raspopovic and two coauthors hold shares of SensArs Neuroprosthetics, a start-up company dealing with the commercialization of neurocontrolled artificial limbs.

[email protected]

SOURCE: Petrini FM et al. Nat Med. 2019 Sep 9. doi: 10.1038/s41591-019-0567-3.

A prosthetic leg that elicits the sensation of knee motion and the feeling of the sole of the foot touching the ground may improve walking performance and reduce phantom limb pain, according to a proof-of-concept study with two patients.

Huntstock/thinkstockphotos

With the bionic leg system, the patients performed better during clinically important tests indoors and outdoors, study author Stanisa Raspopovic, PhD, explained during a press briefing about the research. The findings were published in Nature Medicine.

The results indicate that the use of sensory feedback “could be common practice” in prosthetic devices in the future, he said. Dr. Raspopovic is a researcher at Swiss Federal Institute of Technology Zürich and a founder of SensArs Neuroprosthetics, which is based in Lausanne, Switzerland.

Neural prosthetics allow the nervous system and external devices to interact. These brain-machine interfaces may improve quality of life for patients with brain or spinal cord injuries, degenerative disease, or loss of limbs.

“Conventional leg prostheses do not convey sensory information about motion or interaction with the ground to above-knee amputees, thereby reducing confidence and walking speed in the users,” the study authors wrote. Users may also have high levels of mental and physical fatigue, and the lack of physiologic feedback from the extremity to the brain may contribute to the generation of phantom limb pain.

To evaluate whether neural sensory feedback restoration could address these issues, investigators conducted a study with two patients who had undergone transfemoral amputations as a result of traumatic events. The patients were implanted with four intraneural stimulation electrodes in the remaining tibial nerve. The prosthetic leg device included sensors to represent foot touch and pressure and knee joint angle. The sensors transmitted sensory signals to the nervous system through the stimulation electrodes in the tibial nerve.

When the patients walked outdoors over a path traced in the sand, “participants’ speeds were significantly higher when sensory feedback was provided,” the authors wrote. One participant walked 3.56 m/min faster, and the other walked 5.68 m/min faster.

The participants also rated their confidence in the prosthesis on a scale from 0 to 10. For patient 1, self-rated confidence improved from 4.85 to 7.71 with the device. Patient 2 reported a confidence level that climbed from 2.7 to 5.55.

When tested indoors, both patients reached a 0.5 km/hour higher speed on the treadmill when stimulation was provided and both had a lower mean rate of oxygen uptake during the sensory feedback trials, the study authors reported.

Levels of phantom limb pain also decreased significantly after 10-minute stimulation sessions, but not during control sessions.

Longer studies with more patients are required, and fully implantable devices without transcutaneous cables need to be developed, the authors wrote.

Grants from the European Research Council, European Commission, and Swiss National Science Foundation funded the research. Dr. Raspopovic and two coauthors hold shares of SensArs Neuroprosthetics, a start-up company dealing with the commercialization of neurocontrolled artificial limbs.

[email protected]

SOURCE: Petrini FM et al. Nat Med. 2019 Sep 9. doi: 10.1038/s41591-019-0567-3.

A prosthetic leg that elicits the sensation of knee motion and the feeling of the sole of the foot touching the ground may improve walking performance and reduce phantom limb pain, according to a proof-of-concept study with two patients.

Huntstock/thinkstockphotos

With the bionic leg system, the patients performed better during clinically important tests indoors and outdoors, study author Stanisa Raspopovic, PhD, explained during a press briefing about the research. The findings were published in Nature Medicine.

The results indicate that the use of sensory feedback “could be common practice” in prosthetic devices in the future, he said. Dr. Raspopovic is a researcher at Swiss Federal Institute of Technology Zürich and a founder of SensArs Neuroprosthetics, which is based in Lausanne, Switzerland.

Neural prosthetics allow the nervous system and external devices to interact. These brain-machine interfaces may improve quality of life for patients with brain or spinal cord injuries, degenerative disease, or loss of limbs.

“Conventional leg prostheses do not convey sensory information about motion or interaction with the ground to above-knee amputees, thereby reducing confidence and walking speed in the users,” the study authors wrote. Users may also have high levels of mental and physical fatigue, and the lack of physiologic feedback from the extremity to the brain may contribute to the generation of phantom limb pain.

To evaluate whether neural sensory feedback restoration could address these issues, investigators conducted a study with two patients who had undergone transfemoral amputations as a result of traumatic events. The patients were implanted with four intraneural stimulation electrodes in the remaining tibial nerve. The prosthetic leg device included sensors to represent foot touch and pressure and knee joint angle. The sensors transmitted sensory signals to the nervous system through the stimulation electrodes in the tibial nerve.

When the patients walked outdoors over a path traced in the sand, “participants’ speeds were significantly higher when sensory feedback was provided,” the authors wrote. One participant walked 3.56 m/min faster, and the other walked 5.68 m/min faster.

The participants also rated their confidence in the prosthesis on a scale from 0 to 10. For patient 1, self-rated confidence improved from 4.85 to 7.71 with the device. Patient 2 reported a confidence level that climbed from 2.7 to 5.55.

When tested indoors, both patients reached a 0.5 km/hour higher speed on the treadmill when stimulation was provided and both had a lower mean rate of oxygen uptake during the sensory feedback trials, the study authors reported.

Levels of phantom limb pain also decreased significantly after 10-minute stimulation sessions, but not during control sessions.

Longer studies with more patients are required, and fully implantable devices without transcutaneous cables need to be developed, the authors wrote.

Grants from the European Research Council, European Commission, and Swiss National Science Foundation funded the research. Dr. Raspopovic and two coauthors hold shares of SensArs Neuroprosthetics, a start-up company dealing with the commercialization of neurocontrolled artificial limbs.

[email protected]

SOURCE: Petrini FM et al. Nat Med. 2019 Sep 9. doi: 10.1038/s41591-019-0567-3.

Migraines are associated with a significantly greater risk of Alzheimer’s disease and all forms of dementia except vascular dementia, according to research published online Sept. 4 in the International Journal of Geriatric Psychiatry.

In the Manitoba Study of Health and Aging, a population-based, prospective cohort study, 679 community-dwelling adults with a mean age of 75.9 years were followed for 5 years. Participants screened as cognitively intact at baseline had complete data on migraine history and all covariates at baseline and were assessed for cognitive outcomes 5 years later.

The study showed that a history of migraines was associated with a 2.97-fold greater likelihood of dementia, after adjustment for age, education, and a history of stroke, compared with individuals without a history of migraine. Individuals with Alzheimer’s disease were more than four times more likely to have a history of migraines (odds ratio 4.22).

However, researchers found no significant association between vascular dementia and a history of migraines, either before or after adjusting for confounders but particularly after incorporating a history of stroke into the model.

Lead investigator Suzanne L. Tyas, PhD, associate professor in the School of Public Health and Health Systems at the University of Waterloo, Ont., and coauthors suggested that the association between migraine and dementia was largely driven by the strong association between migraines and Alzheimer’s disease.

“This interpretation is supported by the weaker association for dementia than for Alzheimer’s disease, reflecting a dilution of the association with migraines across all types of dementia including vascular dementia, where a significant association was not found,” the researchers wrote.

The study population was 61.9% female, and no men reporting a history of migraine were diagnosed with dementia. While the study reflected a strong association between migraine and dementia in women, the researchers said they were unable to assess potential gender differences in this association.

Commenting on possible mechanisms behind the association, the authors wrote that there were overlaps underlying the biological mechanisms of migraine and dementia. Vascular risk factors such as diabetes, hypertension, heart attack, and stroke are associated with the development of dementia, and a relationship of these risk factors and migraine also has been seen.

“Many of the mechanisms involved in migraine neurophysiology, such as inflammation and reduced cerebral blood flow, are also underlying causes of dementia,” they wrote. “Repeated activation of these pathways in chronic migraineurs has been shown to cause permanent neurological and vascular damage.”

They also observed that the association could be influenced by genetic factors, as individuals with presenilin-1 mutations, which predispose them to Alzheimer’s disease, are more likely to experience migraines or recurrent headaches.

They suggested their findings could inform preventive strategies and treatments for Alzheimer’s disease, as well as interventions such as earlier screening for cognitive decline in individuals who experience migraines.

The study was funded by Manitoba Health and the National Health Research and Development Program of Health Canada. No conflicts of interest were declared.
 

SOURCE: Morton R et al. Int J Geriatr Psychiatry, 2019 Sep 4. doi: 10.1002/gps.5180.

Migraines are associated with a significantly greater risk of Alzheimer’s disease and all forms of dementia except vascular dementia, according to research published online Sept. 4 in the International Journal of Geriatric Psychiatry.

In the Manitoba Study of Health and Aging, a population-based, prospective cohort study, 679 community-dwelling adults with a mean age of 75.9 years were followed for 5 years. Participants screened as cognitively intact at baseline had complete data on migraine history and all covariates at baseline and were assessed for cognitive outcomes 5 years later.

The study showed that a history of migraines was associated with a 2.97-fold greater likelihood of dementia, after adjustment for age, education, and a history of stroke, compared with individuals without a history of migraine. Individuals with Alzheimer’s disease were more than four times more likely to have a history of migraines (odds ratio 4.22).

However, researchers found no significant association between vascular dementia and a history of migraines, either before or after adjusting for confounders but particularly after incorporating a history of stroke into the model.

Lead investigator Suzanne L. Tyas, PhD, associate professor in the School of Public Health and Health Systems at the University of Waterloo, Ont., and coauthors suggested that the association between migraine and dementia was largely driven by the strong association between migraines and Alzheimer’s disease.

“This interpretation is supported by the weaker association for dementia than for Alzheimer’s disease, reflecting a dilution of the association with migraines across all types of dementia including vascular dementia, where a significant association was not found,” the researchers wrote.

The study population was 61.9% female, and no men reporting a history of migraine were diagnosed with dementia. While the study reflected a strong association between migraine and dementia in women, the researchers said they were unable to assess potential gender differences in this association.

Commenting on possible mechanisms behind the association, the authors wrote that there were overlaps underlying the biological mechanisms of migraine and dementia. Vascular risk factors such as diabetes, hypertension, heart attack, and stroke are associated with the development of dementia, and a relationship of these risk factors and migraine also has been seen.

“Many of the mechanisms involved in migraine neurophysiology, such as inflammation and reduced cerebral blood flow, are also underlying causes of dementia,” they wrote. “Repeated activation of these pathways in chronic migraineurs has been shown to cause permanent neurological and vascular damage.”

They also observed that the association could be influenced by genetic factors, as individuals with presenilin-1 mutations, which predispose them to Alzheimer’s disease, are more likely to experience migraines or recurrent headaches.

They suggested their findings could inform preventive strategies and treatments for Alzheimer’s disease, as well as interventions such as earlier screening for cognitive decline in individuals who experience migraines.

The study was funded by Manitoba Health and the National Health Research and Development Program of Health Canada. No conflicts of interest were declared.
 

SOURCE: Morton R et al. Int J Geriatr Psychiatry, 2019 Sep 4. doi: 10.1002/gps.5180.

Migraines are associated with a significantly greater risk of Alzheimer’s disease and all forms of dementia except vascular dementia, according to research published online Sept. 4 in the International Journal of Geriatric Psychiatry.

In the Manitoba Study of Health and Aging, a population-based, prospective cohort study, 679 community-dwelling adults with a mean age of 75.9 years were followed for 5 years. Participants screened as cognitively intact at baseline had complete data on migraine history and all covariates at baseline and were assessed for cognitive outcomes 5 years later.

The study showed that a history of migraines was associated with a 2.97-fold greater likelihood of dementia, after adjustment for age, education, and a history of stroke, compared with individuals without a history of migraine. Individuals with Alzheimer’s disease were more than four times more likely to have a history of migraines (odds ratio 4.22).

However, researchers found no significant association between vascular dementia and a history of migraines, either before or after adjusting for confounders but particularly after incorporating a history of stroke into the model.

Lead investigator Suzanne L. Tyas, PhD, associate professor in the School of Public Health and Health Systems at the University of Waterloo, Ont., and coauthors suggested that the association between migraine and dementia was largely driven by the strong association between migraines and Alzheimer’s disease.

“This interpretation is supported by the weaker association for dementia than for Alzheimer’s disease, reflecting a dilution of the association with migraines across all types of dementia including vascular dementia, where a significant association was not found,” the researchers wrote.

The study population was 61.9% female, and no men reporting a history of migraine were diagnosed with dementia. While the study reflected a strong association between migraine and dementia in women, the researchers said they were unable to assess potential gender differences in this association.

Commenting on possible mechanisms behind the association, the authors wrote that there were overlaps underlying the biological mechanisms of migraine and dementia. Vascular risk factors such as diabetes, hypertension, heart attack, and stroke are associated with the development of dementia, and a relationship of these risk factors and migraine also has been seen.

“Many of the mechanisms involved in migraine neurophysiology, such as inflammation and reduced cerebral blood flow, are also underlying causes of dementia,” they wrote. “Repeated activation of these pathways in chronic migraineurs has been shown to cause permanent neurological and vascular damage.”

They also observed that the association could be influenced by genetic factors, as individuals with presenilin-1 mutations, which predispose them to Alzheimer’s disease, are more likely to experience migraines or recurrent headaches.

They suggested their findings could inform preventive strategies and treatments for Alzheimer’s disease, as well as interventions such as earlier screening for cognitive decline in individuals who experience migraines.

The study was funded by Manitoba Health and the National Health Research and Development Program of Health Canada. No conflicts of interest were declared.
 

SOURCE: Morton R et al. Int J Geriatr Psychiatry, 2019 Sep 4. doi: 10.1002/gps.5180.

EVIDENCE SUMMARY

All NSAIDs at maximum clinical doses reduced large joint OA pain more effectively than placebo and acetaminophen based on data from a network meta-analysis of 129 RCTs with 32,129 patients (TABLE 1).¹ When various doses of NSAIDs are ranked for efficacy based on their effect size compared to placebo, diclofenac 150 mg/d had the greatest treatment effect, followed by ibuprofen 2400 mg/d.² Lower doses of NSAIDs—including diclofenac 70 mg/d, naproxen 750 mg/d, and ibuprofen 1200 mg/d—were not statistically superior to placebo (TABLE 2).²

Selective vs nonselective. There was no statistical difference in pain relief between the selective COX-2 inhibitor celecoxib and the nonselective NSAIDs naproxen, diclofenac, and ibuprofen (TABLE 1).¹

Meloxicam. A systematic review of 16 RCTs and 22,886 patients found that meloxicam reduced pain more effectively than placebo (10-point visual analogue scale [VAS] score pain difference of –6.8; 95% CI, –9.3 to –4.2) but was marginally less effective than other NSAIDs (VAS score pain difference of 1.7; 95% CI, 0.8 to 2.7).³

Acetaminophen. Data from 6 RCTs involving 2083 adults with knee OA indicate acetaminophen did not achieve clinical significance compared to placebo (TABLE 1).¹ Another meta-analysis of 5 RCTs involving 1741 patients with hip or knee OA also demonstrated that acetaminophen failed to achieve a clinically significant effect on pain, defined as a reduction of 9 mm on a 0 to 100 mm VAS (–3.7; 95% CI, –5.5 to –1.9).⁴ Another network meta-analysis of 6 RCTs including 58,556 patients with knee or hip OA, with the primary outcome of pain (using a hierarchy of pain scores, with global pain score taking precedence) also found no clinically significant difference between acetaminophen at the highest dose (4000 mg/d) and placebo (–0.17; 95% credible interval [CrI], –0.27 to –0.6).²

RECOMMENDATIONS

In a systematic review of mixed evidence-based and expert opinion recommendations and guidelines on the management of OA, 10 of the 11 guidelines that included pharmacologic management recommended acetaminophen as a first-line agent, followed by topical NSAIDs, and then oral NSAIDs. The exception is the most recent American Academy of Orthopaedic Surgeons guideline, which continues to recommend NSAIDs but is now unable to recommend for or against acetaminophen.⁵

EVIDENCE SUMMARY

All NSAIDs at maximum clinical doses reduced large joint OA pain more effectively than placebo and acetaminophen based on data from a network meta-analysis of 129 RCTs with 32,129 patients (TABLE 1).¹ When various doses of NSAIDs are ranked for efficacy based on their effect size compared to placebo, diclofenac 150 mg/d had the greatest treatment effect, followed by ibuprofen 2400 mg/d.² Lower doses of NSAIDs—including diclofenac 70 mg/d, naproxen 750 mg/d, and ibuprofen 1200 mg/d—were not statistically superior to placebo (TABLE 2).²

Selective vs nonselective. There was no statistical difference in pain relief between the selective COX-2 inhibitor celecoxib and the nonselective NSAIDs naproxen, diclofenac, and ibuprofen (TABLE 1).¹

Meloxicam. A systematic review of 16 RCTs and 22,886 patients found that meloxicam reduced pain more effectively than placebo (10-point visual analogue scale [VAS] score pain difference of –6.8; 95% CI, –9.3 to –4.2) but was marginally less effective than other NSAIDs (VAS score pain difference of 1.7; 95% CI, 0.8 to 2.7).³

Acetaminophen. Data from 6 RCTs involving 2083 adults with knee OA indicate acetaminophen did not achieve clinical significance compared to placebo (TABLE 1).¹ Another meta-analysis of 5 RCTs involving 1741 patients with hip or knee OA also demonstrated that acetaminophen failed to achieve a clinically significant effect on pain, defined as a reduction of 9 mm on a 0 to 100 mm VAS (–3.7; 95% CI, –5.5 to –1.9).⁴ Another network meta-analysis of 6 RCTs including 58,556 patients with knee or hip OA, with the primary outcome of pain (using a hierarchy of pain scores, with global pain score taking precedence) also found no clinically significant difference between acetaminophen at the highest dose (4000 mg/d) and placebo (–0.17; 95% credible interval [CrI], –0.27 to –0.6).²

RECOMMENDATIONS

In a systematic review of mixed evidence-based and expert opinion recommendations and guidelines on the management of OA, 10 of the 11 guidelines that included pharmacologic management recommended acetaminophen as a first-line agent, followed by topical NSAIDs, and then oral NSAIDs. The exception is the most recent American Academy of Orthopaedic Surgeons guideline, which continues to recommend NSAIDs but is now unable to recommend for or against acetaminophen.⁵

EVIDENCE SUMMARY

All NSAIDs at maximum clinical doses reduced large joint OA pain more effectively than placebo and acetaminophen based on data from a network meta-analysis of 129 RCTs with 32,129 patients (TABLE 1).¹ When various doses of NSAIDs are ranked for efficacy based on their effect size compared to placebo, diclofenac 150 mg/d had the greatest treatment effect, followed by ibuprofen 2400 mg/d.² Lower doses of NSAIDs—including diclofenac 70 mg/d, naproxen 750 mg/d, and ibuprofen 1200 mg/d—were not statistically superior to placebo (TABLE 2).²

Selective vs nonselective. There was no statistical difference in pain relief between the selective COX-2 inhibitor celecoxib and the nonselective NSAIDs naproxen, diclofenac, and ibuprofen (TABLE 1).¹

Meloxicam. A systematic review of 16 RCTs and 22,886 patients found that meloxicam reduced pain more effectively than placebo (10-point visual analogue scale [VAS] score pain difference of –6.8; 95% CI, –9.3 to –4.2) but was marginally less effective than other NSAIDs (VAS score pain difference of 1.7; 95% CI, 0.8 to 2.7).³

Acetaminophen. Data from 6 RCTs involving 2083 adults with knee OA indicate acetaminophen did not achieve clinical significance compared to placebo (TABLE 1).¹ Another meta-analysis of 5 RCTs involving 1741 patients with hip or knee OA also demonstrated that acetaminophen failed to achieve a clinically significant effect on pain, defined as a reduction of 9 mm on a 0 to 100 mm VAS (–3.7; 95% CI, –5.5 to –1.9).⁴ Another network meta-analysis of 6 RCTs including 58,556 patients with knee or hip OA, with the primary outcome of pain (using a hierarchy of pain scores, with global pain score taking precedence) also found no clinically significant difference between acetaminophen at the highest dose (4000 mg/d) and placebo (–0.17; 95% credible interval [CrI], –0.27 to –0.6).²

RECOMMENDATIONS

In a systematic review of mixed evidence-based and expert opinion recommendations and guidelines on the management of OA, 10 of the 11 guidelines that included pharmacologic management recommended acetaminophen as a first-line agent, followed by topical NSAIDs, and then oral NSAIDs. The exception is the most recent American Academy of Orthopaedic Surgeons guideline, which continues to recommend NSAIDs but is now unable to recommend for or against acetaminophen.⁵

CASE 1

Robin S is a 40-year-old woman who has never had children or been pregnant. She is in a relationship with a woman so does not use contraception. She has no family history of cancer. She presents with worsening bilateral breast pain that starts 10 days before the onset of her period. The pain has been present for about 4 years, but it has worsened over the last 6 months such that she is unable to wear a bra during these 10 days, finds lying in bed on her side too painful for sleep, and is unable to exercise. She has tried to eliminate caffeine from her diet and takes ibuprofen, but neither of these interventions has controlled her pain. Her breast exam is normal except for diffuse tenderness over both breasts.

CASE 2

Meg R is a 50-year-old healthy woman. She is a G2P2 who breastfed each of her children for 1 year. She does not smoke. She has no family history of breast cancer or other malignancies. She presents with 2 months of deep, left-sided breast pain. She describes the pain as constant, progressive, dull, and achy. She points to a spot in the upper outer quadrant of her left breast and describes the pain as being close to her ribs. She had a screening mammogram 3 weeks earlier that was normal, with findings of dense breasts. She did not tell the technician that she was having pain. Clinical breast examination of both breasts reveals tenderness to deep palpation of the left breast. She has dense breasts but a focal mass is not palpated.

Mastalgia, or breast pain, is one of the most common breast symptoms seen in primary care and a common reason for referrals to breast surgeons. Up to 70% of women will experience breast pain during their lifetime—most in their premenopausal years.^1,2

The most common type of breast pain is cyclic (ie, relating to the menstrual cycle); it accounts for up to 70% of all cases of breast pain in women.^1,3 The other 2 types of breast pain are noncyclic and extramammary. The cause of cyclic breast pain is unclear, but it is likely hormonally mediated and multifactorial. In the vast majority of women with breast pain, no distinct etiology is found, and there is a very low incidence of breast cancer.^2,4

Up to 70% of women will experience breast pain during their lifetime, most in their premenopausal years.

In this review, we describe how to proceed when a woman who is not breastfeeding presents with cyclic or noncyclic breast pain.

Evaluation: Focus on the pain, medications, and history

Evaluation of breast pain should begin with the patient describing the pain, including its quality, location, radiation, and relationship to the menstrual cycle. It’s important to inquire about recent trauma or aggravating activities and to order a pregnancy test for women of childbearing age.¹

Cyclic mastalgia is typically described as diffuse, either unilateral or bilateral, with an aching or heavy quality. The pain is often felt in the upper outer quadrant of the breast with radiation to the axilla. It most commonly occurs during the luteal phase of the menstrual cycle, improves with the onset of menses, and is thought to be related to the increased water content in breast stroma caused by increasing hormone levels during the luteal phase.^5-7

Continue to: Noncyclic mastalgia

Noncyclic mastalgia is typically unilateral and localized within 1 quadrant of the breast; however, women may report diffuse pain with radiation to the axilla. The pain is often described as burning, achy, or as soreness.^5,6 There can be considerable overlap in the presentations of cyclic and noncyclic pain and differentiating between the 2 is often not necessary as management is similar.⁸

A thorough review of medications is important as several drugs have been associated with breast pain. These include oral contraceptives, hormone therapy, antidepressants (selective serotonin reuptake inhibitors [SSRIs], venlafaxine, mirtazapine), antipsychotics (haloperidol), and some cardiovascular agents (spironolactone, digoxin).⁵

Inquiring about stress, caffeine intake, smoking status, and bra usage may also yield useful information. Increased stress and caffeine intake have been associated with mastalgia,⁷ and women who are heavy smokers are more likely to have noncyclic hypersensitive breast pain.⁹ In addition, women with large breasts often have noncyclic breast pain, particularly if they don’t wear a sufficiently supportive bra.³

Medical, surgical, family history. Relevant aspects of a woman’s past medical, surgical, and family history include prior breast mass or biopsy, breast surgery, and risk factors associated with breast cancer (menarche age < 12 years, menopause age > 55 years, nulliparity, exposure to ionizing radiation, and family history of breast or ovarian cancer).¹ A thorough history should include questions to evaluate for extra-mammary etiologies of breast pain such as those that are musculoskeletal or dermatologic in nature (TABLE 1^1,5,8,10).

Using an objective measure of pain is not only helpful for evaluating the pain itself, but also for determining the effectiveness of treatment strategies. When using the Cardiff Breast Pain Chart, for example, menstrual cycle and level of pain are recorded on a calendar (see www.breastcancercare.org.uk/sites/default/files/files/breast_pain_chart.pdf).¹¹ If the pain is determined to be cyclic, the concern for malignancy is significantly lower.²

Continue to: Ensure that the physical exam is thorough

Ensure that the physical exam is thorough

Women presenting with breast pain should undergo a clinical breast exam in both the upright and supine positions. Inspect for asymmetry, erythema, rashes, skin dimpling, nipple discharge, and retraction/inversion. Palpate the breasts for any suspicious masses, asymmetry, or tenderness, as well as for axillary and/or supraclavicular lymphadenopathy and chest wall tenderness. This is facilitated by having the patient lie in the lateral decubitus position, allowing the breast to fall away from the chest wall.^5,12,13

Imaging: Preferred method depends on the age of the patient

Women with a palpable mass should be referred for diagnostic imaging (FIGURE 1^1,14). Ultrasonography is the recommended modality for women < 30 years of age (TABLE 2¹⁵). For women between the ages of 30 and 39 years, appropriate initial imaging includes ultrasound, diagnostic mammography, or digital breast tomosynthesis (DBT). For women ≥ 40 years of age, diagnostic mammography or DBT is recommended.¹⁵

Cyclic breast pain. Women with cyclic breast pain do not require further evaluation with imaging. Reassurance and symptomatic treatment is appropriate in most cases, as the risk of malignancy is very low in the absence of other concerning signs or symptoms. A screening mammogram may be appropriate for women > 40 years of age who have not had one in the preceding 12 months.^1-3,10,12,15

Noncyclic breast pain. In contrast, imaging may be appropriate in women who present with noncyclic breast pain depending on the woman’s age and whether the pain is focal (≤ 25% of the breast and axillary tissue) or diffuse (> 25% of the breast and axillary tissue). Although evidence suggests that the risk of malignancy in women with noncyclic breast pain is low, the American College of Radiology advises that imaging may be useful in some patients to provide reassurance and to exclude a treatable cause of breast pain.^3,14 In women with focal pain, ultrasound alone is the preferred modality for women < 30 years of age and ultrasound plus diagnostic mammography is recommended for women ≥ 30 years of age.^3,14

In one small study, the use of ultrasonography in women ages < 30 years with focal breast pain had a sensitivity of 100% and a negative predictive value of 100%.¹⁶ Similarly, another small retrospective study in older women (average age 56 years) with focal breast pain and no palpable mass showed that ultrasound plus diagnostic mammography had a negative predictive value of 100%.⁴ DBT may be used in place of mammography to rule out malignancy in this setting.

Continue to: In general...

In general, routine imaging is not indicated for women with noncyclic diffuse breast pain, although diagnostic mammography or DBT may be considered in women ≥ 40 years of age ¹⁴ (see “Less common diagnoses with breast pain”^4,5,17-21).

Continue to: Treatment...

Nonrandomized studies suggest that reassurance that mastalgia is benign is enough to treat up to 70% of women.^8,22,23 Cyclic breast pain is usually treated symptomatically since the likelihood of breast cancer is extremely low in absence of clinical breast examination abnormalities.² Because treatment for cyclic and noncyclic mastalgia overlaps, available treatments are discussed together on the following pages.

Lifestyle factors associated with breast pain include stress, caffeine consumption, smoking, and having breastfed 3 or more children (P < .05).⁹ Although restriction of caffeine, fat, and salt intake may be attempted to address breast pain, no randomized control trials (RCTs) of these interventions have demonstrated effectiveness in reducing mastalgia.^8,10

Breast imaging is critical in patients with a palpable mass or focal pain but is not necessary in patients with cyclic pain.

Although not supported by RCTs, first-line treatment of mastalgia includes a recommendation that women, particularly those with large, heavy breasts, wear a well-fitted and supportive bra.^8,10

Complementary and alternative medicine treatments for mastalgia

A number of complementary and alternative medicine treatments have demonstrated benefit in treating mastalgia and are often tried before pharmacologic agents (TABLE 3^24-28). Keep in mind, though, that these therapies are not regulated by the US Food and Drug Administration (FDA). So it’s wise to review particular products with your patient before she buys them (or ask her to bring in any bottles of product for you to review).

Flaxseed, omega-3 fatty acids, and soy milk. Flaxseed, a source of phytoestrogens and omega-3 fatty acids, has been shown to reduce cyclic breast pain in 2 small RCTs.^24,25 Breast pain scores were significantly lower for patients ingesting 25 g/d of flaxseed powder compared with placebo.^24,25 Omega-3 fatty acids were also more effective than placebo for relief of cyclic breast pain in 2 small RCTs.^25,26 Another small RCT demonstrated that women who drank soy milk had a nonsignificant improvement in breast pain compared with those who drank cow’s milk.²⁷

Continue to: Chasteberry

Chasteberry. One RCT demonstrated that Vitex agnus-castus, a chasteberry fruit extract, produced significant and clinically meaningful improvement in visual analogue pain scores for mastalgia, with few adverse effects.²⁹ Another RCT assessing breast fullness as part of the premenstrual syndrome showed significant improvement in breast discomfort for women treated with Vitex ­agnus-castus.³⁰

Evening primrose oil (EPO). In at least one small study, EPO was effective in controlling breast pain.²⁸ A more recent meta-analysis of all of the EPO trials including gamolenic acid (the active ingredient of EPO) showed no significant difference in mastalgia compared with placebo.³¹

Pharmacologic Tx options: Start with NSAIDs

Oral nonsteroidal anti-inflammatory drugs (NSAIDs) are often recommended as a first-line treatment for mastalgia and are likely effective for some women; however, there is currently insufficient evidence that oral NSAIDs (or acetaminophen) improve pain (TABLE 4^32-37; FIGURE 2^5,13,17). Nevertheless, the potential benefits are thought to outweigh the risk of adverse effects in most patients. A small RCT did demonstrate that topical diclofenac was effective in patients with cyclic and noncyclic mastalgia.³⁸

SSRIs. A meta-analysis of 10 double-blind RCTs of SSRIs used in women with premenstrual symptoms, including 4 studies that specifically included physical symptoms such as breast pain, showed SSRIs to be more effective than placebo at relieving breast pain.³⁵

Progesterones. Several studies have found topical, oral, and injected progesterone ineffective at reducing breast pain.^8,36,39 However, one RCT did show topical vaginal micronized progesterone used in the luteal phase to be effective in reducing breast pain by at least 50%.³⁶

Continue to: Oral contraceptives

Oral contraceptives. For women who use oral contraceptive pills and experience cyclic breast pain, continuous dosing (skipping the pill-free week) or using a lower dose of estrogen may improve symptoms. Postmenopausal women with mastalgia that developed with initiation of hormone therapy may benefit from discontinuing hormone therapy or decreasing the estrogen dose; however, there are no RCTs to offer conclusive evidence of the effectiveness of these interventions.¹⁰

Danazol. Women with severe mastalgia that does not respond to more benign therapies may require hormone therapy. As with all symptom management, it is imperative to engage the patient in a shared decision-making conversation about the risks and benefits of this treatment strategy. Women must be able to balance the potential adverse effects of agents such as danazol and tamoxifen with the need to alleviate pain and improve quality of life.

Oral NSAIDs are often recommended as first-line treatment for mastalgia.

Danazol is the only medication FDA-approved for the treatment of mastalgia. Danazol is an androgen that blocks the release of other gonadotropins to limit hormonal stimulation of breast tissue. One RCT demonstrated that danazol (100 mg bid) reduces breast pain in 60% to 90% of women, although adverse effects often limit utility.⁴⁰ Adverse effects of danazol include weight gain, hot flashes, deepening of the voice, hirsutism, menorrhagia or amenorrhea, muscle cramps, and androgenic effects on a fetus.^8,31,40 Danazol may be best used cyclically during the luteal phase of the menstrual cycle to limit these adverse effects with reduction of the dose to 100 mg/d after relief of symptoms.^31,40

Tamoxifen, a selective estrogen receptor modulator, has been shown to reduce breast pain in 80% to 90% of women, although it is not indicated for mastalgia.⁴⁰ Tamoxifen may cause endometrial thickening, hot flashes, menstrual irregularity, venous thromboembolism, and teratogenicity. The 10 mg/d dose appears to be as effective at improving symptoms as the 20 mg/d dose with fewer adverse effects.^8,31,40

In a head-to-head randomized trial, tamoxifen was superior to danazol for relief of breast pain with fewer adverse effects.³⁴ Experts recommend limiting use of tamoxifen and danazol to 3 to 6 months. Neither of these drugs is considered safe in pregnancy.

Continue to: Bromocriptine

Bromocriptine, a prolactin inhibitor, has been shown to be more effective than placebo in reducing breast pain, although nausea and dizziness contribute to high discontinuation rates. Bromocriptine is less effective than danazol.⁴⁰

Goserelin, which is not available in the United States, is a gonadorelin analog (luteinizing hormone-releasing hormone analog) that produces reversible ovarian suppression. One RCT showed that goserelin injection may be more effective than placebo in reducing breast pain.³⁷ Adverse effects include vaginal dryness, hot flashes, decreased libido, oily skin or hair, decreased breast size, and irritability. It is recommended as treatment only for severe refractory mastalgia and that it be used no longer than 6 months.^31,37

CASE 1

You reassure Ms. S that her history and physical exam are consistent with cyclic breast pain and not malignancy. You review the current US Preventive Services Task Force recommendations for breast cancer screening in women ages 40 to 49 years (Grade C; women who place a higher value on the potential benefit than the potential harms may choose screening).⁴¹ Based on shared decision-making,you offer her a screening mammogram, which returns normal. After confirming that she is using an appropriately-sized supportive bra, you recommend adding 25 g/d of ground flaxseed to her diet.

Women presenting with breast pain should undergo a clinical breast exam in both the upright and supine positions.

After 2 months she reports a 30% improvement in her pain. You then recommend chasteberry extract 4.2 mg/d, which provides additional relief to the point where she can now sleep better and walk for exercise.

CASE 2

You order a diagnostic mammogram of the left breast, which is normal, and an ultrasound that demonstrates a 6-cm deep mass. A biopsy determines that Ms. R has invasive lobular breast cancer—an extremely unlikely outcome of breast pain. She elects to have a double mastectomy and reconstruction and is doing well 4 years later.

CORRESPONDENCE
Sarina Schrager, MD, MS, University of Wisconsin Department of Family Medicine and Community Health, 1100 Delaplaine Ct., Madison, WI, 53715; [email protected].

CASE 1

Robin S is a 40-year-old woman who has never had children or been pregnant. She is in a relationship with a woman so does not use contraception. She has no family history of cancer. She presents with worsening bilateral breast pain that starts 10 days before the onset of her period. The pain has been present for about 4 years, but it has worsened over the last 6 months such that she is unable to wear a bra during these 10 days, finds lying in bed on her side too painful for sleep, and is unable to exercise. She has tried to eliminate caffeine from her diet and takes ibuprofen, but neither of these interventions has controlled her pain. Her breast exam is normal except for diffuse tenderness over both breasts.

CASE 2

Meg R is a 50-year-old healthy woman. She is a G2P2 who breastfed each of her children for 1 year. She does not smoke. She has no family history of breast cancer or other malignancies. She presents with 2 months of deep, left-sided breast pain. She describes the pain as constant, progressive, dull, and achy. She points to a spot in the upper outer quadrant of her left breast and describes the pain as being close to her ribs. She had a screening mammogram 3 weeks earlier that was normal, with findings of dense breasts. She did not tell the technician that she was having pain. Clinical breast examination of both breasts reveals tenderness to deep palpation of the left breast. She has dense breasts but a focal mass is not palpated.

Mastalgia, or breast pain, is one of the most common breast symptoms seen in primary care and a common reason for referrals to breast surgeons. Up to 70% of women will experience breast pain during their lifetime—most in their premenopausal years.^1,2

The most common type of breast pain is cyclic (ie, relating to the menstrual cycle); it accounts for up to 70% of all cases of breast pain in women.^1,3 The other 2 types of breast pain are noncyclic and extramammary. The cause of cyclic breast pain is unclear, but it is likely hormonally mediated and multifactorial. In the vast majority of women with breast pain, no distinct etiology is found, and there is a very low incidence of breast cancer.^2,4

Up to 70% of women will experience breast pain during their lifetime, most in their premenopausal years.

In this review, we describe how to proceed when a woman who is not breastfeeding presents with cyclic or noncyclic breast pain.

Evaluation: Focus on the pain, medications, and history

Evaluation of breast pain should begin with the patient describing the pain, including its quality, location, radiation, and relationship to the menstrual cycle. It’s important to inquire about recent trauma or aggravating activities and to order a pregnancy test for women of childbearing age.¹

Cyclic mastalgia is typically described as diffuse, either unilateral or bilateral, with an aching or heavy quality. The pain is often felt in the upper outer quadrant of the breast with radiation to the axilla. It most commonly occurs during the luteal phase of the menstrual cycle, improves with the onset of menses, and is thought to be related to the increased water content in breast stroma caused by increasing hormone levels during the luteal phase.^5-7

Continue to: Noncyclic mastalgia

Noncyclic mastalgia is typically unilateral and localized within 1 quadrant of the breast; however, women may report diffuse pain with radiation to the axilla. The pain is often described as burning, achy, or as soreness.^5,6 There can be considerable overlap in the presentations of cyclic and noncyclic pain and differentiating between the 2 is often not necessary as management is similar.⁸

A thorough review of medications is important as several drugs have been associated with breast pain. These include oral contraceptives, hormone therapy, antidepressants (selective serotonin reuptake inhibitors [SSRIs], venlafaxine, mirtazapine), antipsychotics (haloperidol), and some cardiovascular agents (spironolactone, digoxin).⁵

Inquiring about stress, caffeine intake, smoking status, and bra usage may also yield useful information. Increased stress and caffeine intake have been associated with mastalgia,⁷ and women who are heavy smokers are more likely to have noncyclic hypersensitive breast pain.⁹ In addition, women with large breasts often have noncyclic breast pain, particularly if they don’t wear a sufficiently supportive bra.³

Medical, surgical, family history. Relevant aspects of a woman’s past medical, surgical, and family history include prior breast mass or biopsy, breast surgery, and risk factors associated with breast cancer (menarche age < 12 years, menopause age > 55 years, nulliparity, exposure to ionizing radiation, and family history of breast or ovarian cancer).¹ A thorough history should include questions to evaluate for extra-mammary etiologies of breast pain such as those that are musculoskeletal or dermatologic in nature (TABLE 1^1,5,8,10).

Using an objective measure of pain is not only helpful for evaluating the pain itself, but also for determining the effectiveness of treatment strategies. When using the Cardiff Breast Pain Chart, for example, menstrual cycle and level of pain are recorded on a calendar (see www.breastcancercare.org.uk/sites/default/files/files/breast_pain_chart.pdf).¹¹ If the pain is determined to be cyclic, the concern for malignancy is significantly lower.²

Continue to: Ensure that the physical exam is thorough

Ensure that the physical exam is thorough

Women presenting with breast pain should undergo a clinical breast exam in both the upright and supine positions. Inspect for asymmetry, erythema, rashes, skin dimpling, nipple discharge, and retraction/inversion. Palpate the breasts for any suspicious masses, asymmetry, or tenderness, as well as for axillary and/or supraclavicular lymphadenopathy and chest wall tenderness. This is facilitated by having the patient lie in the lateral decubitus position, allowing the breast to fall away from the chest wall.^5,12,13

Imaging: Preferred method depends on the age of the patient

Women with a palpable mass should be referred for diagnostic imaging (FIGURE 1^1,14). Ultrasonography is the recommended modality for women < 30 years of age (TABLE 2¹⁵). For women between the ages of 30 and 39 years, appropriate initial imaging includes ultrasound, diagnostic mammography, or digital breast tomosynthesis (DBT). For women ≥ 40 years of age, diagnostic mammography or DBT is recommended.¹⁵

Cyclic breast pain. Women with cyclic breast pain do not require further evaluation with imaging. Reassurance and symptomatic treatment is appropriate in most cases, as the risk of malignancy is very low in the absence of other concerning signs or symptoms. A screening mammogram may be appropriate for women > 40 years of age who have not had one in the preceding 12 months.^1-3,10,12,15

Noncyclic breast pain. In contrast, imaging may be appropriate in women who present with noncyclic breast pain depending on the woman’s age and whether the pain is focal (≤ 25% of the breast and axillary tissue) or diffuse (> 25% of the breast and axillary tissue). Although evidence suggests that the risk of malignancy in women with noncyclic breast pain is low, the American College of Radiology advises that imaging may be useful in some patients to provide reassurance and to exclude a treatable cause of breast pain.^3,14 In women with focal pain, ultrasound alone is the preferred modality for women < 30 years of age and ultrasound plus diagnostic mammography is recommended for women ≥ 30 years of age.^3,14

In one small study, the use of ultrasonography in women ages < 30 years with focal breast pain had a sensitivity of 100% and a negative predictive value of 100%.¹⁶ Similarly, another small retrospective study in older women (average age 56 years) with focal breast pain and no palpable mass showed that ultrasound plus diagnostic mammography had a negative predictive value of 100%.⁴ DBT may be used in place of mammography to rule out malignancy in this setting.

Continue to: In general...

In general, routine imaging is not indicated for women with noncyclic diffuse breast pain, although diagnostic mammography or DBT may be considered in women ≥ 40 years of age ¹⁴ (see “Less common diagnoses with breast pain”^4,5,17-21).

Continue to: Treatment...

Nonrandomized studies suggest that reassurance that mastalgia is benign is enough to treat up to 70% of women.^8,22,23 Cyclic breast pain is usually treated symptomatically since the likelihood of breast cancer is extremely low in absence of clinical breast examination abnormalities.² Because treatment for cyclic and noncyclic mastalgia overlaps, available treatments are discussed together on the following pages.

Lifestyle factors associated with breast pain include stress, caffeine consumption, smoking, and having breastfed 3 or more children (P < .05).⁹ Although restriction of caffeine, fat, and salt intake may be attempted to address breast pain, no randomized control trials (RCTs) of these interventions have demonstrated effectiveness in reducing mastalgia.^8,10

Breast imaging is critical in patients with a palpable mass or focal pain but is not necessary in patients with cyclic pain.

Although not supported by RCTs, first-line treatment of mastalgia includes a recommendation that women, particularly those with large, heavy breasts, wear a well-fitted and supportive bra.^8,10

Complementary and alternative medicine treatments for mastalgia

A number of complementary and alternative medicine treatments have demonstrated benefit in treating mastalgia and are often tried before pharmacologic agents (TABLE 3^24-28). Keep in mind, though, that these therapies are not regulated by the US Food and Drug Administration (FDA). So it’s wise to review particular products with your patient before she buys them (or ask her to bring in any bottles of product for you to review).

Flaxseed, omega-3 fatty acids, and soy milk. Flaxseed, a source of phytoestrogens and omega-3 fatty acids, has been shown to reduce cyclic breast pain in 2 small RCTs.^24,25 Breast pain scores were significantly lower for patients ingesting 25 g/d of flaxseed powder compared with placebo.^24,25 Omega-3 fatty acids were also more effective than placebo for relief of cyclic breast pain in 2 small RCTs.^25,26 Another small RCT demonstrated that women who drank soy milk had a nonsignificant improvement in breast pain compared with those who drank cow’s milk.²⁷

Continue to: Chasteberry

Chasteberry. One RCT demonstrated that Vitex agnus-castus, a chasteberry fruit extract, produced significant and clinically meaningful improvement in visual analogue pain scores for mastalgia, with few adverse effects.²⁹ Another RCT assessing breast fullness as part of the premenstrual syndrome showed significant improvement in breast discomfort for women treated with Vitex ­agnus-castus.³⁰

Evening primrose oil (EPO). In at least one small study, EPO was effective in controlling breast pain.²⁸ A more recent meta-analysis of all of the EPO trials including gamolenic acid (the active ingredient of EPO) showed no significant difference in mastalgia compared with placebo.³¹

Pharmacologic Tx options: Start with NSAIDs

Oral nonsteroidal anti-inflammatory drugs (NSAIDs) are often recommended as a first-line treatment for mastalgia and are likely effective for some women; however, there is currently insufficient evidence that oral NSAIDs (or acetaminophen) improve pain (TABLE 4^32-37; FIGURE 2^5,13,17). Nevertheless, the potential benefits are thought to outweigh the risk of adverse effects in most patients. A small RCT did demonstrate that topical diclofenac was effective in patients with cyclic and noncyclic mastalgia.³⁸

SSRIs. A meta-analysis of 10 double-blind RCTs of SSRIs used in women with premenstrual symptoms, including 4 studies that specifically included physical symptoms such as breast pain, showed SSRIs to be more effective than placebo at relieving breast pain.³⁵

Progesterones. Several studies have found topical, oral, and injected progesterone ineffective at reducing breast pain.^8,36,39 However, one RCT did show topical vaginal micronized progesterone used in the luteal phase to be effective in reducing breast pain by at least 50%.³⁶

Continue to: Oral contraceptives

Oral contraceptives. For women who use oral contraceptive pills and experience cyclic breast pain, continuous dosing (skipping the pill-free week) or using a lower dose of estrogen may improve symptoms. Postmenopausal women with mastalgia that developed with initiation of hormone therapy may benefit from discontinuing hormone therapy or decreasing the estrogen dose; however, there are no RCTs to offer conclusive evidence of the effectiveness of these interventions.¹⁰

Danazol. Women with severe mastalgia that does not respond to more benign therapies may require hormone therapy. As with all symptom management, it is imperative to engage the patient in a shared decision-making conversation about the risks and benefits of this treatment strategy. Women must be able to balance the potential adverse effects of agents such as danazol and tamoxifen with the need to alleviate pain and improve quality of life.

Oral NSAIDs are often recommended as first-line treatment for mastalgia.

Danazol is the only medication FDA-approved for the treatment of mastalgia. Danazol is an androgen that blocks the release of other gonadotropins to limit hormonal stimulation of breast tissue. One RCT demonstrated that danazol (100 mg bid) reduces breast pain in 60% to 90% of women, although adverse effects often limit utility.⁴⁰ Adverse effects of danazol include weight gain, hot flashes, deepening of the voice, hirsutism, menorrhagia or amenorrhea, muscle cramps, and androgenic effects on a fetus.^8,31,40 Danazol may be best used cyclically during the luteal phase of the menstrual cycle to limit these adverse effects with reduction of the dose to 100 mg/d after relief of symptoms.^31,40

Tamoxifen, a selective estrogen receptor modulator, has been shown to reduce breast pain in 80% to 90% of women, although it is not indicated for mastalgia.⁴⁰ Tamoxifen may cause endometrial thickening, hot flashes, menstrual irregularity, venous thromboembolism, and teratogenicity. The 10 mg/d dose appears to be as effective at improving symptoms as the 20 mg/d dose with fewer adverse effects.^8,31,40

In a head-to-head randomized trial, tamoxifen was superior to danazol for relief of breast pain with fewer adverse effects.³⁴ Experts recommend limiting use of tamoxifen and danazol to 3 to 6 months. Neither of these drugs is considered safe in pregnancy.

Continue to: Bromocriptine

Bromocriptine, a prolactin inhibitor, has been shown to be more effective than placebo in reducing breast pain, although nausea and dizziness contribute to high discontinuation rates. Bromocriptine is less effective than danazol.⁴⁰

Goserelin, which is not available in the United States, is a gonadorelin analog (luteinizing hormone-releasing hormone analog) that produces reversible ovarian suppression. One RCT showed that goserelin injection may be more effective than placebo in reducing breast pain.³⁷ Adverse effects include vaginal dryness, hot flashes, decreased libido, oily skin or hair, decreased breast size, and irritability. It is recommended as treatment only for severe refractory mastalgia and that it be used no longer than 6 months.^31,37

CASE 1

You reassure Ms. S that her history and physical exam are consistent with cyclic breast pain and not malignancy. You review the current US Preventive Services Task Force recommendations for breast cancer screening in women ages 40 to 49 years (Grade C; women who place a higher value on the potential benefit than the potential harms may choose screening).⁴¹ Based on shared decision-making,you offer her a screening mammogram, which returns normal. After confirming that she is using an appropriately-sized supportive bra, you recommend adding 25 g/d of ground flaxseed to her diet.

Women presenting with breast pain should undergo a clinical breast exam in both the upright and supine positions.

After 2 months she reports a 30% improvement in her pain. You then recommend chasteberry extract 4.2 mg/d, which provides additional relief to the point where she can now sleep better and walk for exercise.

CASE 2

You order a diagnostic mammogram of the left breast, which is normal, and an ultrasound that demonstrates a 6-cm deep mass. A biopsy determines that Ms. R has invasive lobular breast cancer—an extremely unlikely outcome of breast pain. She elects to have a double mastectomy and reconstruction and is doing well 4 years later.

CORRESPONDENCE
Sarina Schrager, MD, MS, University of Wisconsin Department of Family Medicine and Community Health, 1100 Delaplaine Ct., Madison, WI, 53715; [email protected].

CASE 1

Robin S is a 40-year-old woman who has never had children or been pregnant. She is in a relationship with a woman so does not use contraception. She has no family history of cancer. She presents with worsening bilateral breast pain that starts 10 days before the onset of her period. The pain has been present for about 4 years, but it has worsened over the last 6 months such that she is unable to wear a bra during these 10 days, finds lying in bed on her side too painful for sleep, and is unable to exercise. She has tried to eliminate caffeine from her diet and takes ibuprofen, but neither of these interventions has controlled her pain. Her breast exam is normal except for diffuse tenderness over both breasts.

CASE 2

Meg R is a 50-year-old healthy woman. She is a G2P2 who breastfed each of her children for 1 year. She does not smoke. She has no family history of breast cancer or other malignancies. She presents with 2 months of deep, left-sided breast pain. She describes the pain as constant, progressive, dull, and achy. She points to a spot in the upper outer quadrant of her left breast and describes the pain as being close to her ribs. She had a screening mammogram 3 weeks earlier that was normal, with findings of dense breasts. She did not tell the technician that she was having pain. Clinical breast examination of both breasts reveals tenderness to deep palpation of the left breast. She has dense breasts but a focal mass is not palpated.

Mastalgia, or breast pain, is one of the most common breast symptoms seen in primary care and a common reason for referrals to breast surgeons. Up to 70% of women will experience breast pain during their lifetime—most in their premenopausal years.^1,2

The most common type of breast pain is cyclic (ie, relating to the menstrual cycle); it accounts for up to 70% of all cases of breast pain in women.^1,3 The other 2 types of breast pain are noncyclic and extramammary. The cause of cyclic breast pain is unclear, but it is likely hormonally mediated and multifactorial. In the vast majority of women with breast pain, no distinct etiology is found, and there is a very low incidence of breast cancer.^2,4

Up to 70% of women will experience breast pain during their lifetime, most in their premenopausal years.

In this review, we describe how to proceed when a woman who is not breastfeeding presents with cyclic or noncyclic breast pain.

Evaluation: Focus on the pain, medications, and history

Evaluation of breast pain should begin with the patient describing the pain, including its quality, location, radiation, and relationship to the menstrual cycle. It’s important to inquire about recent trauma or aggravating activities and to order a pregnancy test for women of childbearing age.¹

Cyclic mastalgia is typically described as diffuse, either unilateral or bilateral, with an aching or heavy quality. The pain is often felt in the upper outer quadrant of the breast with radiation to the axilla. It most commonly occurs during the luteal phase of the menstrual cycle, improves with the onset of menses, and is thought to be related to the increased water content in breast stroma caused by increasing hormone levels during the luteal phase.^5-7

Continue to: Noncyclic mastalgia

Noncyclic mastalgia is typically unilateral and localized within 1 quadrant of the breast; however, women may report diffuse pain with radiation to the axilla. The pain is often described as burning, achy, or as soreness.^5,6 There can be considerable overlap in the presentations of cyclic and noncyclic pain and differentiating between the 2 is often not necessary as management is similar.⁸

A thorough review of medications is important as several drugs have been associated with breast pain. These include oral contraceptives, hormone therapy, antidepressants (selective serotonin reuptake inhibitors [SSRIs], venlafaxine, mirtazapine), antipsychotics (haloperidol), and some cardiovascular agents (spironolactone, digoxin).⁵

Inquiring about stress, caffeine intake, smoking status, and bra usage may also yield useful information. Increased stress and caffeine intake have been associated with mastalgia,⁷ and women who are heavy smokers are more likely to have noncyclic hypersensitive breast pain.⁹ In addition, women with large breasts often have noncyclic breast pain, particularly if they don’t wear a sufficiently supportive bra.³

Medical, surgical, family history. Relevant aspects of a woman’s past medical, surgical, and family history include prior breast mass or biopsy, breast surgery, and risk factors associated with breast cancer (menarche age < 12 years, menopause age > 55 years, nulliparity, exposure to ionizing radiation, and family history of breast or ovarian cancer).¹ A thorough history should include questions to evaluate for extra-mammary etiologies of breast pain such as those that are musculoskeletal or dermatologic in nature (TABLE 1^1,5,8,10).

Using an objective measure of pain is not only helpful for evaluating the pain itself, but also for determining the effectiveness of treatment strategies. When using the Cardiff Breast Pain Chart, for example, menstrual cycle and level of pain are recorded on a calendar (see www.breastcancercare.org.uk/sites/default/files/files/breast_pain_chart.pdf).¹¹ If the pain is determined to be cyclic, the concern for malignancy is significantly lower.²

Continue to: Ensure that the physical exam is thorough

Ensure that the physical exam is thorough

Women presenting with breast pain should undergo a clinical breast exam in both the upright and supine positions. Inspect for asymmetry, erythema, rashes, skin dimpling, nipple discharge, and retraction/inversion. Palpate the breasts for any suspicious masses, asymmetry, or tenderness, as well as for axillary and/or supraclavicular lymphadenopathy and chest wall tenderness. This is facilitated by having the patient lie in the lateral decubitus position, allowing the breast to fall away from the chest wall.^5,12,13

Imaging: Preferred method depends on the age of the patient

Women with a palpable mass should be referred for diagnostic imaging (FIGURE 1^1,14). Ultrasonography is the recommended modality for women < 30 years of age (TABLE 2¹⁵). For women between the ages of 30 and 39 years, appropriate initial imaging includes ultrasound, diagnostic mammography, or digital breast tomosynthesis (DBT). For women ≥ 40 years of age, diagnostic mammography or DBT is recommended.¹⁵

Cyclic breast pain. Women with cyclic breast pain do not require further evaluation with imaging. Reassurance and symptomatic treatment is appropriate in most cases, as the risk of malignancy is very low in the absence of other concerning signs or symptoms. A screening mammogram may be appropriate for women > 40 years of age who have not had one in the preceding 12 months.^1-3,10,12,15

Noncyclic breast pain. In contrast, imaging may be appropriate in women who present with noncyclic breast pain depending on the woman’s age and whether the pain is focal (≤ 25% of the breast and axillary tissue) or diffuse (> 25% of the breast and axillary tissue). Although evidence suggests that the risk of malignancy in women with noncyclic breast pain is low, the American College of Radiology advises that imaging may be useful in some patients to provide reassurance and to exclude a treatable cause of breast pain.^3,14 In women with focal pain, ultrasound alone is the preferred modality for women < 30 years of age and ultrasound plus diagnostic mammography is recommended for women ≥ 30 years of age.^3,14

In one small study, the use of ultrasonography in women ages < 30 years with focal breast pain had a sensitivity of 100% and a negative predictive value of 100%.¹⁶ Similarly, another small retrospective study in older women (average age 56 years) with focal breast pain and no palpable mass showed that ultrasound plus diagnostic mammography had a negative predictive value of 100%.⁴ DBT may be used in place of mammography to rule out malignancy in this setting.

Continue to: In general...

In general, routine imaging is not indicated for women with noncyclic diffuse breast pain, although diagnostic mammography or DBT may be considered in women ≥ 40 years of age ¹⁴ (see “Less common diagnoses with breast pain”^4,5,17-21).

Continue to: Treatment...

Nonrandomized studies suggest that reassurance that mastalgia is benign is enough to treat up to 70% of women.^8,22,23 Cyclic breast pain is usually treated symptomatically since the likelihood of breast cancer is extremely low in absence of clinical breast examination abnormalities.² Because treatment for cyclic and noncyclic mastalgia overlaps, available treatments are discussed together on the following pages.

Lifestyle factors associated with breast pain include stress, caffeine consumption, smoking, and having breastfed 3 or more children (P < .05).⁹ Although restriction of caffeine, fat, and salt intake may be attempted to address breast pain, no randomized control trials (RCTs) of these interventions have demonstrated effectiveness in reducing mastalgia.^8,10

Breast imaging is critical in patients with a palpable mass or focal pain but is not necessary in patients with cyclic pain.

Although not supported by RCTs, first-line treatment of mastalgia includes a recommendation that women, particularly those with large, heavy breasts, wear a well-fitted and supportive bra.^8,10

Complementary and alternative medicine treatments for mastalgia

A number of complementary and alternative medicine treatments have demonstrated benefit in treating mastalgia and are often tried before pharmacologic agents (TABLE 3^24-28). Keep in mind, though, that these therapies are not regulated by the US Food and Drug Administration (FDA). So it’s wise to review particular products with your patient before she buys them (or ask her to bring in any bottles of product for you to review).

Flaxseed, omega-3 fatty acids, and soy milk. Flaxseed, a source of phytoestrogens and omega-3 fatty acids, has been shown to reduce cyclic breast pain in 2 small RCTs.^24,25 Breast pain scores were significantly lower for patients ingesting 25 g/d of flaxseed powder compared with placebo.^24,25 Omega-3 fatty acids were also more effective than placebo for relief of cyclic breast pain in 2 small RCTs.^25,26 Another small RCT demonstrated that women who drank soy milk had a nonsignificant improvement in breast pain compared with those who drank cow’s milk.²⁷

Continue to: Chasteberry

Chasteberry. One RCT demonstrated that Vitex agnus-castus, a chasteberry fruit extract, produced significant and clinically meaningful improvement in visual analogue pain scores for mastalgia, with few adverse effects.²⁹ Another RCT assessing breast fullness as part of the premenstrual syndrome showed significant improvement in breast discomfort for women treated with Vitex ­agnus-castus.³⁰

Evening primrose oil (EPO). In at least one small study, EPO was effective in controlling breast pain.²⁸ A more recent meta-analysis of all of the EPO trials including gamolenic acid (the active ingredient of EPO) showed no significant difference in mastalgia compared with placebo.³¹

Pharmacologic Tx options: Start with NSAIDs

Oral nonsteroidal anti-inflammatory drugs (NSAIDs) are often recommended as a first-line treatment for mastalgia and are likely effective for some women; however, there is currently insufficient evidence that oral NSAIDs (or acetaminophen) improve pain (TABLE 4^32-37; FIGURE 2^5,13,17). Nevertheless, the potential benefits are thought to outweigh the risk of adverse effects in most patients. A small RCT did demonstrate that topical diclofenac was effective in patients with cyclic and noncyclic mastalgia.³⁸

SSRIs. A meta-analysis of 10 double-blind RCTs of SSRIs used in women with premenstrual symptoms, including 4 studies that specifically included physical symptoms such as breast pain, showed SSRIs to be more effective than placebo at relieving breast pain.³⁵

Progesterones. Several studies have found topical, oral, and injected progesterone ineffective at reducing breast pain.^8,36,39 However, one RCT did show topical vaginal micronized progesterone used in the luteal phase to be effective in reducing breast pain by at least 50%.³⁶

Continue to: Oral contraceptives

Oral contraceptives. For women who use oral contraceptive pills and experience cyclic breast pain, continuous dosing (skipping the pill-free week) or using a lower dose of estrogen may improve symptoms. Postmenopausal women with mastalgia that developed with initiation of hormone therapy may benefit from discontinuing hormone therapy or decreasing the estrogen dose; however, there are no RCTs to offer conclusive evidence of the effectiveness of these interventions.¹⁰

Danazol. Women with severe mastalgia that does not respond to more benign therapies may require hormone therapy. As with all symptom management, it is imperative to engage the patient in a shared decision-making conversation about the risks and benefits of this treatment strategy. Women must be able to balance the potential adverse effects of agents such as danazol and tamoxifen with the need to alleviate pain and improve quality of life.

Oral NSAIDs are often recommended as first-line treatment for mastalgia.

Danazol is the only medication FDA-approved for the treatment of mastalgia. Danazol is an androgen that blocks the release of other gonadotropins to limit hormonal stimulation of breast tissue. One RCT demonstrated that danazol (100 mg bid) reduces breast pain in 60% to 90% of women, although adverse effects often limit utility.⁴⁰ Adverse effects of danazol include weight gain, hot flashes, deepening of the voice, hirsutism, menorrhagia or amenorrhea, muscle cramps, and androgenic effects on a fetus.^8,31,40 Danazol may be best used cyclically during the luteal phase of the menstrual cycle to limit these adverse effects with reduction of the dose to 100 mg/d after relief of symptoms.^31,40

Tamoxifen, a selective estrogen receptor modulator, has been shown to reduce breast pain in 80% to 90% of women, although it is not indicated for mastalgia.⁴⁰ Tamoxifen may cause endometrial thickening, hot flashes, menstrual irregularity, venous thromboembolism, and teratogenicity. The 10 mg/d dose appears to be as effective at improving symptoms as the 20 mg/d dose with fewer adverse effects.^8,31,40

In a head-to-head randomized trial, tamoxifen was superior to danazol for relief of breast pain with fewer adverse effects.³⁴ Experts recommend limiting use of tamoxifen and danazol to 3 to 6 months. Neither of these drugs is considered safe in pregnancy.

Continue to: Bromocriptine

Bromocriptine, a prolactin inhibitor, has been shown to be more effective than placebo in reducing breast pain, although nausea and dizziness contribute to high discontinuation rates. Bromocriptine is less effective than danazol.⁴⁰

Goserelin, which is not available in the United States, is a gonadorelin analog (luteinizing hormone-releasing hormone analog) that produces reversible ovarian suppression. One RCT showed that goserelin injection may be more effective than placebo in reducing breast pain.³⁷ Adverse effects include vaginal dryness, hot flashes, decreased libido, oily skin or hair, decreased breast size, and irritability. It is recommended as treatment only for severe refractory mastalgia and that it be used no longer than 6 months.^31,37

CASE 1

You reassure Ms. S that her history and physical exam are consistent with cyclic breast pain and not malignancy. You review the current US Preventive Services Task Force recommendations for breast cancer screening in women ages 40 to 49 years (Grade C; women who place a higher value on the potential benefit than the potential harms may choose screening).⁴¹ Based on shared decision-making,you offer her a screening mammogram, which returns normal. After confirming that she is using an appropriately-sized supportive bra, you recommend adding 25 g/d of ground flaxseed to her diet.

Women presenting with breast pain should undergo a clinical breast exam in both the upright and supine positions.

After 2 months she reports a 30% improvement in her pain. You then recommend chasteberry extract 4.2 mg/d, which provides additional relief to the point where she can now sleep better and walk for exercise.

CASE 2

You order a diagnostic mammogram of the left breast, which is normal, and an ultrasound that demonstrates a 6-cm deep mass. A biopsy determines that Ms. R has invasive lobular breast cancer—an extremely unlikely outcome of breast pain. She elects to have a double mastectomy and reconstruction and is doing well 4 years later.

CORRESPONDENCE
Sarina Schrager, MD, MS, University of Wisconsin Department of Family Medicine and Community Health, 1100 Delaplaine Ct., Madison, WI, 53715; [email protected].

More financial reinforcements are arriving in the battle against the opioid crisis, with the Trump administration promising more than $1.8 billion in new funds to help states address the crisis.

Speaking at a Sept. 4 press conference announcing the funding, President Donald Trump said the money will be used “to increase access to medication and medication-assisted treatment and mental health resources, which are critical for ending homelessness and getting people the help they deserve.” The president added that the grants also will help state and local governments obtain high-quality, comprehensive data.

The Centers for Disease Control and Prevention will provide more than $900 million in new funding over the next 3 years to “advance the understanding of the opioid overdose epidemic and to scale-up prevention and response activities,” the Department of Health & Human Services said in a statement announcing the funding.

“This money will help states and local communities track overdose data and develop strategies that save lives,” HHS Secretary Alex Azar said during the press conference.

He noted that, when the Trump administration began, overdose data were published with a 12-month lag. That lag has since shortened to 6 months. One of the goals with the new funding is to bring data publishing as close to real time as possible.

Separately, the Substance Abuse and Mental Health Services Administration awarded $932 million to all 50 states as part of its State Opioid Response grants, which “provide flexible funding to state governments to support prevention, treatment, and recovery services in the ways that meet the needs of their state,” according to the HHS statement.

That flexibility “can mean everything from expanding the use of medication-assisted treatment in criminal justice settings or in rural areas via telemedicine, to youth-focused community-based prevention efforts,” Secretary Azar explained. The funds can also support employment coaching and naloxone distribution, he added.

[email protected]

More financial reinforcements are arriving in the battle against the opioid crisis, with the Trump administration promising more than $1.8 billion in new funds to help states address the crisis.

Speaking at a Sept. 4 press conference announcing the funding, President Donald Trump said the money will be used “to increase access to medication and medication-assisted treatment and mental health resources, which are critical for ending homelessness and getting people the help they deserve.” The president added that the grants also will help state and local governments obtain high-quality, comprehensive data.

The Centers for Disease Control and Prevention will provide more than $900 million in new funding over the next 3 years to “advance the understanding of the opioid overdose epidemic and to scale-up prevention and response activities,” the Department of Health & Human Services said in a statement announcing the funding.

“This money will help states and local communities track overdose data and develop strategies that save lives,” HHS Secretary Alex Azar said during the press conference.

He noted that, when the Trump administration began, overdose data were published with a 12-month lag. That lag has since shortened to 6 months. One of the goals with the new funding is to bring data publishing as close to real time as possible.

Separately, the Substance Abuse and Mental Health Services Administration awarded $932 million to all 50 states as part of its State Opioid Response grants, which “provide flexible funding to state governments to support prevention, treatment, and recovery services in the ways that meet the needs of their state,” according to the HHS statement.

That flexibility “can mean everything from expanding the use of medication-assisted treatment in criminal justice settings or in rural areas via telemedicine, to youth-focused community-based prevention efforts,” Secretary Azar explained. The funds can also support employment coaching and naloxone distribution, he added.

[email protected]

More financial reinforcements are arriving in the battle against the opioid crisis, with the Trump administration promising more than $1.8 billion in new funds to help states address the crisis.

Speaking at a Sept. 4 press conference announcing the funding, President Donald Trump said the money will be used “to increase access to medication and medication-assisted treatment and mental health resources, which are critical for ending homelessness and getting people the help they deserve.” The president added that the grants also will help state and local governments obtain high-quality, comprehensive data.

The Centers for Disease Control and Prevention will provide more than $900 million in new funding over the next 3 years to “advance the understanding of the opioid overdose epidemic and to scale-up prevention and response activities,” the Department of Health & Human Services said in a statement announcing the funding.

“This money will help states and local communities track overdose data and develop strategies that save lives,” HHS Secretary Alex Azar said during the press conference.

He noted that, when the Trump administration began, overdose data were published with a 12-month lag. That lag has since shortened to 6 months. One of the goals with the new funding is to bring data publishing as close to real time as possible.

Separately, the Substance Abuse and Mental Health Services Administration awarded $932 million to all 50 states as part of its State Opioid Response grants, which “provide flexible funding to state governments to support prevention, treatment, and recovery services in the ways that meet the needs of their state,” according to the HHS statement.

That flexibility “can mean everything from expanding the use of medication-assisted treatment in criminal justice settings or in rural areas via telemedicine, to youth-focused community-based prevention efforts,” Secretary Azar explained. The funds can also support employment coaching and naloxone distribution, he added.

[email protected]

Chronic pain significantly affects 100 million Americans.^1,2 Pain accounts for $560 to $635 billion in annual financial costs to society, including health care costs and loss of productivity (ie, days missed from work, hours of work lost, and lower wages).^2,3 Although pain prevalence exceeds other chronic diseases, such as diabetes mellitus, cancer, and heart disease, it lacks a sufficient body of evidence-based research and guidelines on the underlying mechanisms, valid methods of assessment, and comparative effectiveness of treatments to effectively implement into clinical practice.^2,4 Prevention and treatment of pain are often delayed, inaccessible, or inadequate.² Primary care providers (PCPs) are most often sought for pain management and treat about 52% of chronic pain patients.^2,3,5 Veterans are especially vulnerable to chronic pain and are at risk for inadequate treatment.²

Background

There is an epidemic of drug abuse and mortality from opioid prescription medication.⁶ In the US, rates of overdose deaths from prescription opioids were 6.1 per 100,000 for men and 4.2 per 100,000 for women in 2017. Opioids were involved in 47,600 overdose deaths in 2017, accounting for 67.8% of all drug overdose deaths.⁷

A large number of patients on long-term opioids have preexisting substance use disorders and/or psychiatric disease, further complicating chronic pain management.^8-10 Prescription opioid use has been the precursor for about 80% of people who are now heroin addicts.¹¹ Iatrogenic addiction from prescription medications isn’t easily captured by standard addiction criteria. Consequently, in patients who are on opioid therapy for prolonged periods, separating complex opioid dependence from addiction is difficult.¹² Improved addiction screening and risk mitigation strategies are needed along with aggressive treatment monitoring to curb the opioid epidemic.

Opioid Management in Primary Care

The majority of opioid medications are prescribed by PCPs, which is magnified in the US Department of Veterans Affairs (VA) health care system due to the high prevalence of service-related injuries.^3,13 The VA is at the forefront of addressing the complexities of opioid addiction through several initiatives.¹⁴ The ability to offer the frequent visits needed to safely manage patients prescribed opioids and the integration of mental health and addiction treatment are often lacking in non-VA primary care clinics. Therefore, a key to solving the opioid crisis is developing these capabilities so they can be delivered within the primary care setting. There is substantial evidence in support of nonopioid alternatives to chronic pain management, including other pharmacologic approaches, exercise, physical therapy, acupuncture, weight loss, smoking cessation, chiropractic care, cognitive behavioral therapy (CBT), and other integrative health modalities.

A 2009 VA directive mandated the development of a comprehensive, integrated, systemwide approach to pain management.¹⁵ The VA Stepped-Care Biopsychosocial Model for Pain Management is dependent on timely access to secondary consultation from pain medicine, behavioral health, physical medicine, and other specialty consultation.¹⁵

History of VHA SCAN-ECHO Model

The Specialty Care Access Network–Extension for Community Health Outcomes (SCAN-ECHO) is a Veterans Health Administration (VHA) adaptation of a program that originated at the University of Mexico.^16,17 The SCAN-ECHO model uses a multisite videoconferencing network to provide specialty care consultations to PCPs and patient aligned care teams (PACTs). During the 60- to 90-minute weekly sessions, case presentations are analyzed in real time so that over time, the PCPs gain knowledge, competency, and confidence in learning how to handle complex chronic conditions.

Since its implementation, the SCAN-ECHO program has been adopted across the VHA in a variety of specialties. One program, the SCAN-ECHO for Pain Management (SCAN-ECHO-PM) was implemented in 7 VHA networks in 31 states, spanning 47 medical centers and 148 community-based outpatient clinics (CBOCs).¹⁸ The SCAN-ECHO-PM program successfully conducted 257 multidisciplinary pain consultations between 2011 and 2013, resulting in increased initiation of nonopioid medications.¹⁸

The aim of this article is to describe the implementation of a multicomponent primary care-based pain clinic with a fully integrated mental health service and addiction service at the North Florida/South Georgia Veterans Health System (NF/SGVHS). A practiced-based intervention of the biopsychosocial model with robust patient engagement has guided the development of the NF/SGVHS pain clinic (Figure 1).^4,19

Pain CLinic

NF/SGVHS comprises the Malcom Randall and Lake City VA medical centers (VAMCs) hospitals, 3 satellite outpatient clinics, and 8 CBOCs. Spanning 33 counties in North Florida and 19 counties in South Georgia, the NF/SGVHS serves more than 140,000 patients. In 2010, the Malcom Randall VAMC established a multidisciplinary primary care pain clinic to manage veterans at high-risk for noncancer chronic pain and addiction. The noncancer pain policy was revised after garnering support from stakeholders who treat chronic pain, including the chiefs of psychiatry, rehabilitation medicine, neurosurgery, psychology, interventional pain, pharmacy, nursing, addiction medicine, and primary care. The clinic is staffed by primary care physicians trained in internal medicine and family medicine and is structured with 1-hour first visits, and 30-minute follow-up visits to allow enough time for comprehensive evaluation while meeting the needs for close follow-up support.

All physicians in the clinic have buprenorphine prescribing credentials to aid in the management of opioid addiction, as some patients feel more comfortable receiving addiction treatment in a primary care setting. The multimodal care model consists of several services that include addiction psychiatrists, interventional pain specialists, pain psychologists, and pain pharmacologists who coordinate the care to the veterans. The addiction psychiatrists offer a full range of services with inpatient residential and outpatient programs. Through recurring meetings with primary care pain clinic staff, the addiction psychiatrists are available to discuss use of buprenorphine and arrange follow-up for patients with complex pain addiction. There is ongoing collaboration to develop the best care plan that meets the patient’s needs for chronic pain, addiction, and/or mental health issues. The interventional pain service has 3 fellowship-trained pain care providers who deliver comprehensive evaluation, pharmacologic recommendations, and a full range of interventional and complementary therapies with an emphasis on objective functional improvement. Pain care providers offer alternatives to patients who are being weaned from opioids and support the multidisciplinary patient engagement model.

The pain psychology program, established in 2011, delivers CBT to 5 onsite locations and 5 telehealth locations. The service includes an advanced CBT program and a couples CBT program. The pharmacy pain fellowship program provides staff for an outpatient e-consult pain management service and an inpatient pharmacy consult service. Harnessing pain specialty pharmacists, the pharmacy service addresses pharmacokinetic issues, urine drug screen (UDS) results, opioid tapering and discharge planning for pain, addiction and mental health needs. The NF/SGVHS Primary Care Pain Clinic was established to support PCPs who did not feel comfortable managing chronic pain patients. These patients were typically on high-dose opioid therapy (> 100-mg morphine equivalent daily doses [MEDDs]); patients with a history of opioid addiction; patients with an addiction to opioids combined with benzodiazepines; and patients with comorbid medical issues (eg, sleep apnea), which complicated their management. The process of addressing opioid safety in these complex pain patients can be labor intensive and generally cannot be accomplished in a brief visit in a primary care setting where many other medical problems often need to be addressed.

Most patients on high-dose opioids are fearful of any changes in their medications. The difficult conversation regarding opioid safety is a lengthy one and frequently will occur over multiple visits. In addition, safely tapering opioids requires frequent follow-up to provide psychological support and to address withdrawal and mental health issues that may arise. As opioids are tapered, the clinic reinforces improved pain care through a multimodal biopsychosocial model. All veterans receiving pain care outside the VA are monitored annually to assure they are receiving evidence-based pain care as defined by the biopsychosocial model.

Education

Since 2011, the NF/SGVHS SCAN-ECHO pain and addiction educational forum has created > 50 hours of approved annual continuing medical education (CME) on pain management and addiction for PCPs. Initially, the 1-hour weekly educational audioconferences presented a pain management case along with related topics and involved specialists from interventional pain, physical therapy, psychiatry, nursing, neurology, and psychology departments. In 2013, in conjunction with the VA SCAN-ECHO program of Hunter Holmes McGuire VAMC in Richmond, Virginia, and Walter Reed National Military Medical Center in Bethesda, Maryland, the audioconference was expanded to 2 days each week with additional topics on addiction management. Residency and fellowship rotations were developed that specifically targeted fellows from psychiatry, pharmacology, and interventional pain departments.

Currently, an 8-session pain school is delivered onsite and at 7 telehealth locations. The school is a collaborative effort involving interventional pain, psychology, pharmacy, nutrition, and the primary care pain clinic staff. As the cornerstone of the program, the pain school stresses the biopsychosocial patient engagement model.

Program Evaluation

The VA is equipped with multiple telehealth service networks that allow for the delivery of programs, such as the pain school, a pain psychology program, and a yoga program, onsite or offsite. The VA Computerized Patient Record System (CPRS) manages electronic health records, allowing for rapid chart review and e-consults. The NF/SGVHS Pain Management Program provides about 1500 e-consults yearly. The CPRS includes templates with pain metrics to help PCPs deliver pain care more efficiently and evaluate performance measures. This system also allows for the capture of data to track improvements in the care of the veterans served.

From 2012 to 2017, more than 5000 NF/SGVHS patients were weaned from opioids. Overall, there was an 87% reduction in patients receiving opioids ( ≥ 100-mg MEDDs) within the NF/SGVHS, which is significantly more than the 49% seen nationally across the VHA (Figure 2). Percent reduction was calculated by taking the difference in number of patients receiving opioids in 2012 and 2017, dividing by the number of patients receiving opioids in 2012 and multiplying by 100. The largest proportion of opioid dose reductions for NF/SGVHS and VHA patients, respectively, were seen in 300-mg to 399-mg MEDDs (95% vs 67%, respectively); followed by ≥ 400-mg MEDDs (94% vs 71%, respectively); 200-mg to 299-mg MEDDs (91% vs 58%, respectively); and 100-mg to 199-mg MEDDs (84% vs 40%, respectively). When examining NF/SGVHS trends over time, there has been a consistent decline in patients prescribed opioids (18 223 in 2012 compared with 12 877 in 2017) with similar trends in benzodiazepine-opioid combination therapy (2694 in 2012 compared with 833 in 2017) (Figure 3).

Similar declines are seen when patients are stratified by the MEDD (Figure 4). From 2012 to 2017, 92% of the patients were successfully tapered off doses ≥ 400-mg MEDD (2012, n = 72; 2017, n = 6), and tapered off 300-mg to 399-mg MEDD (2012, n = 107; 2017, n = 5); 95% were tapered off 200-mg to 299-mg MEDD (2012, n = 262; 2017, n = 22); and 86% were tapered off 100-mg to 199-mg MEDD (2012, n = 876; 2017; n = 127).

Conclusion

Successful integration of primary care with mental health and addiction services is paramount to aggressively taper patients with chronic pain from opioids. There is evidence that drug dependence and chronic pain should be treated like other chronic illness.²⁰ Both chronic pain and addiction can be treated with a multidimensional self-management approach. In view of the high incidence of mental health and addiction associated with opioid use, it makes sense that an integrated, 1-stop pain and addiction clinic that understands and addresses both issues is more likely to improve patient outcomes.

Acknowledgments

This material is the result of work supported by the resources and facilities at the North Florida/South Georgia Veterans Health System, Geriatric Research Education Clinical Center in Gainesville, Florida.

Chronic pain significantly affects 100 million Americans.^1,2 Pain accounts for $560 to $635 billion in annual financial costs to society, including health care costs and loss of productivity (ie, days missed from work, hours of work lost, and lower wages).^2,3 Although pain prevalence exceeds other chronic diseases, such as diabetes mellitus, cancer, and heart disease, it lacks a sufficient body of evidence-based research and guidelines on the underlying mechanisms, valid methods of assessment, and comparative effectiveness of treatments to effectively implement into clinical practice.^2,4 Prevention and treatment of pain are often delayed, inaccessible, or inadequate.² Primary care providers (PCPs) are most often sought for pain management and treat about 52% of chronic pain patients.^2,3,5 Veterans are especially vulnerable to chronic pain and are at risk for inadequate treatment.²

Background

There is an epidemic of drug abuse and mortality from opioid prescription medication.⁶ In the US, rates of overdose deaths from prescription opioids were 6.1 per 100,000 for men and 4.2 per 100,000 for women in 2017. Opioids were involved in 47,600 overdose deaths in 2017, accounting for 67.8% of all drug overdose deaths.⁷

A large number of patients on long-term opioids have preexisting substance use disorders and/or psychiatric disease, further complicating chronic pain management.^8-10 Prescription opioid use has been the precursor for about 80% of people who are now heroin addicts.¹¹ Iatrogenic addiction from prescription medications isn’t easily captured by standard addiction criteria. Consequently, in patients who are on opioid therapy for prolonged periods, separating complex opioid dependence from addiction is difficult.¹² Improved addiction screening and risk mitigation strategies are needed along with aggressive treatment monitoring to curb the opioid epidemic.

Opioid Management in Primary Care

The majority of opioid medications are prescribed by PCPs, which is magnified in the US Department of Veterans Affairs (VA) health care system due to the high prevalence of service-related injuries.^3,13 The VA is at the forefront of addressing the complexities of opioid addiction through several initiatives.¹⁴ The ability to offer the frequent visits needed to safely manage patients prescribed opioids and the integration of mental health and addiction treatment are often lacking in non-VA primary care clinics. Therefore, a key to solving the opioid crisis is developing these capabilities so they can be delivered within the primary care setting. There is substantial evidence in support of nonopioid alternatives to chronic pain management, including other pharmacologic approaches, exercise, physical therapy, acupuncture, weight loss, smoking cessation, chiropractic care, cognitive behavioral therapy (CBT), and other integrative health modalities.

A 2009 VA directive mandated the development of a comprehensive, integrated, systemwide approach to pain management.¹⁵ The VA Stepped-Care Biopsychosocial Model for Pain Management is dependent on timely access to secondary consultation from pain medicine, behavioral health, physical medicine, and other specialty consultation.¹⁵

History of VHA SCAN-ECHO Model

The Specialty Care Access Network–Extension for Community Health Outcomes (SCAN-ECHO) is a Veterans Health Administration (VHA) adaptation of a program that originated at the University of Mexico.^16,17 The SCAN-ECHO model uses a multisite videoconferencing network to provide specialty care consultations to PCPs and patient aligned care teams (PACTs). During the 60- to 90-minute weekly sessions, case presentations are analyzed in real time so that over time, the PCPs gain knowledge, competency, and confidence in learning how to handle complex chronic conditions.

Since its implementation, the SCAN-ECHO program has been adopted across the VHA in a variety of specialties. One program, the SCAN-ECHO for Pain Management (SCAN-ECHO-PM) was implemented in 7 VHA networks in 31 states, spanning 47 medical centers and 148 community-based outpatient clinics (CBOCs).¹⁸ The SCAN-ECHO-PM program successfully conducted 257 multidisciplinary pain consultations between 2011 and 2013, resulting in increased initiation of nonopioid medications.¹⁸

The aim of this article is to describe the implementation of a multicomponent primary care-based pain clinic with a fully integrated mental health service and addiction service at the North Florida/South Georgia Veterans Health System (NF/SGVHS). A practiced-based intervention of the biopsychosocial model with robust patient engagement has guided the development of the NF/SGVHS pain clinic (Figure 1).^4,19

Pain CLinic

NF/SGVHS comprises the Malcom Randall and Lake City VA medical centers (VAMCs) hospitals, 3 satellite outpatient clinics, and 8 CBOCs. Spanning 33 counties in North Florida and 19 counties in South Georgia, the NF/SGVHS serves more than 140,000 patients. In 2010, the Malcom Randall VAMC established a multidisciplinary primary care pain clinic to manage veterans at high-risk for noncancer chronic pain and addiction. The noncancer pain policy was revised after garnering support from stakeholders who treat chronic pain, including the chiefs of psychiatry, rehabilitation medicine, neurosurgery, psychology, interventional pain, pharmacy, nursing, addiction medicine, and primary care. The clinic is staffed by primary care physicians trained in internal medicine and family medicine and is structured with 1-hour first visits, and 30-minute follow-up visits to allow enough time for comprehensive evaluation while meeting the needs for close follow-up support.

All physicians in the clinic have buprenorphine prescribing credentials to aid in the management of opioid addiction, as some patients feel more comfortable receiving addiction treatment in a primary care setting. The multimodal care model consists of several services that include addiction psychiatrists, interventional pain specialists, pain psychologists, and pain pharmacologists who coordinate the care to the veterans. The addiction psychiatrists offer a full range of services with inpatient residential and outpatient programs. Through recurring meetings with primary care pain clinic staff, the addiction psychiatrists are available to discuss use of buprenorphine and arrange follow-up for patients with complex pain addiction. There is ongoing collaboration to develop the best care plan that meets the patient’s needs for chronic pain, addiction, and/or mental health issues. The interventional pain service has 3 fellowship-trained pain care providers who deliver comprehensive evaluation, pharmacologic recommendations, and a full range of interventional and complementary therapies with an emphasis on objective functional improvement. Pain care providers offer alternatives to patients who are being weaned from opioids and support the multidisciplinary patient engagement model.

The pain psychology program, established in 2011, delivers CBT to 5 onsite locations and 5 telehealth locations. The service includes an advanced CBT program and a couples CBT program. The pharmacy pain fellowship program provides staff for an outpatient e-consult pain management service and an inpatient pharmacy consult service. Harnessing pain specialty pharmacists, the pharmacy service addresses pharmacokinetic issues, urine drug screen (UDS) results, opioid tapering and discharge planning for pain, addiction and mental health needs. The NF/SGVHS Primary Care Pain Clinic was established to support PCPs who did not feel comfortable managing chronic pain patients. These patients were typically on high-dose opioid therapy (> 100-mg morphine equivalent daily doses [MEDDs]); patients with a history of opioid addiction; patients with an addiction to opioids combined with benzodiazepines; and patients with comorbid medical issues (eg, sleep apnea), which complicated their management. The process of addressing opioid safety in these complex pain patients can be labor intensive and generally cannot be accomplished in a brief visit in a primary care setting where many other medical problems often need to be addressed.

Most patients on high-dose opioids are fearful of any changes in their medications. The difficult conversation regarding opioid safety is a lengthy one and frequently will occur over multiple visits. In addition, safely tapering opioids requires frequent follow-up to provide psychological support and to address withdrawal and mental health issues that may arise. As opioids are tapered, the clinic reinforces improved pain care through a multimodal biopsychosocial model. All veterans receiving pain care outside the VA are monitored annually to assure they are receiving evidence-based pain care as defined by the biopsychosocial model.

Education

Since 2011, the NF/SGVHS SCAN-ECHO pain and addiction educational forum has created > 50 hours of approved annual continuing medical education (CME) on pain management and addiction for PCPs. Initially, the 1-hour weekly educational audioconferences presented a pain management case along with related topics and involved specialists from interventional pain, physical therapy, psychiatry, nursing, neurology, and psychology departments. In 2013, in conjunction with the VA SCAN-ECHO program of Hunter Holmes McGuire VAMC in Richmond, Virginia, and Walter Reed National Military Medical Center in Bethesda, Maryland, the audioconference was expanded to 2 days each week with additional topics on addiction management. Residency and fellowship rotations were developed that specifically targeted fellows from psychiatry, pharmacology, and interventional pain departments.

Currently, an 8-session pain school is delivered onsite and at 7 telehealth locations. The school is a collaborative effort involving interventional pain, psychology, pharmacy, nutrition, and the primary care pain clinic staff. As the cornerstone of the program, the pain school stresses the biopsychosocial patient engagement model.

Program Evaluation

The VA is equipped with multiple telehealth service networks that allow for the delivery of programs, such as the pain school, a pain psychology program, and a yoga program, onsite or offsite. The VA Computerized Patient Record System (CPRS) manages electronic health records, allowing for rapid chart review and e-consults. The NF/SGVHS Pain Management Program provides about 1500 e-consults yearly. The CPRS includes templates with pain metrics to help PCPs deliver pain care more efficiently and evaluate performance measures. This system also allows for the capture of data to track improvements in the care of the veterans served.

From 2012 to 2017, more than 5000 NF/SGVHS patients were weaned from opioids. Overall, there was an 87% reduction in patients receiving opioids ( ≥ 100-mg MEDDs) within the NF/SGVHS, which is significantly more than the 49% seen nationally across the VHA (Figure 2). Percent reduction was calculated by taking the difference in number of patients receiving opioids in 2012 and 2017, dividing by the number of patients receiving opioids in 2012 and multiplying by 100. The largest proportion of opioid dose reductions for NF/SGVHS and VHA patients, respectively, were seen in 300-mg to 399-mg MEDDs (95% vs 67%, respectively); followed by ≥ 400-mg MEDDs (94% vs 71%, respectively); 200-mg to 299-mg MEDDs (91% vs 58%, respectively); and 100-mg to 199-mg MEDDs (84% vs 40%, respectively). When examining NF/SGVHS trends over time, there has been a consistent decline in patients prescribed opioids (18 223 in 2012 compared with 12 877 in 2017) with similar trends in benzodiazepine-opioid combination therapy (2694 in 2012 compared with 833 in 2017) (Figure 3).

Similar declines are seen when patients are stratified by the MEDD (Figure 4). From 2012 to 2017, 92% of the patients were successfully tapered off doses ≥ 400-mg MEDD (2012, n = 72; 2017, n = 6), and tapered off 300-mg to 399-mg MEDD (2012, n = 107; 2017, n = 5); 95% were tapered off 200-mg to 299-mg MEDD (2012, n = 262; 2017, n = 22); and 86% were tapered off 100-mg to 199-mg MEDD (2012, n = 876; 2017; n = 127).

Conclusion

Successful integration of primary care with mental health and addiction services is paramount to aggressively taper patients with chronic pain from opioids. There is evidence that drug dependence and chronic pain should be treated like other chronic illness.²⁰ Both chronic pain and addiction can be treated with a multidimensional self-management approach. In view of the high incidence of mental health and addiction associated with opioid use, it makes sense that an integrated, 1-stop pain and addiction clinic that understands and addresses both issues is more likely to improve patient outcomes.

Acknowledgments

This material is the result of work supported by the resources and facilities at the North Florida/South Georgia Veterans Health System, Geriatric Research Education Clinical Center in Gainesville, Florida.

Chronic pain significantly affects 100 million Americans.^1,2 Pain accounts for $560 to $635 billion in annual financial costs to society, including health care costs and loss of productivity (ie, days missed from work, hours of work lost, and lower wages).^2,3 Although pain prevalence exceeds other chronic diseases, such as diabetes mellitus, cancer, and heart disease, it lacks a sufficient body of evidence-based research and guidelines on the underlying mechanisms, valid methods of assessment, and comparative effectiveness of treatments to effectively implement into clinical practice.^2,4 Prevention and treatment of pain are often delayed, inaccessible, or inadequate.² Primary care providers (PCPs) are most often sought for pain management and treat about 52% of chronic pain patients.^2,3,5 Veterans are especially vulnerable to chronic pain and are at risk for inadequate treatment.²

Background

There is an epidemic of drug abuse and mortality from opioid prescription medication.⁶ In the US, rates of overdose deaths from prescription opioids were 6.1 per 100,000 for men and 4.2 per 100,000 for women in 2017. Opioids were involved in 47,600 overdose deaths in 2017, accounting for 67.8% of all drug overdose deaths.⁷

A large number of patients on long-term opioids have preexisting substance use disorders and/or psychiatric disease, further complicating chronic pain management.^8-10 Prescription opioid use has been the precursor for about 80% of people who are now heroin addicts.¹¹ Iatrogenic addiction from prescription medications isn’t easily captured by standard addiction criteria. Consequently, in patients who are on opioid therapy for prolonged periods, separating complex opioid dependence from addiction is difficult.¹² Improved addiction screening and risk mitigation strategies are needed along with aggressive treatment monitoring to curb the opioid epidemic.

Opioid Management in Primary Care

The majority of opioid medications are prescribed by PCPs, which is magnified in the US Department of Veterans Affairs (VA) health care system due to the high prevalence of service-related injuries.^3,13 The VA is at the forefront of addressing the complexities of opioid addiction through several initiatives.¹⁴ The ability to offer the frequent visits needed to safely manage patients prescribed opioids and the integration of mental health and addiction treatment are often lacking in non-VA primary care clinics. Therefore, a key to solving the opioid crisis is developing these capabilities so they can be delivered within the primary care setting. There is substantial evidence in support of nonopioid alternatives to chronic pain management, including other pharmacologic approaches, exercise, physical therapy, acupuncture, weight loss, smoking cessation, chiropractic care, cognitive behavioral therapy (CBT), and other integrative health modalities.

A 2009 VA directive mandated the development of a comprehensive, integrated, systemwide approach to pain management.¹⁵ The VA Stepped-Care Biopsychosocial Model for Pain Management is dependent on timely access to secondary consultation from pain medicine, behavioral health, physical medicine, and other specialty consultation.¹⁵

History of VHA SCAN-ECHO Model

The Specialty Care Access Network–Extension for Community Health Outcomes (SCAN-ECHO) is a Veterans Health Administration (VHA) adaptation of a program that originated at the University of Mexico.^16,17 The SCAN-ECHO model uses a multisite videoconferencing network to provide specialty care consultations to PCPs and patient aligned care teams (PACTs). During the 60- to 90-minute weekly sessions, case presentations are analyzed in real time so that over time, the PCPs gain knowledge, competency, and confidence in learning how to handle complex chronic conditions.

Since its implementation, the SCAN-ECHO program has been adopted across the VHA in a variety of specialties. One program, the SCAN-ECHO for Pain Management (SCAN-ECHO-PM) was implemented in 7 VHA networks in 31 states, spanning 47 medical centers and 148 community-based outpatient clinics (CBOCs).¹⁸ The SCAN-ECHO-PM program successfully conducted 257 multidisciplinary pain consultations between 2011 and 2013, resulting in increased initiation of nonopioid medications.¹⁸

The aim of this article is to describe the implementation of a multicomponent primary care-based pain clinic with a fully integrated mental health service and addiction service at the North Florida/South Georgia Veterans Health System (NF/SGVHS). A practiced-based intervention of the biopsychosocial model with robust patient engagement has guided the development of the NF/SGVHS pain clinic (Figure 1).^4,19

Pain CLinic

NF/SGVHS comprises the Malcom Randall and Lake City VA medical centers (VAMCs) hospitals, 3 satellite outpatient clinics, and 8 CBOCs. Spanning 33 counties in North Florida and 19 counties in South Georgia, the NF/SGVHS serves more than 140,000 patients. In 2010, the Malcom Randall VAMC established a multidisciplinary primary care pain clinic to manage veterans at high-risk for noncancer chronic pain and addiction. The noncancer pain policy was revised after garnering support from stakeholders who treat chronic pain, including the chiefs of psychiatry, rehabilitation medicine, neurosurgery, psychology, interventional pain, pharmacy, nursing, addiction medicine, and primary care. The clinic is staffed by primary care physicians trained in internal medicine and family medicine and is structured with 1-hour first visits, and 30-minute follow-up visits to allow enough time for comprehensive evaluation while meeting the needs for close follow-up support.

All physicians in the clinic have buprenorphine prescribing credentials to aid in the management of opioid addiction, as some patients feel more comfortable receiving addiction treatment in a primary care setting. The multimodal care model consists of several services that include addiction psychiatrists, interventional pain specialists, pain psychologists, and pain pharmacologists who coordinate the care to the veterans. The addiction psychiatrists offer a full range of services with inpatient residential and outpatient programs. Through recurring meetings with primary care pain clinic staff, the addiction psychiatrists are available to discuss use of buprenorphine and arrange follow-up for patients with complex pain addiction. There is ongoing collaboration to develop the best care plan that meets the patient’s needs for chronic pain, addiction, and/or mental health issues. The interventional pain service has 3 fellowship-trained pain care providers who deliver comprehensive evaluation, pharmacologic recommendations, and a full range of interventional and complementary therapies with an emphasis on objective functional improvement. Pain care providers offer alternatives to patients who are being weaned from opioids and support the multidisciplinary patient engagement model.

The pain psychology program, established in 2011, delivers CBT to 5 onsite locations and 5 telehealth locations. The service includes an advanced CBT program and a couples CBT program. The pharmacy pain fellowship program provides staff for an outpatient e-consult pain management service and an inpatient pharmacy consult service. Harnessing pain specialty pharmacists, the pharmacy service addresses pharmacokinetic issues, urine drug screen (UDS) results, opioid tapering and discharge planning for pain, addiction and mental health needs. The NF/SGVHS Primary Care Pain Clinic was established to support PCPs who did not feel comfortable managing chronic pain patients. These patients were typically on high-dose opioid therapy (> 100-mg morphine equivalent daily doses [MEDDs]); patients with a history of opioid addiction; patients with an addiction to opioids combined with benzodiazepines; and patients with comorbid medical issues (eg, sleep apnea), which complicated their management. The process of addressing opioid safety in these complex pain patients can be labor intensive and generally cannot be accomplished in a brief visit in a primary care setting where many other medical problems often need to be addressed.

Most patients on high-dose opioids are fearful of any changes in their medications. The difficult conversation regarding opioid safety is a lengthy one and frequently will occur over multiple visits. In addition, safely tapering opioids requires frequent follow-up to provide psychological support and to address withdrawal and mental health issues that may arise. As opioids are tapered, the clinic reinforces improved pain care through a multimodal biopsychosocial model. All veterans receiving pain care outside the VA are monitored annually to assure they are receiving evidence-based pain care as defined by the biopsychosocial model.

Education

Since 2011, the NF/SGVHS SCAN-ECHO pain and addiction educational forum has created > 50 hours of approved annual continuing medical education (CME) on pain management and addiction for PCPs. Initially, the 1-hour weekly educational audioconferences presented a pain management case along with related topics and involved specialists from interventional pain, physical therapy, psychiatry, nursing, neurology, and psychology departments. In 2013, in conjunction with the VA SCAN-ECHO program of Hunter Holmes McGuire VAMC in Richmond, Virginia, and Walter Reed National Military Medical Center in Bethesda, Maryland, the audioconference was expanded to 2 days each week with additional topics on addiction management. Residency and fellowship rotations were developed that specifically targeted fellows from psychiatry, pharmacology, and interventional pain departments.

Currently, an 8-session pain school is delivered onsite and at 7 telehealth locations. The school is a collaborative effort involving interventional pain, psychology, pharmacy, nutrition, and the primary care pain clinic staff. As the cornerstone of the program, the pain school stresses the biopsychosocial patient engagement model.

Program Evaluation

The VA is equipped with multiple telehealth service networks that allow for the delivery of programs, such as the pain school, a pain psychology program, and a yoga program, onsite or offsite. The VA Computerized Patient Record System (CPRS) manages electronic health records, allowing for rapid chart review and e-consults. The NF/SGVHS Pain Management Program provides about 1500 e-consults yearly. The CPRS includes templates with pain metrics to help PCPs deliver pain care more efficiently and evaluate performance measures. This system also allows for the capture of data to track improvements in the care of the veterans served.

From 2012 to 2017, more than 5000 NF/SGVHS patients were weaned from opioids. Overall, there was an 87% reduction in patients receiving opioids ( ≥ 100-mg MEDDs) within the NF/SGVHS, which is significantly more than the 49% seen nationally across the VHA (Figure 2). Percent reduction was calculated by taking the difference in number of patients receiving opioids in 2012 and 2017, dividing by the number of patients receiving opioids in 2012 and multiplying by 100. The largest proportion of opioid dose reductions for NF/SGVHS and VHA patients, respectively, were seen in 300-mg to 399-mg MEDDs (95% vs 67%, respectively); followed by ≥ 400-mg MEDDs (94% vs 71%, respectively); 200-mg to 299-mg MEDDs (91% vs 58%, respectively); and 100-mg to 199-mg MEDDs (84% vs 40%, respectively). When examining NF/SGVHS trends over time, there has been a consistent decline in patients prescribed opioids (18 223 in 2012 compared with 12 877 in 2017) with similar trends in benzodiazepine-opioid combination therapy (2694 in 2012 compared with 833 in 2017) (Figure 3).

Similar declines are seen when patients are stratified by the MEDD (Figure 4). From 2012 to 2017, 92% of the patients were successfully tapered off doses ≥ 400-mg MEDD (2012, n = 72; 2017, n = 6), and tapered off 300-mg to 399-mg MEDD (2012, n = 107; 2017, n = 5); 95% were tapered off 200-mg to 299-mg MEDD (2012, n = 262; 2017, n = 22); and 86% were tapered off 100-mg to 199-mg MEDD (2012, n = 876; 2017; n = 127).

Conclusion

Successful integration of primary care with mental health and addiction services is paramount to aggressively taper patients with chronic pain from opioids. There is evidence that drug dependence and chronic pain should be treated like other chronic illness.²⁰ Both chronic pain and addiction can be treated with a multidimensional self-management approach. In view of the high incidence of mental health and addiction associated with opioid use, it makes sense that an integrated, 1-stop pain and addiction clinic that understands and addresses both issues is more likely to improve patient outcomes.

Acknowledgments

This material is the result of work supported by the resources and facilities at the North Florida/South Georgia Veterans Health System, Geriatric Research Education Clinical Center in Gainesville, Florida.

A number of medications commonly prescribed by rheumatologists may interact with cannabidiol oil, investigators at the Imperial College Healthcare NHS Trust, London, reported.

“Patients are increasingly requesting information concerning the safety of CBD oil,” Taryn Youngstein, MD, and associates said in letter to the editor in Rheumatology, but current guidelines on the use of medical cannabis do “not address the potential interactions between CBD oil and medicines frequently used in the rheumatology clinic.”

The most important potential CBD interaction, they suggested, may be with corticosteroids. Hydrocortisone and prednisolone both inhibit the cytochrome P450 enzyme CYP3A, but CBD is a potent inhibitor of CYP3A, so “concomitant use may decrease glucocorticoid clearance and increase risk of systemic [corticosteroid] side effects,” the investigators wrote.

CBD also is known to inhibit the cytochrome P450 isozymes CYP2C9, CYP2D6, CYP2C19, CYP3A4, and CYP1A2, which, alone or in combination, are involved in the metabolization of naproxen, tramadol, amitriptyline, and tofacitinib (Xeljanz), according to a literature search done via the college’s medicine information department that also used the British National Formulary and the Natural Medicines online interaction checker.

The Janus kinase inhibitor tofacitinib is included among the possible interactions, but the other Food and Drug Administration–approved JAK inhibitor, baricitinib (Olumiant), is primarily metabolized by the kidneys and should not have significant interaction with CBD, Dr. Youngstein and associates said. Most of the conventional synthetic and biologic disease-modifying antirheumatic drugs, including methotrexate, hydroxychloroquine, adalimumab (Humira), and abatacept (Orencia), also are expected to be relatively free from CBD interactions.

This first published report on interactions between CBD oil and common rheumatology medications “highlights the importance of taking comprehensive drug histories, by asking directly about drugs considered alternative medicines and food supplements,” they said.

The investigators declared no conflicts of interest, and there was no specific funding for the study.

[email protected]

SOURCE: Wilson-Morkeh H et al. Rheumatology. 2019 July 29. doi: 10.1093/rheumatology/kez304.

A number of medications commonly prescribed by rheumatologists may interact with cannabidiol oil, investigators at the Imperial College Healthcare NHS Trust, London, reported.

“Patients are increasingly requesting information concerning the safety of CBD oil,” Taryn Youngstein, MD, and associates said in letter to the editor in Rheumatology, but current guidelines on the use of medical cannabis do “not address the potential interactions between CBD oil and medicines frequently used in the rheumatology clinic.”

The most important potential CBD interaction, they suggested, may be with corticosteroids. Hydrocortisone and prednisolone both inhibit the cytochrome P450 enzyme CYP3A, but CBD is a potent inhibitor of CYP3A, so “concomitant use may decrease glucocorticoid clearance and increase risk of systemic [corticosteroid] side effects,” the investigators wrote.

CBD also is known to inhibit the cytochrome P450 isozymes CYP2C9, CYP2D6, CYP2C19, CYP3A4, and CYP1A2, which, alone or in combination, are involved in the metabolization of naproxen, tramadol, amitriptyline, and tofacitinib (Xeljanz), according to a literature search done via the college’s medicine information department that also used the British National Formulary and the Natural Medicines online interaction checker.

The Janus kinase inhibitor tofacitinib is included among the possible interactions, but the other Food and Drug Administration–approved JAK inhibitor, baricitinib (Olumiant), is primarily metabolized by the kidneys and should not have significant interaction with CBD, Dr. Youngstein and associates said. Most of the conventional synthetic and biologic disease-modifying antirheumatic drugs, including methotrexate, hydroxychloroquine, adalimumab (Humira), and abatacept (Orencia), also are expected to be relatively free from CBD interactions.

This first published report on interactions between CBD oil and common rheumatology medications “highlights the importance of taking comprehensive drug histories, by asking directly about drugs considered alternative medicines and food supplements,” they said.

The investigators declared no conflicts of interest, and there was no specific funding for the study.

[email protected]

SOURCE: Wilson-Morkeh H et al. Rheumatology. 2019 July 29. doi: 10.1093/rheumatology/kez304.

A number of medications commonly prescribed by rheumatologists may interact with cannabidiol oil, investigators at the Imperial College Healthcare NHS Trust, London, reported.

“Patients are increasingly requesting information concerning the safety of CBD oil,” Taryn Youngstein, MD, and associates said in letter to the editor in Rheumatology, but current guidelines on the use of medical cannabis do “not address the potential interactions between CBD oil and medicines frequently used in the rheumatology clinic.”

The most important potential CBD interaction, they suggested, may be with corticosteroids. Hydrocortisone and prednisolone both inhibit the cytochrome P450 enzyme CYP3A, but CBD is a potent inhibitor of CYP3A, so “concomitant use may decrease glucocorticoid clearance and increase risk of systemic [corticosteroid] side effects,” the investigators wrote.

CBD also is known to inhibit the cytochrome P450 isozymes CYP2C9, CYP2D6, CYP2C19, CYP3A4, and CYP1A2, which, alone or in combination, are involved in the metabolization of naproxen, tramadol, amitriptyline, and tofacitinib (Xeljanz), according to a literature search done via the college’s medicine information department that also used the British National Formulary and the Natural Medicines online interaction checker.

The Janus kinase inhibitor tofacitinib is included among the possible interactions, but the other Food and Drug Administration–approved JAK inhibitor, baricitinib (Olumiant), is primarily metabolized by the kidneys and should not have significant interaction with CBD, Dr. Youngstein and associates said. Most of the conventional synthetic and biologic disease-modifying antirheumatic drugs, including methotrexate, hydroxychloroquine, adalimumab (Humira), and abatacept (Orencia), also are expected to be relatively free from CBD interactions.

This first published report on interactions between CBD oil and common rheumatology medications “highlights the importance of taking comprehensive drug histories, by asking directly about drugs considered alternative medicines and food supplements,” they said.

The investigators declared no conflicts of interest, and there was no specific funding for the study.

[email protected]

SOURCE: Wilson-Morkeh H et al. Rheumatology. 2019 July 29. doi: 10.1093/rheumatology/kez304.