THE CASE

A 24-year-old woman came to our clinic because she had pain in her right foot. Over the previous 4 weeks, she’d noticed increasing pain in the ball of her foot while walking and climbing stairs, particularly in the push-off portion of her gait. She described it as a nagging, localized pain that she rated as a 2 or 3 out of 10. It was an annoyance, but not unbearable. She felt no pain when standing in place or in a non-weight-bearing position.

She denied any trauma to the foot or change in activity, and had been exercising her usual amount (running 2-5 miles per week). Her medical and social histories were unremarkable, and her family history was negative for relevant conditions.

An examination of the right foot revealed no evidence of pes planus, pes cavus, hallux valgus, hammertoes, or other structural abnormalities of the foot or toes. She had no calluses, nor any erythema or edema of the foot or toes. Direct palpation of the medial sesamoid reproduced the patient’s symptoms. Passive dorsiflexion and plantar flexion of the first hallux elicited pain only at the extreme ends of range of motion. Active dorsiflexion and plantar flexion of the right first hallux showed 5 out of 5 strength. A mid-foot squeeze test was negative, and the remainder of the exam was normal.

THE DIAGNOSIS

Pain on palpation of the sesamoids prompted us to gather a more detailed history. The patient had never been a dancer or a long-distance or competitive runner. However, upon delving into possible causes of the pain, she admitted that she was a frequent “knuckle cracker,” and cracked many joints regularly, including the right first metatarsophalangeal joint (MTPJ). She explained that she cracked this joint by hyper-plantarflexing her big toe against the ground, and had been doing this multiple times a day for many years. In the past 4 weeks, she had noticed significant pain in the right first MTPJ while cracking the joint, but she was having difficulty breaking the longstanding habit.

The patient’s description of right foot pain associated with the push-off portion of her gait, and the fact that the pain was exacerbated by the extremes of dorsiflexion and plantar flexion of the great toe, was consistent with MTPJ pain. This, paired with our ability to reproduce the pain by direct palpation of the medial sesamoid, prompted us to make a clinical diagnosis of sesamoiditis. To our knowledge, this is the first case report of sesamoiditis caused by knuckle cracking.

DISCUSSION

Sesamoiditis—chronic pain and inflammation of the hallucal sesamoids—is an overuse or misuse injury that’s typically seen in runners and dancers.¹ The hallucal sesamoids are 2 small bones located underneath the head of the first metatarsal and encased within the flexor hallucus brevis tendon that disperses weight from the head of the first metatarsal during the push-off portion of gait.² Runners and dancers place significant, repetitive axial loading on the sesamoids, which often leads to injury.¹ Although our patient initially seemed to have no typical risk factors for developing sesamoiditis, she later revealed that she regularly cracked the MTPJ, which we believe led to her injury.

Interestingly, despite the common assumption that long-term “cracking” of joints can lead to adverse effects such as osteoarthritis, research has not supported this assumption.^3,4 A retrospective case-control study of patients with and without hand osteoarthritis found no association between knuckle cracking and osteoarthritis, and the prevalence of osteoarthritis was not higher in patients who cracked their knuckles more frequently and for more years.⁴

To our knowledge, this is the first case report of sesamoiditis caused by knuckle cracking.

Nonetheless, there have been reports of acute injuries associated with knuckle cracking, consistent with forcing a joint past its normal range of motion, as is typically done in knuckle cracking.⁵ In forcefully plantarflexing her great toe against a surface until a “crack” was elicited, our patient may have injured the sesamoid by forcing it along the head of the first metatarsal. Conversely, her injury may have been caused by the repetitive displacement of the sesamoid past its usual location, resulting in chronic irritation.

Differential diagnosis includes fracture and stress injury

The differential diagnosis for subacute to chronic pain localized to the sesamoids includes repetitive stress injury (sesamoiditis or capsular strain), fracture or stress fracture, osteoarthritis, osteonecrosis, and gout.^1,2 Given our patient’s age and lack of erythema and edema, osteoarthritis and gout were unlikely.

To treat the injury, eliminate the behavior that caused it

Imaging studies may not be necessary in cases of suspected sesamoiditis because such studies are often negative for sesamoiditis and stress fractures of the sesamoids, and because they typically would not affect how the injury is initially treated.^1,2,6 In cases in which radiographic confirmation of sesamoiditis is necessary to rule out more serious pathology, 99mTc-methylene diphosphonate (99mTc-MDP) bone scan and magnetic resonance imaging (MRI) are far more sensitive than plain films.¹ While a 99mTc-MDP bone scan will show increased uptake at the sesamoids, it has been replaced by MRI, which will show bone marrow edema of the sesamoids and can rule out fracture or osteoarthritis.¹

Sesamoiditis is typically managed with a combination of ice, analgesics, activity modification, and/or orthoses.² Of course, the key to successfully treating sesamoiditis (and all musculoskeletal injuries) is to not only make the diagnosis, but to find the underlying cause in order to prevent continued—or worsening—pain.

Our patient agreed to close follow-up rather than imaging. We established that the only inciting event was the cracking of her MTPJ, and that she should try to eliminate this action before trying other interventions. Our patient stopped cracking her MTPJ and her pain completely resolved in 2 weeks. She remains symptom-free.

THE TAKEAWAY

Ask about knuckle cracking when taking the history of a patient who presents with sesamoiditis, which is characterized by chronic pain and inflammation of the hallucal sesamoids.

THE CASE

A 24-year-old woman came to our clinic because she had pain in her right foot. Over the previous 4 weeks, she’d noticed increasing pain in the ball of her foot while walking and climbing stairs, particularly in the push-off portion of her gait. She described it as a nagging, localized pain that she rated as a 2 or 3 out of 10. It was an annoyance, but not unbearable. She felt no pain when standing in place or in a non-weight-bearing position.

She denied any trauma to the foot or change in activity, and had been exercising her usual amount (running 2-5 miles per week). Her medical and social histories were unremarkable, and her family history was negative for relevant conditions.

An examination of the right foot revealed no evidence of pes planus, pes cavus, hallux valgus, hammertoes, or other structural abnormalities of the foot or toes. She had no calluses, nor any erythema or edema of the foot or toes. Direct palpation of the medial sesamoid reproduced the patient’s symptoms. Passive dorsiflexion and plantar flexion of the first hallux elicited pain only at the extreme ends of range of motion. Active dorsiflexion and plantar flexion of the right first hallux showed 5 out of 5 strength. A mid-foot squeeze test was negative, and the remainder of the exam was normal.

THE DIAGNOSIS

Pain on palpation of the sesamoids prompted us to gather a more detailed history. The patient had never been a dancer or a long-distance or competitive runner. However, upon delving into possible causes of the pain, she admitted that she was a frequent “knuckle cracker,” and cracked many joints regularly, including the right first metatarsophalangeal joint (MTPJ). She explained that she cracked this joint by hyper-plantarflexing her big toe against the ground, and had been doing this multiple times a day for many years. In the past 4 weeks, she had noticed significant pain in the right first MTPJ while cracking the joint, but she was having difficulty breaking the longstanding habit.

The patient’s description of right foot pain associated with the push-off portion of her gait, and the fact that the pain was exacerbated by the extremes of dorsiflexion and plantar flexion of the great toe, was consistent with MTPJ pain. This, paired with our ability to reproduce the pain by direct palpation of the medial sesamoid, prompted us to make a clinical diagnosis of sesamoiditis. To our knowledge, this is the first case report of sesamoiditis caused by knuckle cracking.

DISCUSSION

Sesamoiditis—chronic pain and inflammation of the hallucal sesamoids—is an overuse or misuse injury that’s typically seen in runners and dancers.¹ The hallucal sesamoids are 2 small bones located underneath the head of the first metatarsal and encased within the flexor hallucus brevis tendon that disperses weight from the head of the first metatarsal during the push-off portion of gait.² Runners and dancers place significant, repetitive axial loading on the sesamoids, which often leads to injury.¹ Although our patient initially seemed to have no typical risk factors for developing sesamoiditis, she later revealed that she regularly cracked the MTPJ, which we believe led to her injury.

Interestingly, despite the common assumption that long-term “cracking” of joints can lead to adverse effects such as osteoarthritis, research has not supported this assumption.^3,4 A retrospective case-control study of patients with and without hand osteoarthritis found no association between knuckle cracking and osteoarthritis, and the prevalence of osteoarthritis was not higher in patients who cracked their knuckles more frequently and for more years.⁴

To our knowledge, this is the first case report of sesamoiditis caused by knuckle cracking.

Nonetheless, there have been reports of acute injuries associated with knuckle cracking, consistent with forcing a joint past its normal range of motion, as is typically done in knuckle cracking.⁵ In forcefully plantarflexing her great toe against a surface until a “crack” was elicited, our patient may have injured the sesamoid by forcing it along the head of the first metatarsal. Conversely, her injury may have been caused by the repetitive displacement of the sesamoid past its usual location, resulting in chronic irritation.

Differential diagnosis includes fracture and stress injury

The differential diagnosis for subacute to chronic pain localized to the sesamoids includes repetitive stress injury (sesamoiditis or capsular strain), fracture or stress fracture, osteoarthritis, osteonecrosis, and gout.^1,2 Given our patient’s age and lack of erythema and edema, osteoarthritis and gout were unlikely.

To treat the injury, eliminate the behavior that caused it

Imaging studies may not be necessary in cases of suspected sesamoiditis because such studies are often negative for sesamoiditis and stress fractures of the sesamoids, and because they typically would not affect how the injury is initially treated.^1,2,6 In cases in which radiographic confirmation of sesamoiditis is necessary to rule out more serious pathology, 99mTc-methylene diphosphonate (99mTc-MDP) bone scan and magnetic resonance imaging (MRI) are far more sensitive than plain films.¹ While a 99mTc-MDP bone scan will show increased uptake at the sesamoids, it has been replaced by MRI, which will show bone marrow edema of the sesamoids and can rule out fracture or osteoarthritis.¹

Sesamoiditis is typically managed with a combination of ice, analgesics, activity modification, and/or orthoses.² Of course, the key to successfully treating sesamoiditis (and all musculoskeletal injuries) is to not only make the diagnosis, but to find the underlying cause in order to prevent continued—or worsening—pain.

Our patient agreed to close follow-up rather than imaging. We established that the only inciting event was the cracking of her MTPJ, and that she should try to eliminate this action before trying other interventions. Our patient stopped cracking her MTPJ and her pain completely resolved in 2 weeks. She remains symptom-free.

THE TAKEAWAY

Ask about knuckle cracking when taking the history of a patient who presents with sesamoiditis, which is characterized by chronic pain and inflammation of the hallucal sesamoids.

THE CASE

A 24-year-old woman came to our clinic because she had pain in her right foot. Over the previous 4 weeks, she’d noticed increasing pain in the ball of her foot while walking and climbing stairs, particularly in the push-off portion of her gait. She described it as a nagging, localized pain that she rated as a 2 or 3 out of 10. It was an annoyance, but not unbearable. She felt no pain when standing in place or in a non-weight-bearing position.

She denied any trauma to the foot or change in activity, and had been exercising her usual amount (running 2-5 miles per week). Her medical and social histories were unremarkable, and her family history was negative for relevant conditions.

An examination of the right foot revealed no evidence of pes planus, pes cavus, hallux valgus, hammertoes, or other structural abnormalities of the foot or toes. She had no calluses, nor any erythema or edema of the foot or toes. Direct palpation of the medial sesamoid reproduced the patient’s symptoms. Passive dorsiflexion and plantar flexion of the first hallux elicited pain only at the extreme ends of range of motion. Active dorsiflexion and plantar flexion of the right first hallux showed 5 out of 5 strength. A mid-foot squeeze test was negative, and the remainder of the exam was normal.

THE DIAGNOSIS

Pain on palpation of the sesamoids prompted us to gather a more detailed history. The patient had never been a dancer or a long-distance or competitive runner. However, upon delving into possible causes of the pain, she admitted that she was a frequent “knuckle cracker,” and cracked many joints regularly, including the right first metatarsophalangeal joint (MTPJ). She explained that she cracked this joint by hyper-plantarflexing her big toe against the ground, and had been doing this multiple times a day for many years. In the past 4 weeks, she had noticed significant pain in the right first MTPJ while cracking the joint, but she was having difficulty breaking the longstanding habit.

The patient’s description of right foot pain associated with the push-off portion of her gait, and the fact that the pain was exacerbated by the extremes of dorsiflexion and plantar flexion of the great toe, was consistent with MTPJ pain. This, paired with our ability to reproduce the pain by direct palpation of the medial sesamoid, prompted us to make a clinical diagnosis of sesamoiditis. To our knowledge, this is the first case report of sesamoiditis caused by knuckle cracking.

DISCUSSION

Sesamoiditis—chronic pain and inflammation of the hallucal sesamoids—is an overuse or misuse injury that’s typically seen in runners and dancers.¹ The hallucal sesamoids are 2 small bones located underneath the head of the first metatarsal and encased within the flexor hallucus brevis tendon that disperses weight from the head of the first metatarsal during the push-off portion of gait.² Runners and dancers place significant, repetitive axial loading on the sesamoids, which often leads to injury.¹ Although our patient initially seemed to have no typical risk factors for developing sesamoiditis, she later revealed that she regularly cracked the MTPJ, which we believe led to her injury.

Interestingly, despite the common assumption that long-term “cracking” of joints can lead to adverse effects such as osteoarthritis, research has not supported this assumption.^3,4 A retrospective case-control study of patients with and without hand osteoarthritis found no association between knuckle cracking and osteoarthritis, and the prevalence of osteoarthritis was not higher in patients who cracked their knuckles more frequently and for more years.⁴

To our knowledge, this is the first case report of sesamoiditis caused by knuckle cracking.

Nonetheless, there have been reports of acute injuries associated with knuckle cracking, consistent with forcing a joint past its normal range of motion, as is typically done in knuckle cracking.⁵ In forcefully plantarflexing her great toe against a surface until a “crack” was elicited, our patient may have injured the sesamoid by forcing it along the head of the first metatarsal. Conversely, her injury may have been caused by the repetitive displacement of the sesamoid past its usual location, resulting in chronic irritation.

Differential diagnosis includes fracture and stress injury

The differential diagnosis for subacute to chronic pain localized to the sesamoids includes repetitive stress injury (sesamoiditis or capsular strain), fracture or stress fracture, osteoarthritis, osteonecrosis, and gout.^1,2 Given our patient’s age and lack of erythema and edema, osteoarthritis and gout were unlikely.

To treat the injury, eliminate the behavior that caused it

Imaging studies may not be necessary in cases of suspected sesamoiditis because such studies are often negative for sesamoiditis and stress fractures of the sesamoids, and because they typically would not affect how the injury is initially treated.^1,2,6 In cases in which radiographic confirmation of sesamoiditis is necessary to rule out more serious pathology, 99mTc-methylene diphosphonate (99mTc-MDP) bone scan and magnetic resonance imaging (MRI) are far more sensitive than plain films.¹ While a 99mTc-MDP bone scan will show increased uptake at the sesamoids, it has been replaced by MRI, which will show bone marrow edema of the sesamoids and can rule out fracture or osteoarthritis.¹

Sesamoiditis is typically managed with a combination of ice, analgesics, activity modification, and/or orthoses.² Of course, the key to successfully treating sesamoiditis (and all musculoskeletal injuries) is to not only make the diagnosis, but to find the underlying cause in order to prevent continued—or worsening—pain.

Our patient agreed to close follow-up rather than imaging. We established that the only inciting event was the cracking of her MTPJ, and that she should try to eliminate this action before trying other interventions. Our patient stopped cracking her MTPJ and her pain completely resolved in 2 weeks. She remains symptom-free.

THE TAKEAWAY

Ask about knuckle cracking when taking the history of a patient who presents with sesamoiditis, which is characterized by chronic pain and inflammation of the hallucal sesamoids.

Anticonvulsants, antidepressants, and opioids are the most frequently prescribed medications for neuropathic pain.¹ But some patients are unable to tolerate the adverse effects of these drugs, and others achieve only partial pain relief. What can you offer them?

Combinations of prescription medications are generally considered more effective than monotherapy for painful peripheral neuropathy,¹ but it is unclear which combinations are best. Alternative therapies—several of which have some evidence of safety and efficacy in treating peripheral neuropathy—are another option. Yet trials with alternative therapies, alone or in combination with prescription drugs, are rarely considered.

In fact, physicians are often unfamiliar with these therapies. Many are concerned about the absence of US Food and Drug Administration approval for alternative therapies and the variability in quality control associated with the lack of oversight, as well. Making recommendations about the duration of therapy also presents a challenge because most studies of supplements are relatively short. What’s more, alternative treatments are rarely covered by third-party payers.

Nonetheless, the therapies detailed in the text and TABLE^2-12 that follow are generally well tolerated and appear to be safe. Adding them to your arsenal of therapeutic choices for patients with painful peripheral neuropathy may increase your ability to provide successful treatment.

Acetyl-L-carnitine (ALC)

ALC occurs naturally in the body as L-carnitine and acetyl-carnitine esters, which are converted to carnitines by intracellular enzymes and cell membrane transporters.² ALC has been studied in patients with neuropathy associated with human immunodeficiency virus (HIV), cancer, and diabetes. Potential mechanisms of action include the correction of a deficiency that may be causing the neuropathy (which sometimes occurs in HIV-positive patients¹³ or those taking anticonvulsants¹⁴), a direct antioxidant effect, or an enhanced response to nerve growth factor.¹³

Adding these generally well-tolerated therapies to your arsenal of therapeutic choices for patients may increase your ability to provide successful treatment.

ALC can be given intramuscularly (IM) or orally in doses of 2000 to 3000 mg/d. In one randomized placebo-controlled trial (N=333), patients with diabetic neuropathy received 1000 mg IM followed by an oral dose of 2000 mg every day for a year.⁶ Mean pain scores decreased by 39%, with 67% of those receiving ALC vs 23% of those on placebo showing moderate to marked improvement.

In a pooled analysis (N=1257) of 2 randomized controlled trials (RCTs), patients with diabetes took 1000 mg ALC 3 times daily or placebo for a year.⁷ Cohort pain scores improved by 40% from baseline in the ALC group compared with a 24% improvement for those in the placebo group.

THE BOTTOM LINE ALC is well tolerated, with minor adverse effects such as headache and nausea reported.^6,7 It should not be given to patients taking acenocoumarol or warfarin, however. A major interaction causing an elevated international normalized ratio has been found to occur when either agent is combined with L-carnitine² and could theoretically occur with ALC, as well. No other drug-drug interactions have been documented.²

Alpha lipoic acid (ALA)

Both a fat- and a water-soluble vitamin that is usually obtained from the diet, ALA regenerates endogenous antioxidants like vitamins C and E and glutathione. It is this regenerative mechanism that it is believed to alleviate diabetic neuropathy.² ALA 600 mg/d appears to be effective, although studies suggest that intravenous (IV) use is more effective than oral administration.

IV administration of alpha lipoic acid is more effective than oral administration, but patients run the risk of an allergic reaction at the injection site.

A meta-analysis of 4 RCTs (N=653), 2 with ALA taken orally and 2 involving IV administration, is a case in point.³ The pooled standardized mean difference estimated from all trials showed a reduction in total symptom scores of −2.26 (95% confidence interval [CI], −3.12 to −1.41; P=.00001), with 0 indicating no symptoms, 3 indicating severe symptoms, and a maximum score of 14.64 if all symptoms were severe and continuous. Subgroup analyses revealed a reduction of −1.78 (95% CI, −2.45 to −1.10; P=.00001) for oral ALA and −2.81 (95% CI, −4.16 to −1.46; P=.0001) for IV administration. Doses >600 mg/d did not improve efficacy, but did increase adverse effects such as nausea, vomiting, and dizziness.

In a multicenter RCT (N=460) of ALA 600 mg/d for 4 years, however, no improvement in the primary endpoint (a composite of neuropathy impairment scores and 7 neurophysiologic tests) was found.¹⁵ Although there was a statistically significant improvement in symptoms of neuropathy (−0.68 with ALA compared with +0.61 with placebo), the change was too small to be considered clinically significant.

ALA did slow the progression of neuropathy, however, with 29% of patients in the treatment group experiencing worsening symptoms compared with 38% of those on placebo. There was no difference in tolerability or discontinuation of treatment between the 2 groups.

A recent observational study (N=101) compared the efficacy of pregabalin, carbamazepine, and ALA over a 21-month period.⁴ Although those taking pregabalin had the best response rate, all 3 treatments led to significant improvement in the burning associated with neuropathic pain.

ALA 100 mg bid has been investigated as part of a 3-drug combination (with pregabalin 75 mg bid and methylcobalamin 750 mcg bid) compared with monotherapy (pregabalin 75 mg bid) in an open randomized study (N=30) for 12 weeks.¹⁶ While there was a trend toward improvement in pain relief, sleep interference, and nerve function in the combination therapy group, no statistically significant difference between the 2 groups was found. Nonetheless, more than a third (36%) had a global assessment rating of “excellent” vs one in 5 (20%) of those on pregabalin alone.

THE BOTTOM LINE Overall, ALA is well tolerated; the most common adverse effects are nausea and skin rash. IV administration is more effective than oral administration, but may cause nausea, headache, and an allergic reaction at the injection site.² ALA does have the potential for an interaction with chemotherapy and thyroid hormone and may decrease the effectiveness of these therapies.²

B vitamins

Deficiencies of vitamin B1 (thiamine), B6 (pyridoxine), B12 (cyanocobalamin), and folate are known causes of neuropathy, and correcting them often improves or eliminates the symptoms.¹³ Vitamin B12 deficiency is commonly seen in patients taking metformin;¹⁴ these patients may benefit from supplementation with B12 1000 mcg/d.

Many of the B vitamins have been studied for treatment of neuropathy, but benfotiamine (a lipid-soluble form of thiamine) is thought to be the best option because it is better absorbed across cell membranes than other B vitamins.⁹ A Cochrane review found that benfotiamine alone may be effective for both diabetic and alcoholic neuropathy and that short-term use of higher doses of vitamin B complex (25 mg B1 or 320 mg benfotiamine + 50-720 mg B6 + 1000 mcg B12 daily) may reduce neuropathic pain.⁹

Vitamin B12 deficiency is common in patients taking metformin; they may benefit from supplementation with B12 1000 mcg/d.

A randomized multicenter trial (N=214) found that adding a supplement containing L-methylfolate 3 mg, pyridoxal 5-phosphate 35 mg, and methylcobalamin 2 mg twice daily to other medications (eg, pregabalin, gabapentin, or duloxetine) improved symptoms of diabetic neuropathy.¹⁰ At 24 weeks, those receiving the combination therapy had a 26% decrease in pain symptoms compared with a 15% decrease for those on medication alone, with no significant adverse effects.

THE BOTTOM LINE Overall, vitamin B supplementation is well tolerated and appears to be more effective in relieving neuropathic pain than medication alone.^9,14 But larger studies are needed before its efficacy in treating patients who do not have a deficiency can be established.

Capsaicin

Capsaicin, an ingredient found in peppers, works by binding to nociceptors to selectively stimulate afferent C fibers. This causes the release of substance P, a neurotransmitter that mediates pain, leading to its depletion and resulting in desensitization.² Several meta-analyses and systematic reviews have found that topical capsaicin can be very effective, both as an adjunctive treatment and as monotherapy for neuropathic pain.^11,17,18 The concentration used in the studies was 0.075% capsaicin cream, applied 3 to 4 times a day for 6 to 12 weeks, compared with placebo creams. In all categories studied, capsaicin was either statistically significant or trending in its favor, with the exception of adverse effects.

Capsaicin led to an improvement in daily activities and ability to sleep and a reduction in pain as measured with a visual analog scale and physician global evaluation.^11,17,18

The most notable adverse effects were a burning sensation on the skin and coughing and sneezing caused by inhalation of dried cream. Although the adverse effects were expected to improve after 2 to 7 days of use, a significant number of participants withdrew from the study.

A 7-study meta-analysis showed the effectiveness of an 8% capsaicin patch for treatment of post-herpetic neuralgia and HIV-associated neuropathy.¹² The patch, available only by prescription, was worn every day for 4 weeks (60 minutes daily for post-herpetic neuralgia and 30 minutes a day for HIV-associated neuropathy). The pooled results were statistically significant, but the patch was less effective for patients ages 18 to 40 years and for those of Asian descent. It can be used with other analgesics or as monotherapy, with few adverse reactions.^12,19

THE BOTTOM LINE Since capsaicin is a topical medication, there are no relevant drug-drug interactions. Patients should be cautioned to wash their hands after application, however, and to avoid contact with eyes and open wounds.

Gamma linolenic acid (GLA)

Also known as evening primrose oil, GLA is an omega-6 fatty acid that’s an important constituent of neuronal cell membranes—and believed to decrease neuropathic pain by having some anti-inflammatory effects.² This suggests that therapy with GLA has the potential to improve neuronal phospholipid structure and microcirculation.²

Two placebo-controlled trials (N=22,111) showed improvement in pain scores and multiple neurophysiologic assessments in patients with diabetes treated with GLA (360-480 mg/d).^20,21 The treatment was well tolerated, but the beneficial effect was more pronounced in those with less severe diabetes.

THE BOTTOM LINE The dose of GLA studied (8 to 12 capsules daily) could lead to problems with patient adherence. In addition, GLA should be used with caution in patients who are taking antiplatelet medication or have seizure disorders.² 

Magnesium (Mg)

Mg is highly involved in multiple enzyme systems throughout the body. Although it is very well absorbed from dietary sources,² patients with diabetes, liver disease, and hormonal imbalances, as well as the elderly, are often deficient in Mg. It is unclear how this affects peripheral neuropathy.¹³

Mg may have an antinociceptive effect by decreasing intracellular calcium influx and antagonizing N-methyl-D-aspartate receptors and associated nerve signaling.²² A small RCT (N=80) showed Mg to decrease the severity of neuropathic back pain.²² Patients received Mg sulfate 1 g IV, given over 4 hours, every day for 2 weeks. The infusion was then replaced with Mg oxide 400 mg plus Mg gluconate 100 mg, taken orally twice daily for 4 weeks. An improvement in mean pain score was seen as early as 2 weeks, and scores had decreased by 2.8 points (on a 0-10-point scale) at 6 months.

Another small RCT (N=45) gave patients with neuropathy of postherpetic, traumatic, or surgical (but not diabetic) origin Mg chloride 838 mg orally 3 times a day for 4 weeks.²³ The supplement was taken with meals. Mean pain scores in the treatment group decreased by 3 points, but this was not significantly different from the improvement seen in those on placebo.

Patients with painful diabetic neuropathy may benefit from magnesium (Mg) gluconate 300 mg/d, but supplementation is unsafe for those with renal dysfunction, cardiac conduction abnormalities, or elevated Mg levels.

In a similar study, patients (N=110) with type 1 diabetes and a normal serum Mg but an insufficiency as measured by erythrocyte Mg were given Mg gluconate 300 mg or placebo daily for 5 years.⁸ The supplement slowed the progression of peripheral neuropathy (only 12% of those receiving Mg gluconate experienced a significant worsening of symptoms over the course of the study, compared with 61% of those in the placebo group), but in most cases, it did not lead to an improvement.

No consistent approach to Mg supplementation has been studied, which makes recommending a particular route, dose, or formulation challenging. There is evidence that oral Mg, particularly in the form of Mg oxide, can cause diarrhea, especially in doses >350 mg/d. Mg gluconate and Mg chloride are better tolerated; Mg carbonate should be avoided due to poor oral absorption.²

BOTTOM LINE Mg supplementation appears to slow the progression of diabetic peripheral neuropathy, but is unsafe for patients with renal dysfunction, cardiac conduction abnormalities, or elevated Mg levels.² Caution is required, too, when considering Mg supplementation for patients taking anticoagulants, bisphosphonates, digoxin, potassium-sparing diuretics, or tetracycline antibiotics.²

CORRESPONDENCE 
Mary Onysko, PharmD, BCPS, University of Wyoming, School of Pharmacy Health Sciences Center, Room 292, 1000 E. University Avenue, Laramie, WY 82071; [email protected]

Anticonvulsants, antidepressants, and opioids are the most frequently prescribed medications for neuropathic pain.¹ But some patients are unable to tolerate the adverse effects of these drugs, and others achieve only partial pain relief. What can you offer them?

Combinations of prescription medications are generally considered more effective than monotherapy for painful peripheral neuropathy,¹ but it is unclear which combinations are best. Alternative therapies—several of which have some evidence of safety and efficacy in treating peripheral neuropathy—are another option. Yet trials with alternative therapies, alone or in combination with prescription drugs, are rarely considered.

In fact, physicians are often unfamiliar with these therapies. Many are concerned about the absence of US Food and Drug Administration approval for alternative therapies and the variability in quality control associated with the lack of oversight, as well. Making recommendations about the duration of therapy also presents a challenge because most studies of supplements are relatively short. What’s more, alternative treatments are rarely covered by third-party payers.

Nonetheless, the therapies detailed in the text and TABLE^2-12 that follow are generally well tolerated and appear to be safe. Adding them to your arsenal of therapeutic choices for patients with painful peripheral neuropathy may increase your ability to provide successful treatment.

Acetyl-L-carnitine (ALC)

ALC occurs naturally in the body as L-carnitine and acetyl-carnitine esters, which are converted to carnitines by intracellular enzymes and cell membrane transporters.² ALC has been studied in patients with neuropathy associated with human immunodeficiency virus (HIV), cancer, and diabetes. Potential mechanisms of action include the correction of a deficiency that may be causing the neuropathy (which sometimes occurs in HIV-positive patients¹³ or those taking anticonvulsants¹⁴), a direct antioxidant effect, or an enhanced response to nerve growth factor.¹³

Adding these generally well-tolerated therapies to your arsenal of therapeutic choices for patients may increase your ability to provide successful treatment.

ALC can be given intramuscularly (IM) or orally in doses of 2000 to 3000 mg/d. In one randomized placebo-controlled trial (N=333), patients with diabetic neuropathy received 1000 mg IM followed by an oral dose of 2000 mg every day for a year.⁶ Mean pain scores decreased by 39%, with 67% of those receiving ALC vs 23% of those on placebo showing moderate to marked improvement.

In a pooled analysis (N=1257) of 2 randomized controlled trials (RCTs), patients with diabetes took 1000 mg ALC 3 times daily or placebo for a year.⁷ Cohort pain scores improved by 40% from baseline in the ALC group compared with a 24% improvement for those in the placebo group.

THE BOTTOM LINE ALC is well tolerated, with minor adverse effects such as headache and nausea reported.^6,7 It should not be given to patients taking acenocoumarol or warfarin, however. A major interaction causing an elevated international normalized ratio has been found to occur when either agent is combined with L-carnitine² and could theoretically occur with ALC, as well. No other drug-drug interactions have been documented.²

Alpha lipoic acid (ALA)

Both a fat- and a water-soluble vitamin that is usually obtained from the diet, ALA regenerates endogenous antioxidants like vitamins C and E and glutathione. It is this regenerative mechanism that it is believed to alleviate diabetic neuropathy.² ALA 600 mg/d appears to be effective, although studies suggest that intravenous (IV) use is more effective than oral administration.

IV administration of alpha lipoic acid is more effective than oral administration, but patients run the risk of an allergic reaction at the injection site.

A meta-analysis of 4 RCTs (N=653), 2 with ALA taken orally and 2 involving IV administration, is a case in point.³ The pooled standardized mean difference estimated from all trials showed a reduction in total symptom scores of −2.26 (95% confidence interval [CI], −3.12 to −1.41; P=.00001), with 0 indicating no symptoms, 3 indicating severe symptoms, and a maximum score of 14.64 if all symptoms were severe and continuous. Subgroup analyses revealed a reduction of −1.78 (95% CI, −2.45 to −1.10; P=.00001) for oral ALA and −2.81 (95% CI, −4.16 to −1.46; P=.0001) for IV administration. Doses >600 mg/d did not improve efficacy, but did increase adverse effects such as nausea, vomiting, and dizziness.

In a multicenter RCT (N=460) of ALA 600 mg/d for 4 years, however, no improvement in the primary endpoint (a composite of neuropathy impairment scores and 7 neurophysiologic tests) was found.¹⁵ Although there was a statistically significant improvement in symptoms of neuropathy (−0.68 with ALA compared with +0.61 with placebo), the change was too small to be considered clinically significant.

ALA did slow the progression of neuropathy, however, with 29% of patients in the treatment group experiencing worsening symptoms compared with 38% of those on placebo. There was no difference in tolerability or discontinuation of treatment between the 2 groups.

A recent observational study (N=101) compared the efficacy of pregabalin, carbamazepine, and ALA over a 21-month period.⁴ Although those taking pregabalin had the best response rate, all 3 treatments led to significant improvement in the burning associated with neuropathic pain.

ALA 100 mg bid has been investigated as part of a 3-drug combination (with pregabalin 75 mg bid and methylcobalamin 750 mcg bid) compared with monotherapy (pregabalin 75 mg bid) in an open randomized study (N=30) for 12 weeks.¹⁶ While there was a trend toward improvement in pain relief, sleep interference, and nerve function in the combination therapy group, no statistically significant difference between the 2 groups was found. Nonetheless, more than a third (36%) had a global assessment rating of “excellent” vs one in 5 (20%) of those on pregabalin alone.

THE BOTTOM LINE Overall, ALA is well tolerated; the most common adverse effects are nausea and skin rash. IV administration is more effective than oral administration, but may cause nausea, headache, and an allergic reaction at the injection site.² ALA does have the potential for an interaction with chemotherapy and thyroid hormone and may decrease the effectiveness of these therapies.²

B vitamins

Deficiencies of vitamin B1 (thiamine), B6 (pyridoxine), B12 (cyanocobalamin), and folate are known causes of neuropathy, and correcting them often improves or eliminates the symptoms.¹³ Vitamin B12 deficiency is commonly seen in patients taking metformin;¹⁴ these patients may benefit from supplementation with B12 1000 mcg/d.

Many of the B vitamins have been studied for treatment of neuropathy, but benfotiamine (a lipid-soluble form of thiamine) is thought to be the best option because it is better absorbed across cell membranes than other B vitamins.⁹ A Cochrane review found that benfotiamine alone may be effective for both diabetic and alcoholic neuropathy and that short-term use of higher doses of vitamin B complex (25 mg B1 or 320 mg benfotiamine + 50-720 mg B6 + 1000 mcg B12 daily) may reduce neuropathic pain.⁹

Vitamin B12 deficiency is common in patients taking metformin; they may benefit from supplementation with B12 1000 mcg/d.

A randomized multicenter trial (N=214) found that adding a supplement containing L-methylfolate 3 mg, pyridoxal 5-phosphate 35 mg, and methylcobalamin 2 mg twice daily to other medications (eg, pregabalin, gabapentin, or duloxetine) improved symptoms of diabetic neuropathy.¹⁰ At 24 weeks, those receiving the combination therapy had a 26% decrease in pain symptoms compared with a 15% decrease for those on medication alone, with no significant adverse effects.

THE BOTTOM LINE Overall, vitamin B supplementation is well tolerated and appears to be more effective in relieving neuropathic pain than medication alone.^9,14 But larger studies are needed before its efficacy in treating patients who do not have a deficiency can be established.

Capsaicin

Capsaicin, an ingredient found in peppers, works by binding to nociceptors to selectively stimulate afferent C fibers. This causes the release of substance P, a neurotransmitter that mediates pain, leading to its depletion and resulting in desensitization.² Several meta-analyses and systematic reviews have found that topical capsaicin can be very effective, both as an adjunctive treatment and as monotherapy for neuropathic pain.^11,17,18 The concentration used in the studies was 0.075% capsaicin cream, applied 3 to 4 times a day for 6 to 12 weeks, compared with placebo creams. In all categories studied, capsaicin was either statistically significant or trending in its favor, with the exception of adverse effects.

Capsaicin led to an improvement in daily activities and ability to sleep and a reduction in pain as measured with a visual analog scale and physician global evaluation.^11,17,18

The most notable adverse effects were a burning sensation on the skin and coughing and sneezing caused by inhalation of dried cream. Although the adverse effects were expected to improve after 2 to 7 days of use, a significant number of participants withdrew from the study.

A 7-study meta-analysis showed the effectiveness of an 8% capsaicin patch for treatment of post-herpetic neuralgia and HIV-associated neuropathy.¹² The patch, available only by prescription, was worn every day for 4 weeks (60 minutes daily for post-herpetic neuralgia and 30 minutes a day for HIV-associated neuropathy). The pooled results were statistically significant, but the patch was less effective for patients ages 18 to 40 years and for those of Asian descent. It can be used with other analgesics or as monotherapy, with few adverse reactions.^12,19

THE BOTTOM LINE Since capsaicin is a topical medication, there are no relevant drug-drug interactions. Patients should be cautioned to wash their hands after application, however, and to avoid contact with eyes and open wounds.

Gamma linolenic acid (GLA)

Also known as evening primrose oil, GLA is an omega-6 fatty acid that’s an important constituent of neuronal cell membranes—and believed to decrease neuropathic pain by having some anti-inflammatory effects.² This suggests that therapy with GLA has the potential to improve neuronal phospholipid structure and microcirculation.²

Two placebo-controlled trials (N=22,111) showed improvement in pain scores and multiple neurophysiologic assessments in patients with diabetes treated with GLA (360-480 mg/d).^20,21 The treatment was well tolerated, but the beneficial effect was more pronounced in those with less severe diabetes.

THE BOTTOM LINE The dose of GLA studied (8 to 12 capsules daily) could lead to problems with patient adherence. In addition, GLA should be used with caution in patients who are taking antiplatelet medication or have seizure disorders.² 

Magnesium (Mg)

Mg is highly involved in multiple enzyme systems throughout the body. Although it is very well absorbed from dietary sources,² patients with diabetes, liver disease, and hormonal imbalances, as well as the elderly, are often deficient in Mg. It is unclear how this affects peripheral neuropathy.¹³

Mg may have an antinociceptive effect by decreasing intracellular calcium influx and antagonizing N-methyl-D-aspartate receptors and associated nerve signaling.²² A small RCT (N=80) showed Mg to decrease the severity of neuropathic back pain.²² Patients received Mg sulfate 1 g IV, given over 4 hours, every day for 2 weeks. The infusion was then replaced with Mg oxide 400 mg plus Mg gluconate 100 mg, taken orally twice daily for 4 weeks. An improvement in mean pain score was seen as early as 2 weeks, and scores had decreased by 2.8 points (on a 0-10-point scale) at 6 months.

Another small RCT (N=45) gave patients with neuropathy of postherpetic, traumatic, or surgical (but not diabetic) origin Mg chloride 838 mg orally 3 times a day for 4 weeks.²³ The supplement was taken with meals. Mean pain scores in the treatment group decreased by 3 points, but this was not significantly different from the improvement seen in those on placebo.

Patients with painful diabetic neuropathy may benefit from magnesium (Mg) gluconate 300 mg/d, but supplementation is unsafe for those with renal dysfunction, cardiac conduction abnormalities, or elevated Mg levels.

In a similar study, patients (N=110) with type 1 diabetes and a normal serum Mg but an insufficiency as measured by erythrocyte Mg were given Mg gluconate 300 mg or placebo daily for 5 years.⁸ The supplement slowed the progression of peripheral neuropathy (only 12% of those receiving Mg gluconate experienced a significant worsening of symptoms over the course of the study, compared with 61% of those in the placebo group), but in most cases, it did not lead to an improvement.

No consistent approach to Mg supplementation has been studied, which makes recommending a particular route, dose, or formulation challenging. There is evidence that oral Mg, particularly in the form of Mg oxide, can cause diarrhea, especially in doses >350 mg/d. Mg gluconate and Mg chloride are better tolerated; Mg carbonate should be avoided due to poor oral absorption.²

BOTTOM LINE Mg supplementation appears to slow the progression of diabetic peripheral neuropathy, but is unsafe for patients with renal dysfunction, cardiac conduction abnormalities, or elevated Mg levels.² Caution is required, too, when considering Mg supplementation for patients taking anticoagulants, bisphosphonates, digoxin, potassium-sparing diuretics, or tetracycline antibiotics.²

CORRESPONDENCE 
Mary Onysko, PharmD, BCPS, University of Wyoming, School of Pharmacy Health Sciences Center, Room 292, 1000 E. University Avenue, Laramie, WY 82071; [email protected]

Anticonvulsants, antidepressants, and opioids are the most frequently prescribed medications for neuropathic pain.¹ But some patients are unable to tolerate the adverse effects of these drugs, and others achieve only partial pain relief. What can you offer them?

Combinations of prescription medications are generally considered more effective than monotherapy for painful peripheral neuropathy,¹ but it is unclear which combinations are best. Alternative therapies—several of which have some evidence of safety and efficacy in treating peripheral neuropathy—are another option. Yet trials with alternative therapies, alone or in combination with prescription drugs, are rarely considered.

In fact, physicians are often unfamiliar with these therapies. Many are concerned about the absence of US Food and Drug Administration approval for alternative therapies and the variability in quality control associated with the lack of oversight, as well. Making recommendations about the duration of therapy also presents a challenge because most studies of supplements are relatively short. What’s more, alternative treatments are rarely covered by third-party payers.

Nonetheless, the therapies detailed in the text and TABLE^2-12 that follow are generally well tolerated and appear to be safe. Adding them to your arsenal of therapeutic choices for patients with painful peripheral neuropathy may increase your ability to provide successful treatment.

Acetyl-L-carnitine (ALC)

ALC occurs naturally in the body as L-carnitine and acetyl-carnitine esters, which are converted to carnitines by intracellular enzymes and cell membrane transporters.² ALC has been studied in patients with neuropathy associated with human immunodeficiency virus (HIV), cancer, and diabetes. Potential mechanisms of action include the correction of a deficiency that may be causing the neuropathy (which sometimes occurs in HIV-positive patients¹³ or those taking anticonvulsants¹⁴), a direct antioxidant effect, or an enhanced response to nerve growth factor.¹³

Adding these generally well-tolerated therapies to your arsenal of therapeutic choices for patients may increase your ability to provide successful treatment.

ALC can be given intramuscularly (IM) or orally in doses of 2000 to 3000 mg/d. In one randomized placebo-controlled trial (N=333), patients with diabetic neuropathy received 1000 mg IM followed by an oral dose of 2000 mg every day for a year.⁶ Mean pain scores decreased by 39%, with 67% of those receiving ALC vs 23% of those on placebo showing moderate to marked improvement.

In a pooled analysis (N=1257) of 2 randomized controlled trials (RCTs), patients with diabetes took 1000 mg ALC 3 times daily or placebo for a year.⁷ Cohort pain scores improved by 40% from baseline in the ALC group compared with a 24% improvement for those in the placebo group.

THE BOTTOM LINE ALC is well tolerated, with minor adverse effects such as headache and nausea reported.^6,7 It should not be given to patients taking acenocoumarol or warfarin, however. A major interaction causing an elevated international normalized ratio has been found to occur when either agent is combined with L-carnitine² and could theoretically occur with ALC, as well. No other drug-drug interactions have been documented.²

Alpha lipoic acid (ALA)

Both a fat- and a water-soluble vitamin that is usually obtained from the diet, ALA regenerates endogenous antioxidants like vitamins C and E and glutathione. It is this regenerative mechanism that it is believed to alleviate diabetic neuropathy.² ALA 600 mg/d appears to be effective, although studies suggest that intravenous (IV) use is more effective than oral administration.

IV administration of alpha lipoic acid is more effective than oral administration, but patients run the risk of an allergic reaction at the injection site.

A meta-analysis of 4 RCTs (N=653), 2 with ALA taken orally and 2 involving IV administration, is a case in point.³ The pooled standardized mean difference estimated from all trials showed a reduction in total symptom scores of −2.26 (95% confidence interval [CI], −3.12 to −1.41; P=.00001), with 0 indicating no symptoms, 3 indicating severe symptoms, and a maximum score of 14.64 if all symptoms were severe and continuous. Subgroup analyses revealed a reduction of −1.78 (95% CI, −2.45 to −1.10; P=.00001) for oral ALA and −2.81 (95% CI, −4.16 to −1.46; P=.0001) for IV administration. Doses >600 mg/d did not improve efficacy, but did increase adverse effects such as nausea, vomiting, and dizziness.

In a multicenter RCT (N=460) of ALA 600 mg/d for 4 years, however, no improvement in the primary endpoint (a composite of neuropathy impairment scores and 7 neurophysiologic tests) was found.¹⁵ Although there was a statistically significant improvement in symptoms of neuropathy (−0.68 with ALA compared with +0.61 with placebo), the change was too small to be considered clinically significant.

ALA did slow the progression of neuropathy, however, with 29% of patients in the treatment group experiencing worsening symptoms compared with 38% of those on placebo. There was no difference in tolerability or discontinuation of treatment between the 2 groups.

A recent observational study (N=101) compared the efficacy of pregabalin, carbamazepine, and ALA over a 21-month period.⁴ Although those taking pregabalin had the best response rate, all 3 treatments led to significant improvement in the burning associated with neuropathic pain.

ALA 100 mg bid has been investigated as part of a 3-drug combination (with pregabalin 75 mg bid and methylcobalamin 750 mcg bid) compared with monotherapy (pregabalin 75 mg bid) in an open randomized study (N=30) for 12 weeks.¹⁶ While there was a trend toward improvement in pain relief, sleep interference, and nerve function in the combination therapy group, no statistically significant difference between the 2 groups was found. Nonetheless, more than a third (36%) had a global assessment rating of “excellent” vs one in 5 (20%) of those on pregabalin alone.

THE BOTTOM LINE Overall, ALA is well tolerated; the most common adverse effects are nausea and skin rash. IV administration is more effective than oral administration, but may cause nausea, headache, and an allergic reaction at the injection site.² ALA does have the potential for an interaction with chemotherapy and thyroid hormone and may decrease the effectiveness of these therapies.²

B vitamins

Deficiencies of vitamin B1 (thiamine), B6 (pyridoxine), B12 (cyanocobalamin), and folate are known causes of neuropathy, and correcting them often improves or eliminates the symptoms.¹³ Vitamin B12 deficiency is commonly seen in patients taking metformin;¹⁴ these patients may benefit from supplementation with B12 1000 mcg/d.

Many of the B vitamins have been studied for treatment of neuropathy, but benfotiamine (a lipid-soluble form of thiamine) is thought to be the best option because it is better absorbed across cell membranes than other B vitamins.⁹ A Cochrane review found that benfotiamine alone may be effective for both diabetic and alcoholic neuropathy and that short-term use of higher doses of vitamin B complex (25 mg B1 or 320 mg benfotiamine + 50-720 mg B6 + 1000 mcg B12 daily) may reduce neuropathic pain.⁹

Vitamin B12 deficiency is common in patients taking metformin; they may benefit from supplementation with B12 1000 mcg/d.

A randomized multicenter trial (N=214) found that adding a supplement containing L-methylfolate 3 mg, pyridoxal 5-phosphate 35 mg, and methylcobalamin 2 mg twice daily to other medications (eg, pregabalin, gabapentin, or duloxetine) improved symptoms of diabetic neuropathy.¹⁰ At 24 weeks, those receiving the combination therapy had a 26% decrease in pain symptoms compared with a 15% decrease for those on medication alone, with no significant adverse effects.

THE BOTTOM LINE Overall, vitamin B supplementation is well tolerated and appears to be more effective in relieving neuropathic pain than medication alone.^9,14 But larger studies are needed before its efficacy in treating patients who do not have a deficiency can be established.

Capsaicin

Capsaicin, an ingredient found in peppers, works by binding to nociceptors to selectively stimulate afferent C fibers. This causes the release of substance P, a neurotransmitter that mediates pain, leading to its depletion and resulting in desensitization.² Several meta-analyses and systematic reviews have found that topical capsaicin can be very effective, both as an adjunctive treatment and as monotherapy for neuropathic pain.^11,17,18 The concentration used in the studies was 0.075% capsaicin cream, applied 3 to 4 times a day for 6 to 12 weeks, compared with placebo creams. In all categories studied, capsaicin was either statistically significant or trending in its favor, with the exception of adverse effects.

Capsaicin led to an improvement in daily activities and ability to sleep and a reduction in pain as measured with a visual analog scale and physician global evaluation.^11,17,18

The most notable adverse effects were a burning sensation on the skin and coughing and sneezing caused by inhalation of dried cream. Although the adverse effects were expected to improve after 2 to 7 days of use, a significant number of participants withdrew from the study.

A 7-study meta-analysis showed the effectiveness of an 8% capsaicin patch for treatment of post-herpetic neuralgia and HIV-associated neuropathy.¹² The patch, available only by prescription, was worn every day for 4 weeks (60 minutes daily for post-herpetic neuralgia and 30 minutes a day for HIV-associated neuropathy). The pooled results were statistically significant, but the patch was less effective for patients ages 18 to 40 years and for those of Asian descent. It can be used with other analgesics or as monotherapy, with few adverse reactions.^12,19

THE BOTTOM LINE Since capsaicin is a topical medication, there are no relevant drug-drug interactions. Patients should be cautioned to wash their hands after application, however, and to avoid contact with eyes and open wounds.

Gamma linolenic acid (GLA)

Also known as evening primrose oil, GLA is an omega-6 fatty acid that’s an important constituent of neuronal cell membranes—and believed to decrease neuropathic pain by having some anti-inflammatory effects.² This suggests that therapy with GLA has the potential to improve neuronal phospholipid structure and microcirculation.²

Two placebo-controlled trials (N=22,111) showed improvement in pain scores and multiple neurophysiologic assessments in patients with diabetes treated with GLA (360-480 mg/d).^20,21 The treatment was well tolerated, but the beneficial effect was more pronounced in those with less severe diabetes.

THE BOTTOM LINE The dose of GLA studied (8 to 12 capsules daily) could lead to problems with patient adherence. In addition, GLA should be used with caution in patients who are taking antiplatelet medication or have seizure disorders.² 

Magnesium (Mg)

Mg is highly involved in multiple enzyme systems throughout the body. Although it is very well absorbed from dietary sources,² patients with diabetes, liver disease, and hormonal imbalances, as well as the elderly, are often deficient in Mg. It is unclear how this affects peripheral neuropathy.¹³

Mg may have an antinociceptive effect by decreasing intracellular calcium influx and antagonizing N-methyl-D-aspartate receptors and associated nerve signaling.²² A small RCT (N=80) showed Mg to decrease the severity of neuropathic back pain.²² Patients received Mg sulfate 1 g IV, given over 4 hours, every day for 2 weeks. The infusion was then replaced with Mg oxide 400 mg plus Mg gluconate 100 mg, taken orally twice daily for 4 weeks. An improvement in mean pain score was seen as early as 2 weeks, and scores had decreased by 2.8 points (on a 0-10-point scale) at 6 months.

Another small RCT (N=45) gave patients with neuropathy of postherpetic, traumatic, or surgical (but not diabetic) origin Mg chloride 838 mg orally 3 times a day for 4 weeks.²³ The supplement was taken with meals. Mean pain scores in the treatment group decreased by 3 points, but this was not significantly different from the improvement seen in those on placebo.

Patients with painful diabetic neuropathy may benefit from magnesium (Mg) gluconate 300 mg/d, but supplementation is unsafe for those with renal dysfunction, cardiac conduction abnormalities, or elevated Mg levels.

In a similar study, patients (N=110) with type 1 diabetes and a normal serum Mg but an insufficiency as measured by erythrocyte Mg were given Mg gluconate 300 mg or placebo daily for 5 years.⁸ The supplement slowed the progression of peripheral neuropathy (only 12% of those receiving Mg gluconate experienced a significant worsening of symptoms over the course of the study, compared with 61% of those in the placebo group), but in most cases, it did not lead to an improvement.

No consistent approach to Mg supplementation has been studied, which makes recommending a particular route, dose, or formulation challenging. There is evidence that oral Mg, particularly in the form of Mg oxide, can cause diarrhea, especially in doses >350 mg/d. Mg gluconate and Mg chloride are better tolerated; Mg carbonate should be avoided due to poor oral absorption.²

BOTTOM LINE Mg supplementation appears to slow the progression of diabetic peripheral neuropathy, but is unsafe for patients with renal dysfunction, cardiac conduction abnormalities, or elevated Mg levels.² Caution is required, too, when considering Mg supplementation for patients taking anticoagulants, bisphosphonates, digoxin, potassium-sparing diuretics, or tetracycline antibiotics.²

CORRESPONDENCE 
Mary Onysko, PharmD, BCPS, University of Wyoming, School of Pharmacy Health Sciences Center, Room 292, 1000 E. University Avenue, Laramie, WY 82071; [email protected]

Head contact with other players, not with the ball, is the main source of concussions among high school soccer players, according to research published online ahead of print July 13 in JAMA Pediatrics.

Several studies have shown that heading the ball is responsible for many soccer-related concussions. Some people have called for banning heading, especially among children and adolescents, to make the sport safer. No large study, however, had examined the exact mechanism of head injuries among school-aged soccer players, so such prevention efforts could not be considered evidence-based, said R. Dawn Comstock, PhD, an epidemiologist at the University of Colorado Denver in Aurora.

Dr. Comstock and colleagues performed a retrospective analysis of data from a large, Internet-based sports injury surveillance study, focusing on concussions sustained during soccer practices or games that required medical attention and restricted the athlete’s participation for one or more days. The investigators assessed nationally representative samples of 100 high schools every year for nine years. There were 627 concussions during 1,393,753 athlete exposures among girls (4.50 per 10,000 exposures) and 442 concussions during 1,592,238 athlete exposures among boys (2.78 per 10,000 exposures).

The most common mechanism of concussion was player-to-player contact among boys (68.8%) and girls (51.3%). Contact with the ball accounted for 17% of concussions among boys and 29% among girls.

The number and types of concussion symptoms were the same, regardless of whether the concussion was caused by player-to-player contact or player-to-ball contact. However, symptom resolution time was slightly but significantly longer for both boys and girls when the concussion was caused by collision with a ball or goal post.

“We postulate that banning heading from soccer will have limited effectiveness as a primary prevention mechanism unless such a ban is combined with concurrent efforts to reduce athlete–athlete contact throughout the game,” Dr. Comstock and her associates said.

“It may be culturally more tolerable to the soccer community to attempt to reduce athlete–athlete contact across all phases of play through better enforcement of existing rules, enhanced education of athletes on the rules of the game, and improved coaching of activities such as heading,” rather than simply banning heading, said the researchers.

—Mary Ann Moon

Head contact with other players, not with the ball, is the main source of concussions among high school soccer players, according to research published online ahead of print July 13 in JAMA Pediatrics.

Several studies have shown that heading the ball is responsible for many soccer-related concussions. Some people have called for banning heading, especially among children and adolescents, to make the sport safer. No large study, however, had examined the exact mechanism of head injuries among school-aged soccer players, so such prevention efforts could not be considered evidence-based, said R. Dawn Comstock, PhD, an epidemiologist at the University of Colorado Denver in Aurora.

Dr. Comstock and colleagues performed a retrospective analysis of data from a large, Internet-based sports injury surveillance study, focusing on concussions sustained during soccer practices or games that required medical attention and restricted the athlete’s participation for one or more days. The investigators assessed nationally representative samples of 100 high schools every year for nine years. There were 627 concussions during 1,393,753 athlete exposures among girls (4.50 per 10,000 exposures) and 442 concussions during 1,592,238 athlete exposures among boys (2.78 per 10,000 exposures).

The most common mechanism of concussion was player-to-player contact among boys (68.8%) and girls (51.3%). Contact with the ball accounted for 17% of concussions among boys and 29% among girls.

The number and types of concussion symptoms were the same, regardless of whether the concussion was caused by player-to-player contact or player-to-ball contact. However, symptom resolution time was slightly but significantly longer for both boys and girls when the concussion was caused by collision with a ball or goal post.

“We postulate that banning heading from soccer will have limited effectiveness as a primary prevention mechanism unless such a ban is combined with concurrent efforts to reduce athlete–athlete contact throughout the game,” Dr. Comstock and her associates said.

“It may be culturally more tolerable to the soccer community to attempt to reduce athlete–athlete contact across all phases of play through better enforcement of existing rules, enhanced education of athletes on the rules of the game, and improved coaching of activities such as heading,” rather than simply banning heading, said the researchers.

—Mary Ann Moon

Head contact with other players, not with the ball, is the main source of concussions among high school soccer players, according to research published online ahead of print July 13 in JAMA Pediatrics.

Several studies have shown that heading the ball is responsible for many soccer-related concussions. Some people have called for banning heading, especially among children and adolescents, to make the sport safer. No large study, however, had examined the exact mechanism of head injuries among school-aged soccer players, so such prevention efforts could not be considered evidence-based, said R. Dawn Comstock, PhD, an epidemiologist at the University of Colorado Denver in Aurora.

Dr. Comstock and colleagues performed a retrospective analysis of data from a large, Internet-based sports injury surveillance study, focusing on concussions sustained during soccer practices or games that required medical attention and restricted the athlete’s participation for one or more days. The investigators assessed nationally representative samples of 100 high schools every year for nine years. There were 627 concussions during 1,393,753 athlete exposures among girls (4.50 per 10,000 exposures) and 442 concussions during 1,592,238 athlete exposures among boys (2.78 per 10,000 exposures).

The most common mechanism of concussion was player-to-player contact among boys (68.8%) and girls (51.3%). Contact with the ball accounted for 17% of concussions among boys and 29% among girls.

The number and types of concussion symptoms were the same, regardless of whether the concussion was caused by player-to-player contact or player-to-ball contact. However, symptom resolution time was slightly but significantly longer for both boys and girls when the concussion was caused by collision with a ball or goal post.

“We postulate that banning heading from soccer will have limited effectiveness as a primary prevention mechanism unless such a ban is combined with concurrent efforts to reduce athlete–athlete contact throughout the game,” Dr. Comstock and her associates said.

“It may be culturally more tolerable to the soccer community to attempt to reduce athlete–athlete contact across all phases of play through better enforcement of existing rules, enhanced education of athletes on the rules of the game, and improved coaching of activities such as heading,” rather than simply banning heading, said the researchers.

—Mary Ann Moon

(Reuters Health) - For overweight and obese people with atrial fibrillation, improving cardiorespiratory fitness with exercise may help to reduce or eliminate symptoms, a recent Australian study found.

Participants with the greatest improvements in their cardiorespiratory fitness were less burdened by symptoms of the arrhythmia and more likely to be symptom free during the study, compared to those who had smaller or no fitness improvements.

A possible side effect of the cardio exercise regimen, weight loss, may have also contributed to the improvements, researchers say.

Atrial fibrillation (AF) is a "growing epidemic" and obesity is a risk factor, the study's lead author Prash Sanders, director of the Center for Heart Rhythm Disorders at Royal Adelaide Hospital, told Reuters Health in an email.

The researchers examined the role of cardiorespiratory fitness and the incremental benefit of cardiorespiratory fitness improvement on rhythm control in 308 overweight and obese individuals with AF.

At the start of the study and four years later, participants completed questionnaires about their AF symptoms. The researchers also had patients wear a heart monitor for seven days at a time.

Based on baseline exercise stress testing, 95 people were classified as having low cardiorespiratory fitness, 134 had adequate fitness and 79 were classified as high fitness, Sanders and colleagues report in the Journal of the American College of Cardiology online June 22.

The research team prescribed the patients an exercise program tailored to their age and physical ability, which gradually increased in intensity.

By the end of four years, those who had increased their fitness levels by two metabolic equivalents (METs) or more, and those who lost weight were more likely to have reduced or no AF symptoms than those who improved by less than two METs or not at all.

Though increasing cardiorespiratory fitness seems to be beneficial, Dr. Michael Lloyd, a cardiologist at Emory University Hospital in Atlanta, Georgia, advises caution. "Overweight people should check with their doctor prior to embarking on any exercise program," said Lloyd, who was not involved in the study.

Sanders recommends a tailored exercise program, "in which consideration for age and physical ability should be made so that targets are achieved without risking injuries."

Dr. Waqas Qureshi, a cardiology researcher at Wake Forest University in Winston-Salem, North Carolina, who also was not involved in the study, noted that weight loss from exercise may add to the protection against heart irregularities.

Lloyd, however, emphasized that cardiorespiratory fitness is beneficial even apart from weight loss. "If you are overweight, it's not just the pounds that matter, it's how fit you are. This study shows that increasing your fitness through exercise and lifestyle choices does reduce your chance of having the most common arrhythmia."

(Reuters Health) - For overweight and obese people with atrial fibrillation, improving cardiorespiratory fitness with exercise may help to reduce or eliminate symptoms, a recent Australian study found.

Participants with the greatest improvements in their cardiorespiratory fitness were less burdened by symptoms of the arrhythmia and more likely to be symptom free during the study, compared to those who had smaller or no fitness improvements.

A possible side effect of the cardio exercise regimen, weight loss, may have also contributed to the improvements, researchers say.

Atrial fibrillation (AF) is a "growing epidemic" and obesity is a risk factor, the study's lead author Prash Sanders, director of the Center for Heart Rhythm Disorders at Royal Adelaide Hospital, told Reuters Health in an email.

The researchers examined the role of cardiorespiratory fitness and the incremental benefit of cardiorespiratory fitness improvement on rhythm control in 308 overweight and obese individuals with AF.

At the start of the study and four years later, participants completed questionnaires about their AF symptoms. The researchers also had patients wear a heart monitor for seven days at a time.

Based on baseline exercise stress testing, 95 people were classified as having low cardiorespiratory fitness, 134 had adequate fitness and 79 were classified as high fitness, Sanders and colleagues report in the Journal of the American College of Cardiology online June 22.

The research team prescribed the patients an exercise program tailored to their age and physical ability, which gradually increased in intensity.

By the end of four years, those who had increased their fitness levels by two metabolic equivalents (METs) or more, and those who lost weight were more likely to have reduced or no AF symptoms than those who improved by less than two METs or not at all.

Though increasing cardiorespiratory fitness seems to be beneficial, Dr. Michael Lloyd, a cardiologist at Emory University Hospital in Atlanta, Georgia, advises caution. "Overweight people should check with their doctor prior to embarking on any exercise program," said Lloyd, who was not involved in the study.

Sanders recommends a tailored exercise program, "in which consideration for age and physical ability should be made so that targets are achieved without risking injuries."

Dr. Waqas Qureshi, a cardiology researcher at Wake Forest University in Winston-Salem, North Carolina, who also was not involved in the study, noted that weight loss from exercise may add to the protection against heart irregularities.

Lloyd, however, emphasized that cardiorespiratory fitness is beneficial even apart from weight loss. "If you are overweight, it's not just the pounds that matter, it's how fit you are. This study shows that increasing your fitness through exercise and lifestyle choices does reduce your chance of having the most common arrhythmia."

(Reuters Health) - For overweight and obese people with atrial fibrillation, improving cardiorespiratory fitness with exercise may help to reduce or eliminate symptoms, a recent Australian study found.

Participants with the greatest improvements in their cardiorespiratory fitness were less burdened by symptoms of the arrhythmia and more likely to be symptom free during the study, compared to those who had smaller or no fitness improvements.

A possible side effect of the cardio exercise regimen, weight loss, may have also contributed to the improvements, researchers say.

Atrial fibrillation (AF) is a "growing epidemic" and obesity is a risk factor, the study's lead author Prash Sanders, director of the Center for Heart Rhythm Disorders at Royal Adelaide Hospital, told Reuters Health in an email.

The researchers examined the role of cardiorespiratory fitness and the incremental benefit of cardiorespiratory fitness improvement on rhythm control in 308 overweight and obese individuals with AF.

At the start of the study and four years later, participants completed questionnaires about their AF symptoms. The researchers also had patients wear a heart monitor for seven days at a time.

Based on baseline exercise stress testing, 95 people were classified as having low cardiorespiratory fitness, 134 had adequate fitness and 79 were classified as high fitness, Sanders and colleagues report in the Journal of the American College of Cardiology online June 22.

The research team prescribed the patients an exercise program tailored to their age and physical ability, which gradually increased in intensity.

By the end of four years, those who had increased their fitness levels by two metabolic equivalents (METs) or more, and those who lost weight were more likely to have reduced or no AF symptoms than those who improved by less than two METs or not at all.

Though increasing cardiorespiratory fitness seems to be beneficial, Dr. Michael Lloyd, a cardiologist at Emory University Hospital in Atlanta, Georgia, advises caution. "Overweight people should check with their doctor prior to embarking on any exercise program," said Lloyd, who was not involved in the study.

Sanders recommends a tailored exercise program, "in which consideration for age and physical ability should be made so that targets are achieved without risking injuries."

Dr. Waqas Qureshi, a cardiology researcher at Wake Forest University in Winston-Salem, North Carolina, who also was not involved in the study, noted that weight loss from exercise may add to the protection against heart irregularities.

Lloyd, however, emphasized that cardiorespiratory fitness is beneficial even apart from weight loss. "If you are overweight, it's not just the pounds that matter, it's how fit you are. This study shows that increasing your fitness through exercise and lifestyle choices does reduce your chance of having the most common arrhythmia."

Presenters: Allison Ballantine and Lisa Zaoutis

Physician burnout can be thought of as similar to water level in a reservoir during a drought – there is an imbalance between usage and replenishment. This leads to physician exhaustion, cynicism, and inefficiency. Burnout is a function of both the individual (younger, single, and less resilient are at higher risk) and the environment (high job demands with inadequate resources).

Burnout can affect:

• Job performance. With increased error rates, decreased cognitive function, decreased patient safety, and increased risk medmal litigation.
• Physician retention. A burned out physician is more likely to leave with subsequent practice disruption and cost.
• Physician health. Increased risk of depression, substance abuse, and suicidality.

Interventions can help prevent and mitigate burnout from both a personal and institutional perspective. Individuals can mitigate potential burnout through different strategies. These include having a strong support network and practicing mindfulness to decrease rumination about work related issues. Engaging in relaxing activities that provide reward with low effort as well as physical actions, such as ensuring private time with no calls, will lessen stresses.

Institutional efforts to decrease burnout need to focus on factors that address perceived fairness in the workplace, adequate financial compensation, social recognition, and an appropriate balance between responsibility and authority.

More resources can be found at the speakers’ website and through Christina Maslach, a leading researcher in the field.

Presenters: Allison Ballantine and Lisa Zaoutis

Physician burnout can be thought of as similar to water level in a reservoir during a drought – there is an imbalance between usage and replenishment. This leads to physician exhaustion, cynicism, and inefficiency. Burnout is a function of both the individual (younger, single, and less resilient are at higher risk) and the environment (high job demands with inadequate resources).

Burnout can affect:

• Job performance. With increased error rates, decreased cognitive function, decreased patient safety, and increased risk medmal litigation.
• Physician retention. A burned out physician is more likely to leave with subsequent practice disruption and cost.
• Physician health. Increased risk of depression, substance abuse, and suicidality.

Interventions can help prevent and mitigate burnout from both a personal and institutional perspective. Individuals can mitigate potential burnout through different strategies. These include having a strong support network and practicing mindfulness to decrease rumination about work related issues. Engaging in relaxing activities that provide reward with low effort as well as physical actions, such as ensuring private time with no calls, will lessen stresses.

Institutional efforts to decrease burnout need to focus on factors that address perceived fairness in the workplace, adequate financial compensation, social recognition, and an appropriate balance between responsibility and authority.

More resources can be found at the speakers’ website and through Christina Maslach, a leading researcher in the field.

Presenters: Allison Ballantine and Lisa Zaoutis

Physician burnout can be thought of as similar to water level in a reservoir during a drought – there is an imbalance between usage and replenishment. This leads to physician exhaustion, cynicism, and inefficiency. Burnout is a function of both the individual (younger, single, and less resilient are at higher risk) and the environment (high job demands with inadequate resources).

Burnout can affect:

• Job performance. With increased error rates, decreased cognitive function, decreased patient safety, and increased risk medmal litigation.
• Physician retention. A burned out physician is more likely to leave with subsequent practice disruption and cost.
• Physician health. Increased risk of depression, substance abuse, and suicidality.

Interventions can help prevent and mitigate burnout from both a personal and institutional perspective. Individuals can mitigate potential burnout through different strategies. These include having a strong support network and practicing mindfulness to decrease rumination about work related issues. Engaging in relaxing activities that provide reward with low effort as well as physical actions, such as ensuring private time with no calls, will lessen stresses.

Institutional efforts to decrease burnout need to focus on factors that address perceived fairness in the workplace, adequate financial compensation, social recognition, and an appropriate balance between responsibility and authority.

More resources can be found at the speakers’ website and through Christina Maslach, a leading researcher in the field.

Study authors Christian

Schürch, MD, PhD, (left)

and Adrian Ochsenbein, MD

Photo by Susi Bürki

Combining a tyrosine kinase inhibitor (TKI) with a monoclonal antibody (mAb) may circumvent TKI resistance in chronic myeloid leukemia (CML), according to preclinical research published in Science Translational Medicine.

To understand how TKI resistance develops, researchers analyzed the effect of these drugs on BCR-ABL1⁺ leukemia cell lines, cells from patients with newly diagnosed CML, and mouse models of CML.

The team found that TKIs induce CD70 expression in leukemic stem cells (LSCs) by downregulating microRNA-29. This results in reduced CD70 promoter DNA methylation and upregulation of the transcription factor specificity protein 1 (SP1).

The increase in CD70 triggers CD27 signaling and compensatory Wnt pathway activation. The researchers said this suggests LSCs evade TKIs by activating Wnt signaling through this route.

So the team hypothesized that combination treatment with a TKI and a mAb blocking the CD70/CD27 interaction would eradicate LSCs.

First, they tested an αCD27 mAb alone or in combination with a TKI in leukemia cell lines. Compared to either agent alone, αCD27/imatinib cotreatment significantly (P<0.001) reduced cell growth by inhibiting proliferation and enhancing apoptosis in SD-1 cells.

The researchers observed similar results when they tested the αCD27 mAb and nilotinib in SD-1 cells, as well as when they tested the αCD27 mAb with imatinib or ponatinib in KBM5 and KBM5r cells.

The team noted that αCD27/imatinib cotreatment inhibited Wnt pathway activation significantly stronger than either compound alone (P<0.001) but had little to no effect on Notch, Hedgehog, and MAP kinase pathways.

The researchers also conducted in vitro tests with an αCD70 mAb (clone 41D12-D) that was specifically designed to block the CD70/CD27 interaction without inducing effector functions such as antibody-dependent cell- or complement-mediated cytotoxicity and antibody-dependent cell-mediated phagocytosis.

They found that αCD70/imatinib cotreatment “potently reduced” CD34⁺ CML stem/progenitor cells in liquid cultures by inhibiting proliferation and increasing apoptosis. The combination also significantly impaired colony formation in semisolid cultures when compared to either agent alone (P<0.05).

In addition, αCD70/imatinib cotreatment eliminated human CD34⁺ CML stem/progenitor cells in murine xenografts. The LSCs were completely eradicated in 9 of 12 mice treated.

In a murine CML model, combination treatment with imatinib and an αCD70 mAb (clone FR70) significantly improved survival (P<0.001) compared to either agent alone. And 60% of mice (9 of 15) that received the combination were alive 90 days after transplantation.

The researchers said this suggests the LSCs were completely eradicated or at least effectively controlled long-term.

Study authors Christian

Schürch, MD, PhD, (left)

and Adrian Ochsenbein, MD

Photo by Susi Bürki

Combining a tyrosine kinase inhibitor (TKI) with a monoclonal antibody (mAb) may circumvent TKI resistance in chronic myeloid leukemia (CML), according to preclinical research published in Science Translational Medicine.

To understand how TKI resistance develops, researchers analyzed the effect of these drugs on BCR-ABL1⁺ leukemia cell lines, cells from patients with newly diagnosed CML, and mouse models of CML.

The team found that TKIs induce CD70 expression in leukemic stem cells (LSCs) by downregulating microRNA-29. This results in reduced CD70 promoter DNA methylation and upregulation of the transcription factor specificity protein 1 (SP1).

The increase in CD70 triggers CD27 signaling and compensatory Wnt pathway activation. The researchers said this suggests LSCs evade TKIs by activating Wnt signaling through this route.

So the team hypothesized that combination treatment with a TKI and a mAb blocking the CD70/CD27 interaction would eradicate LSCs.

First, they tested an αCD27 mAb alone or in combination with a TKI in leukemia cell lines. Compared to either agent alone, αCD27/imatinib cotreatment significantly (P<0.001) reduced cell growth by inhibiting proliferation and enhancing apoptosis in SD-1 cells.

The researchers observed similar results when they tested the αCD27 mAb and nilotinib in SD-1 cells, as well as when they tested the αCD27 mAb with imatinib or ponatinib in KBM5 and KBM5r cells.

The team noted that αCD27/imatinib cotreatment inhibited Wnt pathway activation significantly stronger than either compound alone (P<0.001) but had little to no effect on Notch, Hedgehog, and MAP kinase pathways.

The researchers also conducted in vitro tests with an αCD70 mAb (clone 41D12-D) that was specifically designed to block the CD70/CD27 interaction without inducing effector functions such as antibody-dependent cell- or complement-mediated cytotoxicity and antibody-dependent cell-mediated phagocytosis.

They found that αCD70/imatinib cotreatment “potently reduced” CD34⁺ CML stem/progenitor cells in liquid cultures by inhibiting proliferation and increasing apoptosis. The combination also significantly impaired colony formation in semisolid cultures when compared to either agent alone (P<0.05).

In addition, αCD70/imatinib cotreatment eliminated human CD34⁺ CML stem/progenitor cells in murine xenografts. The LSCs were completely eradicated in 9 of 12 mice treated.

In a murine CML model, combination treatment with imatinib and an αCD70 mAb (clone FR70) significantly improved survival (P<0.001) compared to either agent alone. And 60% of mice (9 of 15) that received the combination were alive 90 days after transplantation.

The researchers said this suggests the LSCs were completely eradicated or at least effectively controlled long-term.

Study authors Christian

Schürch, MD, PhD, (left)

and Adrian Ochsenbein, MD

Photo by Susi Bürki

Combining a tyrosine kinase inhibitor (TKI) with a monoclonal antibody (mAb) may circumvent TKI resistance in chronic myeloid leukemia (CML), according to preclinical research published in Science Translational Medicine.

To understand how TKI resistance develops, researchers analyzed the effect of these drugs on BCR-ABL1⁺ leukemia cell lines, cells from patients with newly diagnosed CML, and mouse models of CML.

The team found that TKIs induce CD70 expression in leukemic stem cells (LSCs) by downregulating microRNA-29. This results in reduced CD70 promoter DNA methylation and upregulation of the transcription factor specificity protein 1 (SP1).

The increase in CD70 triggers CD27 signaling and compensatory Wnt pathway activation. The researchers said this suggests LSCs evade TKIs by activating Wnt signaling through this route.

So the team hypothesized that combination treatment with a TKI and a mAb blocking the CD70/CD27 interaction would eradicate LSCs.

First, they tested an αCD27 mAb alone or in combination with a TKI in leukemia cell lines. Compared to either agent alone, αCD27/imatinib cotreatment significantly (P<0.001) reduced cell growth by inhibiting proliferation and enhancing apoptosis in SD-1 cells.

The researchers observed similar results when they tested the αCD27 mAb and nilotinib in SD-1 cells, as well as when they tested the αCD27 mAb with imatinib or ponatinib in KBM5 and KBM5r cells.

The team noted that αCD27/imatinib cotreatment inhibited Wnt pathway activation significantly stronger than either compound alone (P<0.001) but had little to no effect on Notch, Hedgehog, and MAP kinase pathways.

The researchers also conducted in vitro tests with an αCD70 mAb (clone 41D12-D) that was specifically designed to block the CD70/CD27 interaction without inducing effector functions such as antibody-dependent cell- or complement-mediated cytotoxicity and antibody-dependent cell-mediated phagocytosis.

They found that αCD70/imatinib cotreatment “potently reduced” CD34⁺ CML stem/progenitor cells in liquid cultures by inhibiting proliferation and increasing apoptosis. The combination also significantly impaired colony formation in semisolid cultures when compared to either agent alone (P<0.05).

In addition, αCD70/imatinib cotreatment eliminated human CD34⁺ CML stem/progenitor cells in murine xenografts. The LSCs were completely eradicated in 9 of 12 mice treated.

In a murine CML model, combination treatment with imatinib and an αCD70 mAb (clone FR70) significantly improved survival (P<0.001) compared to either agent alone. And 60% of mice (9 of 15) that received the combination were alive 90 days after transplantation.

The researchers said this suggests the LSCs were completely eradicated or at least effectively controlled long-term.

In a widely anticipated judgment on the Affordable Care Act (ACA), the US Supreme Court ruled 6-3 in favor of the law on June 26, 2015. The case at hand, King v. Burwell, challenged whether individuals purchasing health insurance through federal exchanges were eligible for federal premium subsidies. This ruling cemented the ACA into law and avoided a potential calamity in the private health insurance market. Let’s take a closer look.

What the case was about
The ACA allows states to set up their own health insurance exchanges or participate in a federally run exchange. Although the drafters of the ACA had expected each state to set up its own exchange, two-thirds of the states declined to do so, many in opposition to the ACA. As a result, 7 million citizens in 34 states now purchase their health ­insurance through federally created exchanges.

The plaintiffs in King v. Burwell argued that, because the legislation refers to those enrolled “through an Exchange established by the State,” individuals in states with federally run exchanges are not eligible for subsidies.

The law states:

The Supreme Court was asked to decide whether to adhere to those exact words or to honor Congress’ intent to allow individuals to purchase subsidized insurance on any type of exchange.

What might have happened
We’ve explored in previous articles the interconnectedness of many sections of the ACA. Nowhere is that interconnectedness more clearly demonstrated than here. In order to ensure that private health insurers provide better coverage, the law requires them to abide by important consumer protections, including the elimination of “preexisting condition” exclusions. In order to prevent adverse selection and keep insurers solvent under these new rules, all individuals are required to have health care coverage—the individual mandate. If everyone is required to purchase health insurance, it has to be affordable, so lower-income individuals were promised subsidies, paid for 100% by the federal government, to help them cover their premiums when insurance is purchased through an exchange. Take away the subsidies and the whole thing starts to unravel.

The Urban Institute estimated that a Supreme Court ruling in favor of King, which would have eliminated the subsidies in states using a federal exchange, would have reduced federal tax subsidies by $29 billion in 2016, making coverage unaffordable for many and increasing the ranks of the uninsured by 8.2 million people.¹

Louise Sheiner and Brendan Mochoruk of the Brookings Institute speculated that healthy individuals would disproportionately leave the marketplace, triggering 35% increases in insurance premiums for those remaining, as well as significant increases in premiums for those who just lost their subsidies.² Many observers, including these experts, forecast that insurance companies would exit the federal exchanges altogether, triggering a health insurance “death spiral”: As premiums rise, the healthiest customers leave the marketplace, causing premiums to rise more, causing more healthy people to leave, and so on.

Clearly, this Supreme Court decision has had dramatic, long-term, real-world effects on millions of Americans. On the national level, 6,387,789 individuals were at risk of losing their tax credits if the Supreme Court had ruled in favor of King. That number represents more than $1.7 billion in total monthly tax credits. For a look at how a judgment in favor of King would have affected subsidies on a state-by-state basis, see TABLE 1.

How premium subsidies work
Premium subsidies are actually tax credits. Individuals and families can qualify for them to purchase any type of health insurance offered on an exchange, except catastrophic coverage. To receive the premium tax credit for coverage starting in 2015, a marketplace enrollee must:

The premium tax credit caps the amount that an individual or family must spend on their monthly payments for health insurance. The cap depends on the family’s income; lower-income families have a lower cap. The amount of the tax credit remains the same, so a person who purchases a more expensive plan pays the cost difference (TABLE 2).

The ruling’s effect on women’s health
On June 26, American College of Obstetricians and Gynecologists President Mark S. DeFrancesco, MD, MBA, hailed the Supreme Court decision, saying, “Importantly, recent data have shown that newly insured adults under the ACA were more likely to be ­women. Those who did gain coverage through the ACA reported better access to health care and better financial security from medical costs.”

“Without question, many women enrollees were able to purchase health insurance coverage due, in part, to the ACA subsidies that helped make this purchase affordable. In fact, government data have suggested that roughly 85% of health exchange enrollees received subsidies,” Dr. DeFrancesco said.

“If the Supreme Court had overturned this important assistance, approximately 4.8 million women would have been unable to afford the coverage that they need. The impact also would have been widespread; as these women were forced to leave the insurance marketplace, it is likely that premiums throughout the marketplace would have risen dramatically,” he continued.

“Instead, patients—especially the low- and moderate-income American women who have particularly benefited from ACA subsidies—will continue to have the peace of mind that comes with insurance coverage.”

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In a widely anticipated judgment on the Affordable Care Act (ACA), the US Supreme Court ruled 6-3 in favor of the law on June 26, 2015. The case at hand, King v. Burwell, challenged whether individuals purchasing health insurance through federal exchanges were eligible for federal premium subsidies. This ruling cemented the ACA into law and avoided a potential calamity in the private health insurance market. Let’s take a closer look.

What the case was about
The ACA allows states to set up their own health insurance exchanges or participate in a federally run exchange. Although the drafters of the ACA had expected each state to set up its own exchange, two-thirds of the states declined to do so, many in opposition to the ACA. As a result, 7 million citizens in 34 states now purchase their health ­insurance through federally created exchanges.

The plaintiffs in King v. Burwell argued that, because the legislation refers to those enrolled “through an Exchange established by the State,” individuals in states with federally run exchanges are not eligible for subsidies.

The law states:

The Supreme Court was asked to decide whether to adhere to those exact words or to honor Congress’ intent to allow individuals to purchase subsidized insurance on any type of exchange.

What might have happened
We’ve explored in previous articles the interconnectedness of many sections of the ACA. Nowhere is that interconnectedness more clearly demonstrated than here. In order to ensure that private health insurers provide better coverage, the law requires them to abide by important consumer protections, including the elimination of “preexisting condition” exclusions. In order to prevent adverse selection and keep insurers solvent under these new rules, all individuals are required to have health care coverage—the individual mandate. If everyone is required to purchase health insurance, it has to be affordable, so lower-income individuals were promised subsidies, paid for 100% by the federal government, to help them cover their premiums when insurance is purchased through an exchange. Take away the subsidies and the whole thing starts to unravel.

The Urban Institute estimated that a Supreme Court ruling in favor of King, which would have eliminated the subsidies in states using a federal exchange, would have reduced federal tax subsidies by $29 billion in 2016, making coverage unaffordable for many and increasing the ranks of the uninsured by 8.2 million people.¹

Louise Sheiner and Brendan Mochoruk of the Brookings Institute speculated that healthy individuals would disproportionately leave the marketplace, triggering 35% increases in insurance premiums for those remaining, as well as significant increases in premiums for those who just lost their subsidies.² Many observers, including these experts, forecast that insurance companies would exit the federal exchanges altogether, triggering a health insurance “death spiral”: As premiums rise, the healthiest customers leave the marketplace, causing premiums to rise more, causing more healthy people to leave, and so on.

Clearly, this Supreme Court decision has had dramatic, long-term, real-world effects on millions of Americans. On the national level, 6,387,789 individuals were at risk of losing their tax credits if the Supreme Court had ruled in favor of King. That number represents more than $1.7 billion in total monthly tax credits. For a look at how a judgment in favor of King would have affected subsidies on a state-by-state basis, see TABLE 1.

How premium subsidies work
Premium subsidies are actually tax credits. Individuals and families can qualify for them to purchase any type of health insurance offered on an exchange, except catastrophic coverage. To receive the premium tax credit for coverage starting in 2015, a marketplace enrollee must:

The premium tax credit caps the amount that an individual or family must spend on their monthly payments for health insurance. The cap depends on the family’s income; lower-income families have a lower cap. The amount of the tax credit remains the same, so a person who purchases a more expensive plan pays the cost difference (TABLE 2).

The ruling’s effect on women’s health
On June 26, American College of Obstetricians and Gynecologists President Mark S. DeFrancesco, MD, MBA, hailed the Supreme Court decision, saying, “Importantly, recent data have shown that newly insured adults under the ACA were more likely to be ­women. Those who did gain coverage through the ACA reported better access to health care and better financial security from medical costs.”

“Without question, many women enrollees were able to purchase health insurance coverage due, in part, to the ACA subsidies that helped make this purchase affordable. In fact, government data have suggested that roughly 85% of health exchange enrollees received subsidies,” Dr. DeFrancesco said.

“If the Supreme Court had overturned this important assistance, approximately 4.8 million women would have been unable to afford the coverage that they need. The impact also would have been widespread; as these women were forced to leave the insurance marketplace, it is likely that premiums throughout the marketplace would have risen dramatically,” he continued.

“Instead, patients—especially the low- and moderate-income American women who have particularly benefited from ACA subsidies—will continue to have the peace of mind that comes with insurance coverage.”

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In a widely anticipated judgment on the Affordable Care Act (ACA), the US Supreme Court ruled 6-3 in favor of the law on June 26, 2015. The case at hand, King v. Burwell, challenged whether individuals purchasing health insurance through federal exchanges were eligible for federal premium subsidies. This ruling cemented the ACA into law and avoided a potential calamity in the private health insurance market. Let’s take a closer look.

What the case was about
The ACA allows states to set up their own health insurance exchanges or participate in a federally run exchange. Although the drafters of the ACA had expected each state to set up its own exchange, two-thirds of the states declined to do so, many in opposition to the ACA. As a result, 7 million citizens in 34 states now purchase their health ­insurance through federally created exchanges.

The plaintiffs in King v. Burwell argued that, because the legislation refers to those enrolled “through an Exchange established by the State,” individuals in states with federally run exchanges are not eligible for subsidies.

The law states:

The Supreme Court was asked to decide whether to adhere to those exact words or to honor Congress’ intent to allow individuals to purchase subsidized insurance on any type of exchange.

What might have happened
We’ve explored in previous articles the interconnectedness of many sections of the ACA. Nowhere is that interconnectedness more clearly demonstrated than here. In order to ensure that private health insurers provide better coverage, the law requires them to abide by important consumer protections, including the elimination of “preexisting condition” exclusions. In order to prevent adverse selection and keep insurers solvent under these new rules, all individuals are required to have health care coverage—the individual mandate. If everyone is required to purchase health insurance, it has to be affordable, so lower-income individuals were promised subsidies, paid for 100% by the federal government, to help them cover their premiums when insurance is purchased through an exchange. Take away the subsidies and the whole thing starts to unravel.

The Urban Institute estimated that a Supreme Court ruling in favor of King, which would have eliminated the subsidies in states using a federal exchange, would have reduced federal tax subsidies by $29 billion in 2016, making coverage unaffordable for many and increasing the ranks of the uninsured by 8.2 million people.¹

Louise Sheiner and Brendan Mochoruk of the Brookings Institute speculated that healthy individuals would disproportionately leave the marketplace, triggering 35% increases in insurance premiums for those remaining, as well as significant increases in premiums for those who just lost their subsidies.² Many observers, including these experts, forecast that insurance companies would exit the federal exchanges altogether, triggering a health insurance “death spiral”: As premiums rise, the healthiest customers leave the marketplace, causing premiums to rise more, causing more healthy people to leave, and so on.

Clearly, this Supreme Court decision has had dramatic, long-term, real-world effects on millions of Americans. On the national level, 6,387,789 individuals were at risk of losing their tax credits if the Supreme Court had ruled in favor of King. That number represents more than $1.7 billion in total monthly tax credits. For a look at how a judgment in favor of King would have affected subsidies on a state-by-state basis, see TABLE 1.

How premium subsidies work
Premium subsidies are actually tax credits. Individuals and families can qualify for them to purchase any type of health insurance offered on an exchange, except catastrophic coverage. To receive the premium tax credit for coverage starting in 2015, a marketplace enrollee must:

The premium tax credit caps the amount that an individual or family must spend on their monthly payments for health insurance. The cap depends on the family’s income; lower-income families have a lower cap. The amount of the tax credit remains the same, so a person who purchases a more expensive plan pays the cost difference (TABLE 2).

The ruling’s effect on women’s health
On June 26, American College of Obstetricians and Gynecologists President Mark S. DeFrancesco, MD, MBA, hailed the Supreme Court decision, saying, “Importantly, recent data have shown that newly insured adults under the ACA were more likely to be ­women. Those who did gain coverage through the ACA reported better access to health care and better financial security from medical costs.”

“Without question, many women enrollees were able to purchase health insurance coverage due, in part, to the ACA subsidies that helped make this purchase affordable. In fact, government data have suggested that roughly 85% of health exchange enrollees received subsidies,” Dr. DeFrancesco said.

“If the Supreme Court had overturned this important assistance, approximately 4.8 million women would have been unable to afford the coverage that they need. The impact also would have been widespread; as these women were forced to leave the insurance marketplace, it is likely that premiums throughout the marketplace would have risen dramatically,” he continued.

“Instead, patients—especially the low- and moderate-income American women who have particularly benefited from ACA subsidies—will continue to have the peace of mind that comes with insurance coverage.”

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The presentation of a cesarean scar ectopic pregnancy can at times be daunting, especially without familiarity regarding its management. Women with cesarean scar ectopic pregnancy most often have no symptoms, although vaginal bleeding and abdominal pain can present. Upon visual diagnosis with transabdominal or transvaginal ultrasound, the preferred treatment method is direct injection of methotrexate into the gestational sac within the cesarean scar.

In this video, my colleagues review the indications and contraindications for direct injection of  methotrexate as well as alternative treatment methods for this type of nonviable pregnancy that is increasing in frequency (given the US cesarean delivery rate). Demonstrated is the technique for methotrexate injection in the case of a 34-year-old woman (G6P0232) with ultrasound and beta−human chorionic gonadotropin confirmation of cesarean scar ectopic pregnancy.

We hope this video serves as a useful reference in your practice.

Vidyard Video

 

Share your thoughts on this video! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The presentation of a cesarean scar ectopic pregnancy can at times be daunting, especially without familiarity regarding its management. Women with cesarean scar ectopic pregnancy most often have no symptoms, although vaginal bleeding and abdominal pain can present. Upon visual diagnosis with transabdominal or transvaginal ultrasound, the preferred treatment method is direct injection of methotrexate into the gestational sac within the cesarean scar.

In this video, my colleagues review the indications and contraindications for direct injection of  methotrexate as well as alternative treatment methods for this type of nonviable pregnancy that is increasing in frequency (given the US cesarean delivery rate). Demonstrated is the technique for methotrexate injection in the case of a 34-year-old woman (G6P0232) with ultrasound and beta−human chorionic gonadotropin confirmation of cesarean scar ectopic pregnancy.

We hope this video serves as a useful reference in your practice.

Vidyard Video

 

Share your thoughts on this video! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The presentation of a cesarean scar ectopic pregnancy can at times be daunting, especially without familiarity regarding its management. Women with cesarean scar ectopic pregnancy most often have no symptoms, although vaginal bleeding and abdominal pain can present. Upon visual diagnosis with transabdominal or transvaginal ultrasound, the preferred treatment method is direct injection of methotrexate into the gestational sac within the cesarean scar.

In this video, my colleagues review the indications and contraindications for direct injection of  methotrexate as well as alternative treatment methods for this type of nonviable pregnancy that is increasing in frequency (given the US cesarean delivery rate). Demonstrated is the technique for methotrexate injection in the case of a 34-year-old woman (G6P0232) with ultrasound and beta−human chorionic gonadotropin confirmation of cesarean scar ectopic pregnancy.

We hope this video serves as a useful reference in your practice.

Vidyard Video

 

Share your thoughts on this video! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Brilinta (ticagrelor) tablets

Photo courtesy of AstraZeneca

The US Food and Drug Administration (FDA) has announced that confusion between the anticoagulant Brilinta (ticagrelor) and the antidepressant Brintellix (vortioxetine) is resulting in the wrong medication being prescribed or dispensed.

The FDA found the main reason for the confusion is the similarity of the drugs’ brand names.

None of the reports the FDA received indicate that a patient ingested the wrong medication. However, the FDA continues to receive reports of prescribing and dispensing errors.

As of June 2015, the agency has received 50 reports of name confusion between Brintellix and Brilinta. The FDA confirmed that the wrong medication was dispensed to a patient in 12 of the cases and may have been dispensed in 3 additional cases.

About the medications

Brilinta is a P2Y₁₂ platelet inhibitor approved for use in patients with acute coronary syndrome to reduce the rate of thrombotic cardiovascular events. The drug comes in the form of a round, yellow tablet with a “90” above a “T” stamped on one side.

Brintellix is a selective serotonin reuptake inhibitor used to treat major depressive disorder in adults. The medication comes in the form of a tear-shaped tablet stamped with “TL” on one side of the tablet and a number that indicates the tablet strength on the other side. It varies in color depending upon the strength prescribed.

About the error reports

As of June 2015, the FDA has received 50 medication error reports describing brand name confusion with Brintellix (vortioxetine) and Brilinta (ticagrelor). In most cases, Brintellix was mistaken as Brilinta.

Some of the contributing factors to the name confusion included the following:

• Both brand names begin with the same 3 letters
• Both brand names are presented when selecting medications in a computerized physician order entry (CPOE) system
• The pharmacist was not familiar with the new medication Brintellix and so dispensed Brilinta
• The brand names look and sound similar.

Of these 50 reports, the wrong medication was actually dispensed in 12 cases and was possibly dispensed in 3 additional cases but could not be confirmed based on the case narrative information. None of the reports indicated a patient had ingested the wrong medication.

However, in one case, Brintellix was misinterpreted as Brilinta, and the pharmacist did not dispense any medication because the patient had a contraindication to antiplatelet therapy. As a result, the patient went untreated for the psychiatric indication for an unreported period.

In the 12 cases where a wrong medication was actually dispensed, the reports showed that, in 6 cases, the error occurred when prescribing the medication.

Five of these prescribing errors occurred during CPOE. Some CPOE systems auto-populate or present a drop-down menu after the first 3 letters are typed, at which point a prescriber can select the wrong medication.

In the other 6 cases, the error occurred during dispensing of the medication.

FDA recommendations

The FDA is recommending that healthcare professionals reduce the risk of name confusion when prescribing these medications by including the generic names, indications for use, correct dosage, and directions for use.

Healthcare professionals should also ensure that patients understand what their medication is used to treat and encourage patients and their caregivers to read the Medication Guides provided with their Brintellix and Brilinta prescriptions.

Healthcare professionals and patients can report name confusion and medication errors involving Brintellix and Brilinta to the FDA MedWatch Program.

Brilinta (ticagrelor) tablets

Photo courtesy of AstraZeneca

The US Food and Drug Administration (FDA) has announced that confusion between the anticoagulant Brilinta (ticagrelor) and the antidepressant Brintellix (vortioxetine) is resulting in the wrong medication being prescribed or dispensed.

The FDA found the main reason for the confusion is the similarity of the drugs’ brand names.

None of the reports the FDA received indicate that a patient ingested the wrong medication. However, the FDA continues to receive reports of prescribing and dispensing errors.

As of June 2015, the agency has received 50 reports of name confusion between Brintellix and Brilinta. The FDA confirmed that the wrong medication was dispensed to a patient in 12 of the cases and may have been dispensed in 3 additional cases.

About the medications

Brilinta is a P2Y₁₂ platelet inhibitor approved for use in patients with acute coronary syndrome to reduce the rate of thrombotic cardiovascular events. The drug comes in the form of a round, yellow tablet with a “90” above a “T” stamped on one side.

Brintellix is a selective serotonin reuptake inhibitor used to treat major depressive disorder in adults. The medication comes in the form of a tear-shaped tablet stamped with “TL” on one side of the tablet and a number that indicates the tablet strength on the other side. It varies in color depending upon the strength prescribed.

About the error reports

As of June 2015, the FDA has received 50 medication error reports describing brand name confusion with Brintellix (vortioxetine) and Brilinta (ticagrelor). In most cases, Brintellix was mistaken as Brilinta.

Some of the contributing factors to the name confusion included the following:

• Both brand names begin with the same 3 letters
• Both brand names are presented when selecting medications in a computerized physician order entry (CPOE) system
• The pharmacist was not familiar with the new medication Brintellix and so dispensed Brilinta
• The brand names look and sound similar.

Of these 50 reports, the wrong medication was actually dispensed in 12 cases and was possibly dispensed in 3 additional cases but could not be confirmed based on the case narrative information. None of the reports indicated a patient had ingested the wrong medication.

However, in one case, Brintellix was misinterpreted as Brilinta, and the pharmacist did not dispense any medication because the patient had a contraindication to antiplatelet therapy. As a result, the patient went untreated for the psychiatric indication for an unreported period.

In the 12 cases where a wrong medication was actually dispensed, the reports showed that, in 6 cases, the error occurred when prescribing the medication.

Five of these prescribing errors occurred during CPOE. Some CPOE systems auto-populate or present a drop-down menu after the first 3 letters are typed, at which point a prescriber can select the wrong medication.

In the other 6 cases, the error occurred during dispensing of the medication.

FDA recommendations

The FDA is recommending that healthcare professionals reduce the risk of name confusion when prescribing these medications by including the generic names, indications for use, correct dosage, and directions for use.

Healthcare professionals should also ensure that patients understand what their medication is used to treat and encourage patients and their caregivers to read the Medication Guides provided with their Brintellix and Brilinta prescriptions.

Healthcare professionals and patients can report name confusion and medication errors involving Brintellix and Brilinta to the FDA MedWatch Program.

Brilinta (ticagrelor) tablets

Photo courtesy of AstraZeneca

The US Food and Drug Administration (FDA) has announced that confusion between the anticoagulant Brilinta (ticagrelor) and the antidepressant Brintellix (vortioxetine) is resulting in the wrong medication being prescribed or dispensed.

The FDA found the main reason for the confusion is the similarity of the drugs’ brand names.

None of the reports the FDA received indicate that a patient ingested the wrong medication. However, the FDA continues to receive reports of prescribing and dispensing errors.

As of June 2015, the agency has received 50 reports of name confusion between Brintellix and Brilinta. The FDA confirmed that the wrong medication was dispensed to a patient in 12 of the cases and may have been dispensed in 3 additional cases.

About the medications

Brilinta is a P2Y₁₂ platelet inhibitor approved for use in patients with acute coronary syndrome to reduce the rate of thrombotic cardiovascular events. The drug comes in the form of a round, yellow tablet with a “90” above a “T” stamped on one side.

Brintellix is a selective serotonin reuptake inhibitor used to treat major depressive disorder in adults. The medication comes in the form of a tear-shaped tablet stamped with “TL” on one side of the tablet and a number that indicates the tablet strength on the other side. It varies in color depending upon the strength prescribed.

About the error reports

As of June 2015, the FDA has received 50 medication error reports describing brand name confusion with Brintellix (vortioxetine) and Brilinta (ticagrelor). In most cases, Brintellix was mistaken as Brilinta.

Some of the contributing factors to the name confusion included the following:

• Both brand names begin with the same 3 letters
• Both brand names are presented when selecting medications in a computerized physician order entry (CPOE) system
• The pharmacist was not familiar with the new medication Brintellix and so dispensed Brilinta
• The brand names look and sound similar.

Of these 50 reports, the wrong medication was actually dispensed in 12 cases and was possibly dispensed in 3 additional cases but could not be confirmed based on the case narrative information. None of the reports indicated a patient had ingested the wrong medication.

However, in one case, Brintellix was misinterpreted as Brilinta, and the pharmacist did not dispense any medication because the patient had a contraindication to antiplatelet therapy. As a result, the patient went untreated for the psychiatric indication for an unreported period.

In the 12 cases where a wrong medication was actually dispensed, the reports showed that, in 6 cases, the error occurred when prescribing the medication.

Five of these prescribing errors occurred during CPOE. Some CPOE systems auto-populate or present a drop-down menu after the first 3 letters are typed, at which point a prescriber can select the wrong medication.

In the other 6 cases, the error occurred during dispensing of the medication.

FDA recommendations

The FDA is recommending that healthcare professionals reduce the risk of name confusion when prescribing these medications by including the generic names, indications for use, correct dosage, and directions for use.

Healthcare professionals should also ensure that patients understand what their medication is used to treat and encourage patients and their caregivers to read the Medication Guides provided with their Brintellix and Brilinta prescriptions.

Healthcare professionals and patients can report name confusion and medication errors involving Brintellix and Brilinta to the FDA MedWatch Program.

Preparing drug capsules

for a clinical trial

Photo by Esther Dyson

Pharmaceutical companies “underinvest” in long-term research to develop new anticancer drugs, according to a study published in American Economic Review.

Investigators used historical data to show that companies are more likely to develop drugs for late-stage cancers than early stage cancers or cancer prevention, and this is likely because late-stage cancer drugs can be brought to market faster.

The team found that late-stage drugs extend patient survival for shorter periods so that clinical trials for these drugs get wrapped up more quickly. This, in turn, gives drug manufacturers more time to control patented drugs in the marketplace.

“There is a pattern where we get more investment in drugs that take a short time to complete and less investment in drugs that take a longer time to complete,” said study author Heidi Williams, PhD, of the Massachusetts Institute of Technology in Cambridge.

To conduct this study, Dr Williams and her colleagues analyzed 4 decades of clinical trial data from a variety of sources, including the National Cancer Institute and the US Food and Drug Administration. The study encompassed more than 200 subcategories of cancers detected at different stages of development.

In analyzing the data, the investigators divided research and development (R&D) into 2 stages: invention (developing the basic idea for a product to the point where it is patentable) and commercialization (bringing an invented product to market).

They defined the “commercialization lag” of an R&D project as the amount of time between invention and commercialization.

The data showed that patient groups with longer commercialization lags (as proxied by longer survival times) tended to have lower levels of R&D investment than groups with shorter commercialization lags (and survival times).

The investigators also found that when surrogate endpoints (endpoints other than survival) were allowed, there were more trials and money poured into research. This supports the idea that companies are more likely to invest in drugs that will have shorter trials and take less time to develop.

Dr Williams and her colleagues used the surrogate endpoint variation to estimate improvements in cancer survival rates that would have been observed if commercialization lags were reduced. The team estimated that, among US cancer patients diagnosed in 2003, longer commercialization lags resulted in around 890,000 lost life-years.

The investigators noted that commercialization lags reduce both public and private R&D investments, but they found the commercialization lag-R&D correlation is significantly more negative for privately financed trials than publicly financed trials.

The team said that, due to either excessive discounting or the fixed patent term, private incentives decline more rapidly than public incentives, which is what gives rise to the distortion.

Based on their findings, Dr Williams and her colleagues devised 3 new policy approaches that could potentially spark the development of more drugs for early stage cancers or cancer prevention.

The first is expanded use of surrogate endpoints or more research to determine if wider use of surrogate endpoints is valid.

A second possible policy change is more public funding of R&D for anticancer drugs, since such funding is free of short-term, private-sector shareholder pressure to produce returns.

A third potential new policy would be changing the terms of drug patents, which typically run from the time of patent filing to when the drug hits the market.

Preparing drug capsules

for a clinical trial

Photo by Esther Dyson

Pharmaceutical companies “underinvest” in long-term research to develop new anticancer drugs, according to a study published in American Economic Review.

Investigators used historical data to show that companies are more likely to develop drugs for late-stage cancers than early stage cancers or cancer prevention, and this is likely because late-stage cancer drugs can be brought to market faster.

The team found that late-stage drugs extend patient survival for shorter periods so that clinical trials for these drugs get wrapped up more quickly. This, in turn, gives drug manufacturers more time to control patented drugs in the marketplace.

“There is a pattern where we get more investment in drugs that take a short time to complete and less investment in drugs that take a longer time to complete,” said study author Heidi Williams, PhD, of the Massachusetts Institute of Technology in Cambridge.

To conduct this study, Dr Williams and her colleagues analyzed 4 decades of clinical trial data from a variety of sources, including the National Cancer Institute and the US Food and Drug Administration. The study encompassed more than 200 subcategories of cancers detected at different stages of development.

In analyzing the data, the investigators divided research and development (R&D) into 2 stages: invention (developing the basic idea for a product to the point where it is patentable) and commercialization (bringing an invented product to market).

They defined the “commercialization lag” of an R&D project as the amount of time between invention and commercialization.

The data showed that patient groups with longer commercialization lags (as proxied by longer survival times) tended to have lower levels of R&D investment than groups with shorter commercialization lags (and survival times).

The investigators also found that when surrogate endpoints (endpoints other than survival) were allowed, there were more trials and money poured into research. This supports the idea that companies are more likely to invest in drugs that will have shorter trials and take less time to develop.

Dr Williams and her colleagues used the surrogate endpoint variation to estimate improvements in cancer survival rates that would have been observed if commercialization lags were reduced. The team estimated that, among US cancer patients diagnosed in 2003, longer commercialization lags resulted in around 890,000 lost life-years.

The investigators noted that commercialization lags reduce both public and private R&D investments, but they found the commercialization lag-R&D correlation is significantly more negative for privately financed trials than publicly financed trials.

The team said that, due to either excessive discounting or the fixed patent term, private incentives decline more rapidly than public incentives, which is what gives rise to the distortion.

Based on their findings, Dr Williams and her colleagues devised 3 new policy approaches that could potentially spark the development of more drugs for early stage cancers or cancer prevention.

The first is expanded use of surrogate endpoints or more research to determine if wider use of surrogate endpoints is valid.

A second possible policy change is more public funding of R&D for anticancer drugs, since such funding is free of short-term, private-sector shareholder pressure to produce returns.

A third potential new policy would be changing the terms of drug patents, which typically run from the time of patent filing to when the drug hits the market.

Preparing drug capsules

for a clinical trial

Photo by Esther Dyson

Pharmaceutical companies “underinvest” in long-term research to develop new anticancer drugs, according to a study published in American Economic Review.

Investigators used historical data to show that companies are more likely to develop drugs for late-stage cancers than early stage cancers or cancer prevention, and this is likely because late-stage cancer drugs can be brought to market faster.

The team found that late-stage drugs extend patient survival for shorter periods so that clinical trials for these drugs get wrapped up more quickly. This, in turn, gives drug manufacturers more time to control patented drugs in the marketplace.

“There is a pattern where we get more investment in drugs that take a short time to complete and less investment in drugs that take a longer time to complete,” said study author Heidi Williams, PhD, of the Massachusetts Institute of Technology in Cambridge.

To conduct this study, Dr Williams and her colleagues analyzed 4 decades of clinical trial data from a variety of sources, including the National Cancer Institute and the US Food and Drug Administration. The study encompassed more than 200 subcategories of cancers detected at different stages of development.

In analyzing the data, the investigators divided research and development (R&D) into 2 stages: invention (developing the basic idea for a product to the point where it is patentable) and commercialization (bringing an invented product to market).

They defined the “commercialization lag” of an R&D project as the amount of time between invention and commercialization.

The data showed that patient groups with longer commercialization lags (as proxied by longer survival times) tended to have lower levels of R&D investment than groups with shorter commercialization lags (and survival times).

The investigators also found that when surrogate endpoints (endpoints other than survival) were allowed, there were more trials and money poured into research. This supports the idea that companies are more likely to invest in drugs that will have shorter trials and take less time to develop.

Dr Williams and her colleagues used the surrogate endpoint variation to estimate improvements in cancer survival rates that would have been observed if commercialization lags were reduced. The team estimated that, among US cancer patients diagnosed in 2003, longer commercialization lags resulted in around 890,000 lost life-years.

The investigators noted that commercialization lags reduce both public and private R&D investments, but they found the commercialization lag-R&D correlation is significantly more negative for privately financed trials than publicly financed trials.

The team said that, due to either excessive discounting or the fixed patent term, private incentives decline more rapidly than public incentives, which is what gives rise to the distortion.

Based on their findings, Dr Williams and her colleagues devised 3 new policy approaches that could potentially spark the development of more drugs for early stage cancers or cancer prevention.

The first is expanded use of surrogate endpoints or more research to determine if wider use of surrogate endpoints is valid.

A second possible policy change is more public funding of R&D for anticancer drugs, since such funding is free of short-term, private-sector shareholder pressure to produce returns.

A third potential new policy would be changing the terms of drug patents, which typically run from the time of patent filing to when the drug hits the market.