Diabetes

Marijuana, which is still illegal under federal law but legal in 30 states for medical purposes as of this writing, has shown promising results for treating peripheral neuropathy. Studies suggest that cannabis may be an option for patients whose pain responds poorly to standard treatments; however, its use may be restricted by cognitive and psychiatric adverse effects, particularly at high doses.¹

See related editorial

In this article, we discuss the basic pharmacology of cannabis and how it may affect neuropathic pain. We review clinical trials on its use for peripheral neuropathy and provide guidance for its use.

PERIPHERAL NEUROPATHY IS COMMON AND COMPLEX

An estimated 20 million people in the United States suffer from neuropathic pain. The prevalence is higher in certain populations, with 26% of people over age 65 and 30% of patients with diabetes mellitus affected.^2–4

Peripheral neuropathy is a complex, chronic state that occurs when nerve fibers are damaged, dysfunctional, or injured, sending incorrect signals to pain centers in the central nervous system.⁵ It is characterized by weakness, pain, and paresthesias that typically begin in the hands or feet and progress proximally.⁴ Symptoms depend on the number and types of nerves affected.

In many cases, peripheral neuropathy is idiopathic, but common causes include diabetes, alcoholism, human immunodeficiency virus (HIV) infection, and autoimmune disease. Others include toxicity from chemotherapy and heavy metals.

Peripheral neuropathy significantly worsens quality of life and function. Many patients experience emotional, cognitive, and functional problems, resulting in high rates of medical and psychiatric comorbidities and occupational impairment.^4,6,7 Yet despite its clinical and epidemiologic significance, it is often undertreated.⁸

STANDARD TREATMENTS INADEQUATE

Peripheral neuropathy occurs in patients with a wide range of comorbidities and is especially difficult to treat. Mainstays of therapy include anticonvulsants, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors.⁹ A more invasive option is spinal cord stimulation.

These treatments can have considerable adverse effects, and response rates remain suboptimal, with pain relief insufficient to improve quality of life for many patients.^9,10 Better treatments are needed to improve clinical outcomes and patient experience.¹¹

CANNABIS: A MIX OF COMPOUNDS

Cannabis sativa has been used as an analgesic for centuries. The plant contains more than 400 chemical compounds and is often used for its euphoric properties. Long-term use may lead to addiction and cognitive impairment.^12,13

Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the main components and the 2 best-studied cannabinoids with analgesic effects.

THC is the primary psychoactive component of cannabis. Its effects include relaxation, altered perception, heightened sensations, increased libido, and perceptual distortions of time and space. Temporary effects may include decreased short-term memory, dry mouth, impaired motor function, conjunctival injection, paranoia, and anxiety.

CBD is nonpsychoactive and has anti-inflammatory and antioxidant properties. It has been shown to reduce pain and inflammation without the effects of THC.¹⁴

Other compounds in the cannabis plant include phytocannabinoids, flavonoids, and tapenoids, which may produce individual, interactive, or synergistic effects.¹⁵ Different strains of cannabis have varying amounts of the individual components, making comparisons among clinical studies difficult.

THE ENDOCANNABINOID SYSTEM

The endogenous mammalian cannabinoid system plays a regulatory role in the development, homeostasis, and neuroplasticity of the central nervous system. It is also involved in modulating pain transmission in the nociceptive pathway.

Two of the most abundant cannabinoid endogenous ligands are anandamide and 2-arachidonylglycerol.⁹ These endocanna­b­inoids are produced on demand in the central nervous system to reduce pain by acting as a circuit breaker.^16–18 They target the G protein-coupled cannabinoid receptors CB1 and CB2, located throughout the central and peripheral nervous system and in organs and tissues.¹²

CB1 receptors are found primarily in the central nervous system, specifically in areas involved in movement, such as the basal ganglia and cerebellum, as well as in areas involved in memory, such as the hippocampus.¹² They are also abundant in brain regions implicated in conducting and modulating pain signals, including the periaqueductal gray and the dorsal horn of the spinal cord.^16–20

CB2 receptors are mostly found in peripheral tissues and organs, mainly those involved in the immune system, including splenic, tonsillar, and hematopoietic cells.¹² They help regulate inflammation, allodynia, and hyperalgesia.¹⁷

Modifying response to injury

Following a nerve injury, neurons along the nociceptive pathway may become more reactive and responsive in a process known as sensitization.²¹ The process involves a cascade of cellular events that result in sprouting of pain-sensitive nerve endings.^21,22

Cannabinoids are thought to reduce pain by modifying these cellular events. They also inhibit nociceptive conduction in the dorsal horn of the spinal cord and in the ascending spinothalamic tract.²⁰ CB1 receptors found in nociceptive terminals along the peripheral nervous system impede pain conduction, while activation of CB2 receptors in immune cells decreases the release of nociceptive agents.

A number of studies have evaluated cannabis for treating neuropathic pain. Overall, available data support the efficacy of smoked or inhaled cannabis in its flower form when used as monotherapy or adjunctive therapy for relief of neuropathic pain of various etiologies. Many studies also report secondary benefits, including better sleep and functional improvement.^23,24

However, adverse effects are common, especially at high doses, and include difficulty concentrating, lightheadedness, fatigue, and tachycardia. More serious reported adverse effects include anxiety, paranoia, and psychosis.

Wilsey et al, 2008: Neuropathic pain reduced

Wilsey et al²⁵ conducted a double-blind, placebo-controlled crossover study that assessed the effects of smoking cannabis in 38 patients with central or peripheral neuropathic pain. Participants were assigned to smoke either high- or low-dose cannabis (7% or 3.5% delta-9-THC) or placebo cigarettes. Cigarettes were smoked during treatment sessions using the following regimen: 2 puffs at 60 minutes from baseline, 3 puffs at 120 minutes, and 4 puffs at 180 minutes. Patients were assessed after each set of puffs and for 2 hours afterwards. The primary outcome was spontaneous relief of pain as measured by a visual analog scale.

Pain intensity was comparable and significantly reduced in both treatment groups compared with placebo. At the high dose, some participants experienced neurocognitive impairment in attention, learning, memory, and psychomotor speed; only learning and memory declined at the low dose.

Ellis et al, 2009: Pain reduction in HIV neuropathy

Ellis et al²³ conducted a double-blind, placebo-controlled crossover trial in patients with HIV neuropathy that was unresponsive to at least 2 analgesics with different modes of action. During each treatment week, participants were randomly assigned to smoke either active cannabis or placebo, while continuing their standard therapy. Titration started at 4% THC and was adjusted based on tolerability and efficacy. Twenty-eight of the 34 enrolled patients completed both cannabis and placebo treatments. The principal outcome was change in pain intensity from baseline at the end of each week, using the Descriptor Differential Scale of Pain Intensity.

Of the 28 patients, 46% achieved an average pain reduction of 3.3 points (30%). One patient experienced cannabis-induced psychosis, and another developed an intractable cough, which resolved with smoking cessation.

Ware et al, 2010: Reduced posttraumatic or postsurgical neuropathic pain

Ware et al²⁴ performed a randomized crossover trial in 21 patients with posttraumatic or postsurgical neuropathic pain. Participants inhaled 4 different formulations of cannabis (containing 0%, 2.5%, 6.0%, and 9.4% THC) during 4 14-day periods. They inhaled a 25-mg dose through a pipe 3 times a day for the first 5 days of each cycle, followed by a 9-day washout period. Daily average pain intensity was measured using a numeric rating scale. The investigators also assessed mood, sleep, quality of life, and adverse effects.

Patients in the 9.4% THC group reported significantly less pain and better sleep, with average pain scores decreasing from 6.1 to 5.4 on an 11-point scale. Although the benefit was modest, the authors noted that the pain had been refractory to standard treatments.

The number of reported adverse events increased with greater potency and were most commonly throat irritation, burning sensation, headache, dizziness, and fatigue. This study suggests that THC potency affects tolerability, with higher doses eliciting clinically important adverse effects, some of which may reduce the ability to perform activities of daily living, such as driving.

Wilsey et al, 2013: Use in resistant neuropathic pain

Wilsey et al²⁶ conducted another double-blind, placebo-controlled crossover study assessing the effect of vaporized cannabis on central and peripheral neuropathic pain resistant to first-line pharmacotherapies. Dose-effect relationships were explored using medium-dose (3.5%), low-dose (1.3%), and placebo cannabis. The primary outcome measure was a 30% reduction in pain intensity based on a visual analog scale.

In the placebo group, 26% of patients achieved this vs 57% of the low-dose cannabis group and 61% of those receiving the medium dose. No significant difference was found between the 2 active doses in reducing neuropathic pain, and both were more effective than placebo. The number needed to treat to achieve a 30% reduction in pain was about 3 for both cannabis groups compared with placebo. Psychoactive effects were minimal, of short duration, and reversible.

Wallace et al, 2015: Use in diabetic peripheral neuropathy

Wallace et al²⁷ conducted a randomized, double-blind, placebo-controlled crossover study evaluating cannabis for diabetic peripheral neuropathy in 16 patients. Each had experienced at least 6 months of neuropathic pain in their feet. The participants inhaled a single dose of 1%, 4%, or 7% THC cannabis or placebo. Spontaneous pain was reported with a visual analog scale and also tested with a foam brush and von Frey filament at intervals until 4 hours after treatment.

Pain scores were lower with treatment compared with placebo, with high-dose cannabis having the greatest analgesic effect. Pain reduction lasted for the full duration of the test. Cannabis recipients had declines in attention and working memory, with the high-dose group experiencing the greatest impact 15 minutes after treatment. High-dose recipients also had poorer scores on testing of quick task-switching, with the greatest effect at 2 hours.²⁷

Research and market cannabis are not equal

Results of US studies must be qualified. Most have used cannabis provided by the National Institute of Drug Abuse (NIDA),^23–26 which differs in potency from commercially available preparations. This limits the clinical usefulness of the analysis of benefits and risks.

Vergara et al²⁸ found that NIDA varieties contained much lower THC levels and as much as 23 times the cannabinol content as cannabis in state-legalized markets.

Studies based on NIDA varieties likely underestimate the risks of consumer-purchased cannabis, as THC is believed to be most responsible for the risk of psychosis and impaired driving and cognition.^24,28

Studies of CBD alone are limited to preclinical data.²⁹ Evidence suggests that CBD alone or combined with THC can suppress chronic neuropathic pain, and that CBD may have a protective effect after nerve injury.³⁰

Nabiximols, an oromucosal spray preparation with equal amounts of THC and CBD, has been approved in Canada as well as in European countries including the United Kingdom. Although its use has not been associated with many of the adverse effects of inhaled cannabis,^30–32 evidence of efficacy from clinical trials has been mixed.

Lynch et al,³¹ in a 2014 randomized, double-blind, placebo-controlled crossover pilot study³¹ evaluated nabiximols in 16 patients with neuropathic pain related to chemotherapy. No statistically significant difference was found between treatment and placebo. However, the trial was underpowered.

Serpell et al,³² in a 2014 European randomized, placebo-controlled parallel-group study, evaluated 246 patients with peripheral neuropathy with allodynia, with 128 receiving active treatment (THC-CBD oromucosal spray) and 118 receiving placebo. Over the 15-week study, participants continued their current analgesic treatments.

Pain was reduced in the treatment group, but the difference from placebo was not statistically significant. However, the treatment group reported significantly better sleep quality and Patient Global Impression of Change measures (reflecting a patient’s belief of treatment efficacy).

META-ANALYSES CONFIRM EFFECT

Three meta-analyses of available studies of the effects of cannabis on neuropathic pain have been completed.

Andreae et al, 2015: 5 trials, 178 patients

Andreae et al¹ evaluated 5 randomized controlled trials in 178 patients in North America. All had had neuropathy for at least 3 months, with a pain level of at least about 3 on a scale of 10. Two studies had patients with HIV-related neuropathy; the other 3 involved patients with neuropathy related to trauma, diabetes, complex regional pain syndrome, or spinal cord injury. All trials used whole cannabis plant provided by NIDA, and the main outcomes were patient-reported pain scales. No study evaluated pain beyond 2 weeks after trial termination.

They found that 1 of every 5 to 6 patients treated with cannabis had at least a 30% pain reduction.

Nugent et al, 2017: 13 trials, 246 patients

Nugent et al³³ reviewed 13 trials in 246 patients that evaluated the effects of different cannabis-based preparations on either central or peripheral neuropathic pain from various conditions. Actively treated patients were more likely to report a 30% improvement in neuropathic pain. Again, studies tended to be small and brief.

Cochrane review, 2018: 16 trials, 1,750 patients

A Cochrane review³⁴ analyzed 16 trials (in 1,750 patients) lasting 2 to 26 weeks. Treatments included an oromucosal spray with a plant-derived combination of THC and CBD, nabilone, inhaled herbal cannabis, and plant-derived THC.

With cannabis-based treatments, significantly more people achieved 50% or greater pain relief than with placebo (21% vs 17%, number needed to treat 20); 30% pain reduction was achieved in 39% of treated patients vs 33% of patients taking placebo (number needed to treat 11).

On the other hand, significantly more participants withdrew from studies because of adverse events with cannabis-based treatments than placebo (10% vs 5%), with psychiatric disorders occurring in 17% of patients receiving active treatment vs 5% of those receiving placebo (number needed to harm 10). 

The primary studies suffered from methodologic limitations including small size, short duration, and inconsistency of formulations and study designs. Further evaluation of long-term efficacy, tolerability, and addiction potential is critical to determine the risk-benefit ratio.

RISKS OF CANNABIS USE

Like any drug therapy, cannabis has effects that may limit its use. Cannabis can affect a person’s psyche, physiology, and lifestyle.

Impaired attention, task speed

Neurocognitive changes associated with cannabis use—especially dizziness, fatigue, and slowed task-switching—could affect driving and other complex tasks. Evidence indicates that such activities should be avoided in the hours after treatment.^26,27,32,33

Concern over brain development

Most worrisome is the effect of long-term cannabis use on brain development in young adults. Regular use of cannabis at an early age is associated with lower IQ, decline in school performance, and lower rates of high school graduation.³⁵

Avoid in psychiatric patients

It is unlikely that cannabis can be safely used in patients with psychiatric illnesses. Anxiety, depression, and psychotic disorders can be exacerbated by the regular use of cannabis, and the risk of developing these conditions is increased while using cannabis.^36,37

High concentrations of THC (the highest concentration used in the above studies was 9.5%) can cause anxiety, paranoia, and psychosis.

Respiratory effects

Long-term cannabis smoking may cause wheezing, cough, dyspnea, and exacerbations of chronic bronchitis. There is some evidence that symptoms improve after stopping smoking.^33,38

SHOULD WE RECOMMEND CANNABIS?

Where cannabis can be legally used, doctors should be familiar with the literature and its limitations so that they can counsel patients on the best use and potential risks and benefits of cannabis treatment.

A recent conceptualization of pain suggests that a pain score reflects a composite of sensory factors (eg, tissue damage), cognitive factors (eg, beliefs about pain), and affective factors (eg, anxiety, depression).³⁹ Physicians should keep this in mind when evaluating patients to better assess the risks and benefits of cannabis. While pharmacotherapy may address sensory factors, cognitive behavioral therapy may help alter beliefs about the pain as well as anxiety and depressive symptoms that might influence subjective reports.

Ideally, patients being considered for cannabis treatment would have a type of neuropathic pain proven to respond to cannabis in randomized, controlled studies, as well as evidence of failed first-line treatments.

Relative contraindications include depression, anxiety, substance use, psychotic disorders, and respiratory conditions, and these should also be considered.

Although current research shows an analgesic benefit of cannabis on neuropathic pain comparable to that of gabapentin,⁴⁰ further investigation is needed to better evaluate long-term safety, efficacy, and interactions with standard therapies. Until we have a more complete picture, we should use the current literature, along with a thorough knowledge of each patient, to determine if the benefits of cannabis therapy outweigh the risks.

Acknowledgments: We thank Camillo Ferrari, BS, and Christina McMahon, BA, for their helpful comments.

Marijuana, which is still illegal under federal law but legal in 30 states for medical purposes as of this writing, has shown promising results for treating peripheral neuropathy. Studies suggest that cannabis may be an option for patients whose pain responds poorly to standard treatments; however, its use may be restricted by cognitive and psychiatric adverse effects, particularly at high doses.¹

See related editorial

In this article, we discuss the basic pharmacology of cannabis and how it may affect neuropathic pain. We review clinical trials on its use for peripheral neuropathy and provide guidance for its use.

PERIPHERAL NEUROPATHY IS COMMON AND COMPLEX

An estimated 20 million people in the United States suffer from neuropathic pain. The prevalence is higher in certain populations, with 26% of people over age 65 and 30% of patients with diabetes mellitus affected.^2–4

Peripheral neuropathy is a complex, chronic state that occurs when nerve fibers are damaged, dysfunctional, or injured, sending incorrect signals to pain centers in the central nervous system.⁵ It is characterized by weakness, pain, and paresthesias that typically begin in the hands or feet and progress proximally.⁴ Symptoms depend on the number and types of nerves affected.

In many cases, peripheral neuropathy is idiopathic, but common causes include diabetes, alcoholism, human immunodeficiency virus (HIV) infection, and autoimmune disease. Others include toxicity from chemotherapy and heavy metals.

Peripheral neuropathy significantly worsens quality of life and function. Many patients experience emotional, cognitive, and functional problems, resulting in high rates of medical and psychiatric comorbidities and occupational impairment.^4,6,7 Yet despite its clinical and epidemiologic significance, it is often undertreated.⁸

STANDARD TREATMENTS INADEQUATE

Peripheral neuropathy occurs in patients with a wide range of comorbidities and is especially difficult to treat. Mainstays of therapy include anticonvulsants, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors.⁹ A more invasive option is spinal cord stimulation.

These treatments can have considerable adverse effects, and response rates remain suboptimal, with pain relief insufficient to improve quality of life for many patients.^9,10 Better treatments are needed to improve clinical outcomes and patient experience.¹¹

CANNABIS: A MIX OF COMPOUNDS

Cannabis sativa has been used as an analgesic for centuries. The plant contains more than 400 chemical compounds and is often used for its euphoric properties. Long-term use may lead to addiction and cognitive impairment.^12,13

Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the main components and the 2 best-studied cannabinoids with analgesic effects.

THC is the primary psychoactive component of cannabis. Its effects include relaxation, altered perception, heightened sensations, increased libido, and perceptual distortions of time and space. Temporary effects may include decreased short-term memory, dry mouth, impaired motor function, conjunctival injection, paranoia, and anxiety.

CBD is nonpsychoactive and has anti-inflammatory and antioxidant properties. It has been shown to reduce pain and inflammation without the effects of THC.¹⁴

Other compounds in the cannabis plant include phytocannabinoids, flavonoids, and tapenoids, which may produce individual, interactive, or synergistic effects.¹⁵ Different strains of cannabis have varying amounts of the individual components, making comparisons among clinical studies difficult.

THE ENDOCANNABINOID SYSTEM

The endogenous mammalian cannabinoid system plays a regulatory role in the development, homeostasis, and neuroplasticity of the central nervous system. It is also involved in modulating pain transmission in the nociceptive pathway.

Two of the most abundant cannabinoid endogenous ligands are anandamide and 2-arachidonylglycerol.⁹ These endocanna­b­inoids are produced on demand in the central nervous system to reduce pain by acting as a circuit breaker.^16–18 They target the G protein-coupled cannabinoid receptors CB1 and CB2, located throughout the central and peripheral nervous system and in organs and tissues.¹²

CB1 receptors are found primarily in the central nervous system, specifically in areas involved in movement, such as the basal ganglia and cerebellum, as well as in areas involved in memory, such as the hippocampus.¹² They are also abundant in brain regions implicated in conducting and modulating pain signals, including the periaqueductal gray and the dorsal horn of the spinal cord.^16–20

CB2 receptors are mostly found in peripheral tissues and organs, mainly those involved in the immune system, including splenic, tonsillar, and hematopoietic cells.¹² They help regulate inflammation, allodynia, and hyperalgesia.¹⁷

Modifying response to injury

Following a nerve injury, neurons along the nociceptive pathway may become more reactive and responsive in a process known as sensitization.²¹ The process involves a cascade of cellular events that result in sprouting of pain-sensitive nerve endings.^21,22

Cannabinoids are thought to reduce pain by modifying these cellular events. They also inhibit nociceptive conduction in the dorsal horn of the spinal cord and in the ascending spinothalamic tract.²⁰ CB1 receptors found in nociceptive terminals along the peripheral nervous system impede pain conduction, while activation of CB2 receptors in immune cells decreases the release of nociceptive agents.

A number of studies have evaluated cannabis for treating neuropathic pain. Overall, available data support the efficacy of smoked or inhaled cannabis in its flower form when used as monotherapy or adjunctive therapy for relief of neuropathic pain of various etiologies. Many studies also report secondary benefits, including better sleep and functional improvement.^23,24

However, adverse effects are common, especially at high doses, and include difficulty concentrating, lightheadedness, fatigue, and tachycardia. More serious reported adverse effects include anxiety, paranoia, and psychosis.

Wilsey et al, 2008: Neuropathic pain reduced

Wilsey et al²⁵ conducted a double-blind, placebo-controlled crossover study that assessed the effects of smoking cannabis in 38 patients with central or peripheral neuropathic pain. Participants were assigned to smoke either high- or low-dose cannabis (7% or 3.5% delta-9-THC) or placebo cigarettes. Cigarettes were smoked during treatment sessions using the following regimen: 2 puffs at 60 minutes from baseline, 3 puffs at 120 minutes, and 4 puffs at 180 minutes. Patients were assessed after each set of puffs and for 2 hours afterwards. The primary outcome was spontaneous relief of pain as measured by a visual analog scale.

Pain intensity was comparable and significantly reduced in both treatment groups compared with placebo. At the high dose, some participants experienced neurocognitive impairment in attention, learning, memory, and psychomotor speed; only learning and memory declined at the low dose.

Ellis et al, 2009: Pain reduction in HIV neuropathy

Ellis et al²³ conducted a double-blind, placebo-controlled crossover trial in patients with HIV neuropathy that was unresponsive to at least 2 analgesics with different modes of action. During each treatment week, participants were randomly assigned to smoke either active cannabis or placebo, while continuing their standard therapy. Titration started at 4% THC and was adjusted based on tolerability and efficacy. Twenty-eight of the 34 enrolled patients completed both cannabis and placebo treatments. The principal outcome was change in pain intensity from baseline at the end of each week, using the Descriptor Differential Scale of Pain Intensity.

Of the 28 patients, 46% achieved an average pain reduction of 3.3 points (30%). One patient experienced cannabis-induced psychosis, and another developed an intractable cough, which resolved with smoking cessation.

Ware et al, 2010: Reduced posttraumatic or postsurgical neuropathic pain

Ware et al²⁴ performed a randomized crossover trial in 21 patients with posttraumatic or postsurgical neuropathic pain. Participants inhaled 4 different formulations of cannabis (containing 0%, 2.5%, 6.0%, and 9.4% THC) during 4 14-day periods. They inhaled a 25-mg dose through a pipe 3 times a day for the first 5 days of each cycle, followed by a 9-day washout period. Daily average pain intensity was measured using a numeric rating scale. The investigators also assessed mood, sleep, quality of life, and adverse effects.

Patients in the 9.4% THC group reported significantly less pain and better sleep, with average pain scores decreasing from 6.1 to 5.4 on an 11-point scale. Although the benefit was modest, the authors noted that the pain had been refractory to standard treatments.

The number of reported adverse events increased with greater potency and were most commonly throat irritation, burning sensation, headache, dizziness, and fatigue. This study suggests that THC potency affects tolerability, with higher doses eliciting clinically important adverse effects, some of which may reduce the ability to perform activities of daily living, such as driving.

Wilsey et al, 2013: Use in resistant neuropathic pain

Wilsey et al²⁶ conducted another double-blind, placebo-controlled crossover study assessing the effect of vaporized cannabis on central and peripheral neuropathic pain resistant to first-line pharmacotherapies. Dose-effect relationships were explored using medium-dose (3.5%), low-dose (1.3%), and placebo cannabis. The primary outcome measure was a 30% reduction in pain intensity based on a visual analog scale.

In the placebo group, 26% of patients achieved this vs 57% of the low-dose cannabis group and 61% of those receiving the medium dose. No significant difference was found between the 2 active doses in reducing neuropathic pain, and both were more effective than placebo. The number needed to treat to achieve a 30% reduction in pain was about 3 for both cannabis groups compared with placebo. Psychoactive effects were minimal, of short duration, and reversible.

Wallace et al, 2015: Use in diabetic peripheral neuropathy

Wallace et al²⁷ conducted a randomized, double-blind, placebo-controlled crossover study evaluating cannabis for diabetic peripheral neuropathy in 16 patients. Each had experienced at least 6 months of neuropathic pain in their feet. The participants inhaled a single dose of 1%, 4%, or 7% THC cannabis or placebo. Spontaneous pain was reported with a visual analog scale and also tested with a foam brush and von Frey filament at intervals until 4 hours after treatment.

Pain scores were lower with treatment compared with placebo, with high-dose cannabis having the greatest analgesic effect. Pain reduction lasted for the full duration of the test. Cannabis recipients had declines in attention and working memory, with the high-dose group experiencing the greatest impact 15 minutes after treatment. High-dose recipients also had poorer scores on testing of quick task-switching, with the greatest effect at 2 hours.²⁷

Research and market cannabis are not equal

Results of US studies must be qualified. Most have used cannabis provided by the National Institute of Drug Abuse (NIDA),^23–26 which differs in potency from commercially available preparations. This limits the clinical usefulness of the analysis of benefits and risks.

Vergara et al²⁸ found that NIDA varieties contained much lower THC levels and as much as 23 times the cannabinol content as cannabis in state-legalized markets.

Studies based on NIDA varieties likely underestimate the risks of consumer-purchased cannabis, as THC is believed to be most responsible for the risk of psychosis and impaired driving and cognition.^24,28

Studies of CBD alone are limited to preclinical data.²⁹ Evidence suggests that CBD alone or combined with THC can suppress chronic neuropathic pain, and that CBD may have a protective effect after nerve injury.³⁰

Nabiximols, an oromucosal spray preparation with equal amounts of THC and CBD, has been approved in Canada as well as in European countries including the United Kingdom. Although its use has not been associated with many of the adverse effects of inhaled cannabis,^30–32 evidence of efficacy from clinical trials has been mixed.

Lynch et al,³¹ in a 2014 randomized, double-blind, placebo-controlled crossover pilot study³¹ evaluated nabiximols in 16 patients with neuropathic pain related to chemotherapy. No statistically significant difference was found between treatment and placebo. However, the trial was underpowered.

Serpell et al,³² in a 2014 European randomized, placebo-controlled parallel-group study, evaluated 246 patients with peripheral neuropathy with allodynia, with 128 receiving active treatment (THC-CBD oromucosal spray) and 118 receiving placebo. Over the 15-week study, participants continued their current analgesic treatments.

Pain was reduced in the treatment group, but the difference from placebo was not statistically significant. However, the treatment group reported significantly better sleep quality and Patient Global Impression of Change measures (reflecting a patient’s belief of treatment efficacy).

META-ANALYSES CONFIRM EFFECT

Three meta-analyses of available studies of the effects of cannabis on neuropathic pain have been completed.

Andreae et al, 2015: 5 trials, 178 patients

Andreae et al¹ evaluated 5 randomized controlled trials in 178 patients in North America. All had had neuropathy for at least 3 months, with a pain level of at least about 3 on a scale of 10. Two studies had patients with HIV-related neuropathy; the other 3 involved patients with neuropathy related to trauma, diabetes, complex regional pain syndrome, or spinal cord injury. All trials used whole cannabis plant provided by NIDA, and the main outcomes were patient-reported pain scales. No study evaluated pain beyond 2 weeks after trial termination.

They found that 1 of every 5 to 6 patients treated with cannabis had at least a 30% pain reduction.

Nugent et al, 2017: 13 trials, 246 patients

Nugent et al³³ reviewed 13 trials in 246 patients that evaluated the effects of different cannabis-based preparations on either central or peripheral neuropathic pain from various conditions. Actively treated patients were more likely to report a 30% improvement in neuropathic pain. Again, studies tended to be small and brief.

Cochrane review, 2018: 16 trials, 1,750 patients

A Cochrane review³⁴ analyzed 16 trials (in 1,750 patients) lasting 2 to 26 weeks. Treatments included an oromucosal spray with a plant-derived combination of THC and CBD, nabilone, inhaled herbal cannabis, and plant-derived THC.

With cannabis-based treatments, significantly more people achieved 50% or greater pain relief than with placebo (21% vs 17%, number needed to treat 20); 30% pain reduction was achieved in 39% of treated patients vs 33% of patients taking placebo (number needed to treat 11).

On the other hand, significantly more participants withdrew from studies because of adverse events with cannabis-based treatments than placebo (10% vs 5%), with psychiatric disorders occurring in 17% of patients receiving active treatment vs 5% of those receiving placebo (number needed to harm 10). 

The primary studies suffered from methodologic limitations including small size, short duration, and inconsistency of formulations and study designs. Further evaluation of long-term efficacy, tolerability, and addiction potential is critical to determine the risk-benefit ratio.

RISKS OF CANNABIS USE

Like any drug therapy, cannabis has effects that may limit its use. Cannabis can affect a person’s psyche, physiology, and lifestyle.

Impaired attention, task speed

Neurocognitive changes associated with cannabis use—especially dizziness, fatigue, and slowed task-switching—could affect driving and other complex tasks. Evidence indicates that such activities should be avoided in the hours after treatment.^26,27,32,33

Concern over brain development

Most worrisome is the effect of long-term cannabis use on brain development in young adults. Regular use of cannabis at an early age is associated with lower IQ, decline in school performance, and lower rates of high school graduation.³⁵

Avoid in psychiatric patients

It is unlikely that cannabis can be safely used in patients with psychiatric illnesses. Anxiety, depression, and psychotic disorders can be exacerbated by the regular use of cannabis, and the risk of developing these conditions is increased while using cannabis.^36,37

High concentrations of THC (the highest concentration used in the above studies was 9.5%) can cause anxiety, paranoia, and psychosis.

Respiratory effects

Long-term cannabis smoking may cause wheezing, cough, dyspnea, and exacerbations of chronic bronchitis. There is some evidence that symptoms improve after stopping smoking.^33,38

SHOULD WE RECOMMEND CANNABIS?

Where cannabis can be legally used, doctors should be familiar with the literature and its limitations so that they can counsel patients on the best use and potential risks and benefits of cannabis treatment.

A recent conceptualization of pain suggests that a pain score reflects a composite of sensory factors (eg, tissue damage), cognitive factors (eg, beliefs about pain), and affective factors (eg, anxiety, depression).³⁹ Physicians should keep this in mind when evaluating patients to better assess the risks and benefits of cannabis. While pharmacotherapy may address sensory factors, cognitive behavioral therapy may help alter beliefs about the pain as well as anxiety and depressive symptoms that might influence subjective reports.

Ideally, patients being considered for cannabis treatment would have a type of neuropathic pain proven to respond to cannabis in randomized, controlled studies, as well as evidence of failed first-line treatments.

Relative contraindications include depression, anxiety, substance use, psychotic disorders, and respiratory conditions, and these should also be considered.

Although current research shows an analgesic benefit of cannabis on neuropathic pain comparable to that of gabapentin,⁴⁰ further investigation is needed to better evaluate long-term safety, efficacy, and interactions with standard therapies. Until we have a more complete picture, we should use the current literature, along with a thorough knowledge of each patient, to determine if the benefits of cannabis therapy outweigh the risks.

Acknowledgments: We thank Camillo Ferrari, BS, and Christina McMahon, BA, for their helpful comments.

Marijuana, which is still illegal under federal law but legal in 30 states for medical purposes as of this writing, has shown promising results for treating peripheral neuropathy. Studies suggest that cannabis may be an option for patients whose pain responds poorly to standard treatments; however, its use may be restricted by cognitive and psychiatric adverse effects, particularly at high doses.¹

See related editorial

In this article, we discuss the basic pharmacology of cannabis and how it may affect neuropathic pain. We review clinical trials on its use for peripheral neuropathy and provide guidance for its use.

PERIPHERAL NEUROPATHY IS COMMON AND COMPLEX

An estimated 20 million people in the United States suffer from neuropathic pain. The prevalence is higher in certain populations, with 26% of people over age 65 and 30% of patients with diabetes mellitus affected.^2–4

Peripheral neuropathy is a complex, chronic state that occurs when nerve fibers are damaged, dysfunctional, or injured, sending incorrect signals to pain centers in the central nervous system.⁵ It is characterized by weakness, pain, and paresthesias that typically begin in the hands or feet and progress proximally.⁴ Symptoms depend on the number and types of nerves affected.

In many cases, peripheral neuropathy is idiopathic, but common causes include diabetes, alcoholism, human immunodeficiency virus (HIV) infection, and autoimmune disease. Others include toxicity from chemotherapy and heavy metals.

Peripheral neuropathy significantly worsens quality of life and function. Many patients experience emotional, cognitive, and functional problems, resulting in high rates of medical and psychiatric comorbidities and occupational impairment.^4,6,7 Yet despite its clinical and epidemiologic significance, it is often undertreated.⁸

STANDARD TREATMENTS INADEQUATE

Peripheral neuropathy occurs in patients with a wide range of comorbidities and is especially difficult to treat. Mainstays of therapy include anticonvulsants, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors.⁹ A more invasive option is spinal cord stimulation.

These treatments can have considerable adverse effects, and response rates remain suboptimal, with pain relief insufficient to improve quality of life for many patients.^9,10 Better treatments are needed to improve clinical outcomes and patient experience.¹¹

CANNABIS: A MIX OF COMPOUNDS

Cannabis sativa has been used as an analgesic for centuries. The plant contains more than 400 chemical compounds and is often used for its euphoric properties. Long-term use may lead to addiction and cognitive impairment.^12,13

Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the main components and the 2 best-studied cannabinoids with analgesic effects.

THC is the primary psychoactive component of cannabis. Its effects include relaxation, altered perception, heightened sensations, increased libido, and perceptual distortions of time and space. Temporary effects may include decreased short-term memory, dry mouth, impaired motor function, conjunctival injection, paranoia, and anxiety.

CBD is nonpsychoactive and has anti-inflammatory and antioxidant properties. It has been shown to reduce pain and inflammation without the effects of THC.¹⁴

Other compounds in the cannabis plant include phytocannabinoids, flavonoids, and tapenoids, which may produce individual, interactive, or synergistic effects.¹⁵ Different strains of cannabis have varying amounts of the individual components, making comparisons among clinical studies difficult.

THE ENDOCANNABINOID SYSTEM

The endogenous mammalian cannabinoid system plays a regulatory role in the development, homeostasis, and neuroplasticity of the central nervous system. It is also involved in modulating pain transmission in the nociceptive pathway.

Two of the most abundant cannabinoid endogenous ligands are anandamide and 2-arachidonylglycerol.⁹ These endocanna­b­inoids are produced on demand in the central nervous system to reduce pain by acting as a circuit breaker.^16–18 They target the G protein-coupled cannabinoid receptors CB1 and CB2, located throughout the central and peripheral nervous system and in organs and tissues.¹²

CB1 receptors are found primarily in the central nervous system, specifically in areas involved in movement, such as the basal ganglia and cerebellum, as well as in areas involved in memory, such as the hippocampus.¹² They are also abundant in brain regions implicated in conducting and modulating pain signals, including the periaqueductal gray and the dorsal horn of the spinal cord.^16–20

CB2 receptors are mostly found in peripheral tissues and organs, mainly those involved in the immune system, including splenic, tonsillar, and hematopoietic cells.¹² They help regulate inflammation, allodynia, and hyperalgesia.¹⁷

Modifying response to injury

Following a nerve injury, neurons along the nociceptive pathway may become more reactive and responsive in a process known as sensitization.²¹ The process involves a cascade of cellular events that result in sprouting of pain-sensitive nerve endings.^21,22

Cannabinoids are thought to reduce pain by modifying these cellular events. They also inhibit nociceptive conduction in the dorsal horn of the spinal cord and in the ascending spinothalamic tract.²⁰ CB1 receptors found in nociceptive terminals along the peripheral nervous system impede pain conduction, while activation of CB2 receptors in immune cells decreases the release of nociceptive agents.

A number of studies have evaluated cannabis for treating neuropathic pain. Overall, available data support the efficacy of smoked or inhaled cannabis in its flower form when used as monotherapy or adjunctive therapy for relief of neuropathic pain of various etiologies. Many studies also report secondary benefits, including better sleep and functional improvement.^23,24

However, adverse effects are common, especially at high doses, and include difficulty concentrating, lightheadedness, fatigue, and tachycardia. More serious reported adverse effects include anxiety, paranoia, and psychosis.

Wilsey et al, 2008: Neuropathic pain reduced

Wilsey et al²⁵ conducted a double-blind, placebo-controlled crossover study that assessed the effects of smoking cannabis in 38 patients with central or peripheral neuropathic pain. Participants were assigned to smoke either high- or low-dose cannabis (7% or 3.5% delta-9-THC) or placebo cigarettes. Cigarettes were smoked during treatment sessions using the following regimen: 2 puffs at 60 minutes from baseline, 3 puffs at 120 minutes, and 4 puffs at 180 minutes. Patients were assessed after each set of puffs and for 2 hours afterwards. The primary outcome was spontaneous relief of pain as measured by a visual analog scale.

Pain intensity was comparable and significantly reduced in both treatment groups compared with placebo. At the high dose, some participants experienced neurocognitive impairment in attention, learning, memory, and psychomotor speed; only learning and memory declined at the low dose.

Ellis et al, 2009: Pain reduction in HIV neuropathy

Ellis et al²³ conducted a double-blind, placebo-controlled crossover trial in patients with HIV neuropathy that was unresponsive to at least 2 analgesics with different modes of action. During each treatment week, participants were randomly assigned to smoke either active cannabis or placebo, while continuing their standard therapy. Titration started at 4% THC and was adjusted based on tolerability and efficacy. Twenty-eight of the 34 enrolled patients completed both cannabis and placebo treatments. The principal outcome was change in pain intensity from baseline at the end of each week, using the Descriptor Differential Scale of Pain Intensity.

Of the 28 patients, 46% achieved an average pain reduction of 3.3 points (30%). One patient experienced cannabis-induced psychosis, and another developed an intractable cough, which resolved with smoking cessation.

Ware et al, 2010: Reduced posttraumatic or postsurgical neuropathic pain

Ware et al²⁴ performed a randomized crossover trial in 21 patients with posttraumatic or postsurgical neuropathic pain. Participants inhaled 4 different formulations of cannabis (containing 0%, 2.5%, 6.0%, and 9.4% THC) during 4 14-day periods. They inhaled a 25-mg dose through a pipe 3 times a day for the first 5 days of each cycle, followed by a 9-day washout period. Daily average pain intensity was measured using a numeric rating scale. The investigators also assessed mood, sleep, quality of life, and adverse effects.

Patients in the 9.4% THC group reported significantly less pain and better sleep, with average pain scores decreasing from 6.1 to 5.4 on an 11-point scale. Although the benefit was modest, the authors noted that the pain had been refractory to standard treatments.

The number of reported adverse events increased with greater potency and were most commonly throat irritation, burning sensation, headache, dizziness, and fatigue. This study suggests that THC potency affects tolerability, with higher doses eliciting clinically important adverse effects, some of which may reduce the ability to perform activities of daily living, such as driving.

Wilsey et al, 2013: Use in resistant neuropathic pain

Wilsey et al²⁶ conducted another double-blind, placebo-controlled crossover study assessing the effect of vaporized cannabis on central and peripheral neuropathic pain resistant to first-line pharmacotherapies. Dose-effect relationships were explored using medium-dose (3.5%), low-dose (1.3%), and placebo cannabis. The primary outcome measure was a 30% reduction in pain intensity based on a visual analog scale.

In the placebo group, 26% of patients achieved this vs 57% of the low-dose cannabis group and 61% of those receiving the medium dose. No significant difference was found between the 2 active doses in reducing neuropathic pain, and both were more effective than placebo. The number needed to treat to achieve a 30% reduction in pain was about 3 for both cannabis groups compared with placebo. Psychoactive effects were minimal, of short duration, and reversible.

Wallace et al, 2015: Use in diabetic peripheral neuropathy

Wallace et al²⁷ conducted a randomized, double-blind, placebo-controlled crossover study evaluating cannabis for diabetic peripheral neuropathy in 16 patients. Each had experienced at least 6 months of neuropathic pain in their feet. The participants inhaled a single dose of 1%, 4%, or 7% THC cannabis or placebo. Spontaneous pain was reported with a visual analog scale and also tested with a foam brush and von Frey filament at intervals until 4 hours after treatment.

Pain scores were lower with treatment compared with placebo, with high-dose cannabis having the greatest analgesic effect. Pain reduction lasted for the full duration of the test. Cannabis recipients had declines in attention and working memory, with the high-dose group experiencing the greatest impact 15 minutes after treatment. High-dose recipients also had poorer scores on testing of quick task-switching, with the greatest effect at 2 hours.²⁷

Research and market cannabis are not equal

Results of US studies must be qualified. Most have used cannabis provided by the National Institute of Drug Abuse (NIDA),^23–26 which differs in potency from commercially available preparations. This limits the clinical usefulness of the analysis of benefits and risks.

Vergara et al²⁸ found that NIDA varieties contained much lower THC levels and as much as 23 times the cannabinol content as cannabis in state-legalized markets.

Studies based on NIDA varieties likely underestimate the risks of consumer-purchased cannabis, as THC is believed to be most responsible for the risk of psychosis and impaired driving and cognition.^24,28

Studies of CBD alone are limited to preclinical data.²⁹ Evidence suggests that CBD alone or combined with THC can suppress chronic neuropathic pain, and that CBD may have a protective effect after nerve injury.³⁰

Nabiximols, an oromucosal spray preparation with equal amounts of THC and CBD, has been approved in Canada as well as in European countries including the United Kingdom. Although its use has not been associated with many of the adverse effects of inhaled cannabis,^30–32 evidence of efficacy from clinical trials has been mixed.

Lynch et al,³¹ in a 2014 randomized, double-blind, placebo-controlled crossover pilot study³¹ evaluated nabiximols in 16 patients with neuropathic pain related to chemotherapy. No statistically significant difference was found between treatment and placebo. However, the trial was underpowered.

Serpell et al,³² in a 2014 European randomized, placebo-controlled parallel-group study, evaluated 246 patients with peripheral neuropathy with allodynia, with 128 receiving active treatment (THC-CBD oromucosal spray) and 118 receiving placebo. Over the 15-week study, participants continued their current analgesic treatments.

Pain was reduced in the treatment group, but the difference from placebo was not statistically significant. However, the treatment group reported significantly better sleep quality and Patient Global Impression of Change measures (reflecting a patient’s belief of treatment efficacy).

META-ANALYSES CONFIRM EFFECT

Three meta-analyses of available studies of the effects of cannabis on neuropathic pain have been completed.

Andreae et al, 2015: 5 trials, 178 patients

Andreae et al¹ evaluated 5 randomized controlled trials in 178 patients in North America. All had had neuropathy for at least 3 months, with a pain level of at least about 3 on a scale of 10. Two studies had patients with HIV-related neuropathy; the other 3 involved patients with neuropathy related to trauma, diabetes, complex regional pain syndrome, or spinal cord injury. All trials used whole cannabis plant provided by NIDA, and the main outcomes were patient-reported pain scales. No study evaluated pain beyond 2 weeks after trial termination.

They found that 1 of every 5 to 6 patients treated with cannabis had at least a 30% pain reduction.

Nugent et al, 2017: 13 trials, 246 patients

Nugent et al³³ reviewed 13 trials in 246 patients that evaluated the effects of different cannabis-based preparations on either central or peripheral neuropathic pain from various conditions. Actively treated patients were more likely to report a 30% improvement in neuropathic pain. Again, studies tended to be small and brief.

Cochrane review, 2018: 16 trials, 1,750 patients

A Cochrane review³⁴ analyzed 16 trials (in 1,750 patients) lasting 2 to 26 weeks. Treatments included an oromucosal spray with a plant-derived combination of THC and CBD, nabilone, inhaled herbal cannabis, and plant-derived THC.

With cannabis-based treatments, significantly more people achieved 50% or greater pain relief than with placebo (21% vs 17%, number needed to treat 20); 30% pain reduction was achieved in 39% of treated patients vs 33% of patients taking placebo (number needed to treat 11).

On the other hand, significantly more participants withdrew from studies because of adverse events with cannabis-based treatments than placebo (10% vs 5%), with psychiatric disorders occurring in 17% of patients receiving active treatment vs 5% of those receiving placebo (number needed to harm 10). 

The primary studies suffered from methodologic limitations including small size, short duration, and inconsistency of formulations and study designs. Further evaluation of long-term efficacy, tolerability, and addiction potential is critical to determine the risk-benefit ratio.

RISKS OF CANNABIS USE

Like any drug therapy, cannabis has effects that may limit its use. Cannabis can affect a person’s psyche, physiology, and lifestyle.

Impaired attention, task speed

Neurocognitive changes associated with cannabis use—especially dizziness, fatigue, and slowed task-switching—could affect driving and other complex tasks. Evidence indicates that such activities should be avoided in the hours after treatment.^26,27,32,33

Concern over brain development

Most worrisome is the effect of long-term cannabis use on brain development in young adults. Regular use of cannabis at an early age is associated with lower IQ, decline in school performance, and lower rates of high school graduation.³⁵

Avoid in psychiatric patients

It is unlikely that cannabis can be safely used in patients with psychiatric illnesses. Anxiety, depression, and psychotic disorders can be exacerbated by the regular use of cannabis, and the risk of developing these conditions is increased while using cannabis.^36,37

High concentrations of THC (the highest concentration used in the above studies was 9.5%) can cause anxiety, paranoia, and psychosis.

Respiratory effects

Long-term cannabis smoking may cause wheezing, cough, dyspnea, and exacerbations of chronic bronchitis. There is some evidence that symptoms improve after stopping smoking.^33,38

SHOULD WE RECOMMEND CANNABIS?

Where cannabis can be legally used, doctors should be familiar with the literature and its limitations so that they can counsel patients on the best use and potential risks and benefits of cannabis treatment.

A recent conceptualization of pain suggests that a pain score reflects a composite of sensory factors (eg, tissue damage), cognitive factors (eg, beliefs about pain), and affective factors (eg, anxiety, depression).³⁹ Physicians should keep this in mind when evaluating patients to better assess the risks and benefits of cannabis. While pharmacotherapy may address sensory factors, cognitive behavioral therapy may help alter beliefs about the pain as well as anxiety and depressive symptoms that might influence subjective reports.

Ideally, patients being considered for cannabis treatment would have a type of neuropathic pain proven to respond to cannabis in randomized, controlled studies, as well as evidence of failed first-line treatments.

Relative contraindications include depression, anxiety, substance use, psychotic disorders, and respiratory conditions, and these should also be considered.

Although current research shows an analgesic benefit of cannabis on neuropathic pain comparable to that of gabapentin,⁴⁰ further investigation is needed to better evaluate long-term safety, efficacy, and interactions with standard therapies. Until we have a more complete picture, we should use the current literature, along with a thorough knowledge of each patient, to determine if the benefits of cannabis therapy outweigh the risks.

Acknowledgments: We thank Camillo Ferrari, BS, and Christina McMahon, BA, for their helpful comments.

But, after the results of many recent studies, it turns out I should not have been so comfortable after all. This should not be a surprise. We should never be overly confident with our understanding of anything in clinical practice.

In this issue, Dr. Martin Blaser discusses his work, which supports the hypothesis that the currently increased prevalence of obesity and diabetes is at least in part due to reduced diversity in the gut microbiome. The increased exposure to antibiotics through prescriptions for women before and during pregnancy, as well as perhaps their exposure to antibiotics in the environment, results in changes to the gut and vaginal flora that influence the developing gut and likely other anatomic microbiomes in the neonate and infant. Fascinating research done in mice, utilizing fecal transfer experiments, is building an evidence trail to support the concept that the microbiome plays a major role in the development of childhood and adult obesity, and the gut microbiome is influenced by its exposure to antibiotics, perhaps given years earlier.

Knowledge of the gastrointestinal and other human microbiomes is exploding. I now wonder how many seemingly random clinical events associated with antibiotic use that were not understood and were easily dismissed as stochastic warrant formal study. Some of my patients with rheumatoid arthritis have described flares after eating certain foods and transient remissions or exacerbations after treatment with antibiotics. An epidemiologic study has linked the likelihood of developing childhood inflammatory bowel disease with exposure to antibiotics. Even more fascinating are observations that the microbiota composition (influenced by antibiotics) can influence the outcome of cardiac allografts in a murine model and the response of certain tumors to immune checkpoint inhibitors in murine and human studies. The mechanism may relate to the effects of the microbiome on immune cell activation and migration. Several disorders have been linked to specific bacteria in the gut microbiome, and others as diverse as cardiovascular events and the acute inflammatory response to monosodium urate crystals (gout) are affected by metabolites generated by bacteria in the gut.

The use of germ-free and antibiotic-treated mice in the laboratory, with selective repopulation of their gut microbiome with flora harvested from other strains of mice or selected humans, will continue to teach us much about the role that these microbes and other inhabitants play in controlling normal and disease-disrupted homeostasis. C difficile overgrowth after antibiotic exposure, and the successful treatment of refractory C difficile with fecal transplantation,¹ was just the beginning.

The simple writing of a prescription for an antibiotic is a far more complicated and long-lasting affair than most of us have thought.

But, after the results of many recent studies, it turns out I should not have been so comfortable after all. This should not be a surprise. We should never be overly confident with our understanding of anything in clinical practice.

In this issue, Dr. Martin Blaser discusses his work, which supports the hypothesis that the currently increased prevalence of obesity and diabetes is at least in part due to reduced diversity in the gut microbiome. The increased exposure to antibiotics through prescriptions for women before and during pregnancy, as well as perhaps their exposure to antibiotics in the environment, results in changes to the gut and vaginal flora that influence the developing gut and likely other anatomic microbiomes in the neonate and infant. Fascinating research done in mice, utilizing fecal transfer experiments, is building an evidence trail to support the concept that the microbiome plays a major role in the development of childhood and adult obesity, and the gut microbiome is influenced by its exposure to antibiotics, perhaps given years earlier.

Knowledge of the gastrointestinal and other human microbiomes is exploding. I now wonder how many seemingly random clinical events associated with antibiotic use that were not understood and were easily dismissed as stochastic warrant formal study. Some of my patients with rheumatoid arthritis have described flares after eating certain foods and transient remissions or exacerbations after treatment with antibiotics. An epidemiologic study has linked the likelihood of developing childhood inflammatory bowel disease with exposure to antibiotics. Even more fascinating are observations that the microbiota composition (influenced by antibiotics) can influence the outcome of cardiac allografts in a murine model and the response of certain tumors to immune checkpoint inhibitors in murine and human studies. The mechanism may relate to the effects of the microbiome on immune cell activation and migration. Several disorders have been linked to specific bacteria in the gut microbiome, and others as diverse as cardiovascular events and the acute inflammatory response to monosodium urate crystals (gout) are affected by metabolites generated by bacteria in the gut.

The use of germ-free and antibiotic-treated mice in the laboratory, with selective repopulation of their gut microbiome with flora harvested from other strains of mice or selected humans, will continue to teach us much about the role that these microbes and other inhabitants play in controlling normal and disease-disrupted homeostasis. C difficile overgrowth after antibiotic exposure, and the successful treatment of refractory C difficile with fecal transplantation,¹ was just the beginning.

The simple writing of a prescription for an antibiotic is a far more complicated and long-lasting affair than most of us have thought.

But, after the results of many recent studies, it turns out I should not have been so comfortable after all. This should not be a surprise. We should never be overly confident with our understanding of anything in clinical practice.

In this issue, Dr. Martin Blaser discusses his work, which supports the hypothesis that the currently increased prevalence of obesity and diabetes is at least in part due to reduced diversity in the gut microbiome. The increased exposure to antibiotics through prescriptions for women before and during pregnancy, as well as perhaps their exposure to antibiotics in the environment, results in changes to the gut and vaginal flora that influence the developing gut and likely other anatomic microbiomes in the neonate and infant. Fascinating research done in mice, utilizing fecal transfer experiments, is building an evidence trail to support the concept that the microbiome plays a major role in the development of childhood and adult obesity, and the gut microbiome is influenced by its exposure to antibiotics, perhaps given years earlier.

Knowledge of the gastrointestinal and other human microbiomes is exploding. I now wonder how many seemingly random clinical events associated with antibiotic use that were not understood and were easily dismissed as stochastic warrant formal study. Some of my patients with rheumatoid arthritis have described flares after eating certain foods and transient remissions or exacerbations after treatment with antibiotics. An epidemiologic study has linked the likelihood of developing childhood inflammatory bowel disease with exposure to antibiotics. Even more fascinating are observations that the microbiota composition (influenced by antibiotics) can influence the outcome of cardiac allografts in a murine model and the response of certain tumors to immune checkpoint inhibitors in murine and human studies. The mechanism may relate to the effects of the microbiome on immune cell activation and migration. Several disorders have been linked to specific bacteria in the gut microbiome, and others as diverse as cardiovascular events and the acute inflammatory response to monosodium urate crystals (gout) are affected by metabolites generated by bacteria in the gut.

The use of germ-free and antibiotic-treated mice in the laboratory, with selective repopulation of their gut microbiome with flora harvested from other strains of mice or selected humans, will continue to teach us much about the role that these microbes and other inhabitants play in controlling normal and disease-disrupted homeostasis. C difficile overgrowth after antibiotic exposure, and the successful treatment of refractory C difficile with fecal transplantation,¹ was just the beginning.

The simple writing of a prescription for an antibiotic is a far more complicated and long-lasting affair than most of us have thought.

An 82-year-old man with poorly controlled diabetes mellitus presented to our emergency department with a 1-day history of confusion and coffee-ground emesis.

Biopsy study revealed necrosis of the esophageal mucosa. A diagnosis of acute necrotizing esophagitis was made.

ACUTE NECROTIZING ESOPHAGITIS

Acute necrotizing esophagitis is thought to arise from a combination of an ischemic insult to the esophagus, an impaired mucosal barrier system, and a backflow injury from chemical contents of gastric secretions.¹ The tissue hypoperfusion derives from vasculopathy, hypotension, or malnutrition. It is associated with diabetes mellitus, diabetic ketoacidosis, lactic acidosis, alcohol abuse, cirrhosis, renal insufficiency, malignancy, antibiotic use, esophageal infections, and aortic dissection.

The esophagus has a diverse blood supply. The upper esophagus is supplied by the inferior thyroid arteries, the mid-esophagus by the bronchial, proper esophageal, and intercostal arteries, and the distal esophagus by the left gastric and left inferior phrenic arteries.¹

KEY FEATURES AND DIAGNOSTIC CLUES

The necrotic changes are prominent in the distal esophagus, which is more susceptible to ischemia and mucosal injury. The characteristic endoscopic finding is a diffuse black esophagus with a sharp transition to normal mucosa at the gastroesophageal junction.

The differential diagnosis includes melanosis, pseudomelanosis, malignant melanoma, acanthosis nigricans, coal dust deposition, caustic ingestion, radiation esophagitis, and infectious esophagitis caused by cytomegalovirus, herpes simplex virus, Candida albicans, or Klebsiella pneumoniae.^2–4

TREATMENT AND OUTCOME

Avoidance of oral intake and gastric acid suppression with intravenous proton pump inhibitors are recommended to prevent additional injury of the esophageal mucosa.

The condition generally resolves with restored blood flow and treatment of any coexisting illness. However, it may be complicated by perforation (6.8%), mediastinitis (5.7%), or subsequent development of esophageal stricture (10.2%).⁵ Patients with esophageal stricture require endoscopic dilation after mucosal recovery.

The overall risk of death in acute necrotizing esophagitis is high (31.8%) and most often due to the underlying disease, such as sepsis, malignancy, cardiogenic shock, or hypovolemic shock.⁵ The mortality rate directly attributed to complications of acute necrotizing esophagitis is much lower (5.7%).⁵     

An 82-year-old man with poorly controlled diabetes mellitus presented to our emergency department with a 1-day history of confusion and coffee-ground emesis.

Biopsy study revealed necrosis of the esophageal mucosa. A diagnosis of acute necrotizing esophagitis was made.

ACUTE NECROTIZING ESOPHAGITIS

Acute necrotizing esophagitis is thought to arise from a combination of an ischemic insult to the esophagus, an impaired mucosal barrier system, and a backflow injury from chemical contents of gastric secretions.¹ The tissue hypoperfusion derives from vasculopathy, hypotension, or malnutrition. It is associated with diabetes mellitus, diabetic ketoacidosis, lactic acidosis, alcohol abuse, cirrhosis, renal insufficiency, malignancy, antibiotic use, esophageal infections, and aortic dissection.

The esophagus has a diverse blood supply. The upper esophagus is supplied by the inferior thyroid arteries, the mid-esophagus by the bronchial, proper esophageal, and intercostal arteries, and the distal esophagus by the left gastric and left inferior phrenic arteries.¹

KEY FEATURES AND DIAGNOSTIC CLUES

The necrotic changes are prominent in the distal esophagus, which is more susceptible to ischemia and mucosal injury. The characteristic endoscopic finding is a diffuse black esophagus with a sharp transition to normal mucosa at the gastroesophageal junction.

The differential diagnosis includes melanosis, pseudomelanosis, malignant melanoma, acanthosis nigricans, coal dust deposition, caustic ingestion, radiation esophagitis, and infectious esophagitis caused by cytomegalovirus, herpes simplex virus, Candida albicans, or Klebsiella pneumoniae.^2–4

TREATMENT AND OUTCOME

Avoidance of oral intake and gastric acid suppression with intravenous proton pump inhibitors are recommended to prevent additional injury of the esophageal mucosa.

The condition generally resolves with restored blood flow and treatment of any coexisting illness. However, it may be complicated by perforation (6.8%), mediastinitis (5.7%), or subsequent development of esophageal stricture (10.2%).⁵ Patients with esophageal stricture require endoscopic dilation after mucosal recovery.

The overall risk of death in acute necrotizing esophagitis is high (31.8%) and most often due to the underlying disease, such as sepsis, malignancy, cardiogenic shock, or hypovolemic shock.⁵ The mortality rate directly attributed to complications of acute necrotizing esophagitis is much lower (5.7%).⁵     

An 82-year-old man with poorly controlled diabetes mellitus presented to our emergency department with a 1-day history of confusion and coffee-ground emesis.

Biopsy study revealed necrosis of the esophageal mucosa. A diagnosis of acute necrotizing esophagitis was made.

ACUTE NECROTIZING ESOPHAGITIS

Acute necrotizing esophagitis is thought to arise from a combination of an ischemic insult to the esophagus, an impaired mucosal barrier system, and a backflow injury from chemical contents of gastric secretions.¹ The tissue hypoperfusion derives from vasculopathy, hypotension, or malnutrition. It is associated with diabetes mellitus, diabetic ketoacidosis, lactic acidosis, alcohol abuse, cirrhosis, renal insufficiency, malignancy, antibiotic use, esophageal infections, and aortic dissection.

The esophagus has a diverse blood supply. The upper esophagus is supplied by the inferior thyroid arteries, the mid-esophagus by the bronchial, proper esophageal, and intercostal arteries, and the distal esophagus by the left gastric and left inferior phrenic arteries.¹

KEY FEATURES AND DIAGNOSTIC CLUES

The necrotic changes are prominent in the distal esophagus, which is more susceptible to ischemia and mucosal injury. The characteristic endoscopic finding is a diffuse black esophagus with a sharp transition to normal mucosa at the gastroesophageal junction.

The differential diagnosis includes melanosis, pseudomelanosis, malignant melanoma, acanthosis nigricans, coal dust deposition, caustic ingestion, radiation esophagitis, and infectious esophagitis caused by cytomegalovirus, herpes simplex virus, Candida albicans, or Klebsiella pneumoniae.^2–4

TREATMENT AND OUTCOME

Avoidance of oral intake and gastric acid suppression with intravenous proton pump inhibitors are recommended to prevent additional injury of the esophageal mucosa.

The condition generally resolves with restored blood flow and treatment of any coexisting illness. However, it may be complicated by perforation (6.8%), mediastinitis (5.7%), or subsequent development of esophageal stricture (10.2%).⁵ Patients with esophageal stricture require endoscopic dilation after mucosal recovery.

The overall risk of death in acute necrotizing esophagitis is high (31.8%) and most often due to the underlying disease, such as sepsis, malignancy, cardiogenic shock, or hypovolemic shock.⁵ The mortality rate directly attributed to complications of acute necrotizing esophagitis is much lower (5.7%).⁵     

Amputation: Resistance is not futile!

What’s in a toe you may ask? Why worry about saving it? Just amputate and move on ...

Not so! I implore you to resist the desire. We vascular surgeons are accustomed to cutting off toes, even feet and legs. But when it comes to diabetic feet please reconsider. Just because there is osteomyelitis, I argue that does not necessitate amputation.

We all agree that ischemic gangrene and black mummified digits are beyond salvage. That’s not what my concern is. My focus is nonhealing ulcers with underlying osteomyelitis. Whether ischemic in etiology or neuropathic (or both), give salvage a try.

Why is this so important? My opponent will try to convince you that it’s not. He’ll try to sell you on how well people walk after amputation and that functional outcomes are great. But think beyond that for a second.

Amputation changes the foot architecture and weight distribution. In a person with neuropathy, this only predisposes them to more ulcers. More ulcers will mean more infection, which will lead to more amputations. This finally culminates in a major amputation.

In one reported study,¹ researchers followed more than 200,000 diabetics from 2010 until 2013. While the risk of amputation overall was relatively small (0.36% for major and 0.56% for minor amputations), prior minor amputation increased the risk of major amputation 10-fold and increased the risk of another minor (below-ankle) amputation 20-fold. Of those who had a major amputation, 57% died over the 3 years. This is not insignificant.

This does not also consider the morbidity and impact on lifestyle and quality of life for these patients. Many may not walk. Some will be relegated to nursing homes. Some will suffer from phantom limb pain. Many may never return to work. Even more will have difficulty with their daily lives, not to mention the psychological recovery also required.

The foot seems to be the only place where amputation as first-line therapy for osteomyelitis is accepted. We don’t do a hip disarticulation for ischial pressure sores with osteomyelitis. Calvarial osteomyelitis is also treated with antibiotics. I implore you: Don’t treat toes like vestigial organs.

Granted, there are subsets of patients who would benefit from amputations. A patient with painful Charcot foot may elect to have a below-knee amputation and move on with life. Another who has lost jobs or significant time due to recurrence of osteomyelitis may progress. A patient with severe sepsis and infection into a joint may need amputation.

But what other treatment options are there? I’m glad you inquired.

I primarily treat diabetic feet by treating the soft tissue envelope. Even if a patient presents with midfoot infection or necrotizing soft tissue infection, I treat it like a good old-fashioned abscess or necrotizing fasciitis:

1) Drain pus

2) Resect the dead stuff

3) Supportive care (antibiotics, fluids, aggressive wound care, etc.)

I try to leave the bones intact. When bone is exposed I take biopsies for culture and pathology. Any bone destroyed by the infection is focally debrided. I also take a specimen of the “bone margin” that I’m leaving behind and I send this to pathology looking for residual acute osteomyelitis. These steps are important as they dictate duration and choice of antibiotic therapy. This is in keeping with the consensus recommendations published in 2016.²

Even chronic wounds get a similar approach. If there is granulation, let it granulate and see if it will fill the wound. “Just because osteomyelitis is there, it doesn’t mean that for the toe we won’t care!”

There are exceptions of course. If the soft tissue is severely affected so the phalynx protrudes like something from the movie “Coco,” probably that should be amputated. Repeat offenders also may progress to amputation. But otherwise, hold off and give it a chance.

For the inpatient, aggressive irrigation of the wounds using the Veraflo system promotes granulation, even for short hospital stays of 1 week or less. Any ischemic component is worked up and addressed with percutaneous or open revascularization. We treat with prolonged antibiotics, and in questionable cases err on the side of giving long-term courses. These wounds need to be offloaded for tasks of daily living (going to the bathroom, making a sandwich, etc.) but otherwise we instruct patients to be effectively non–weight-bearing on that limb.

We also refer patients for hyperbaric therapy frequently. Now if you’re done groaning, I assure you this is not phony medicine. There is growing evidence to support not only improved rates of healing, but also significant cost savings and improved quality of life.³

In young patients or those with large defects, we also involve plastic and reconstructive surgery for secondary closure approaches (free flaps, adjacent tissue transfers, local autogenous or prosthetic grafting [Integra, Stravix, Dermacell, etc.] or other advanced techniques). This is particularly important in plantar wounds that will need to bear weight in the future, or in young patients for improved functional and cosmetic outcomes. For smaller wounds, we often use dermal/subdermal graft substitutes ourselves.

Even still, in nonambulatory or chronically debilitated and medically high-risk patients, maybe a different option is palliative wound care with or without antibiotics. A nonoperative approach to allow individuals to live the rest of their remaining days without undergoing a morbid and disfiguring amputation is not unreasonable. Many families are thankful for this option when given it. In the absence of refractory pain or overwhelming sepsis, we just let the wound do what it will do, understanding that someday the plan may change. This allows patients to continue to treat the wound without escalation to surgery or resorting to amputation.

In the end, just like we vascular surgeons tailor our “holistic” approach to the needs and desires of a single particular patient, we should approach wounds with a similar attitude. The presence of osteomyelitis in and of itself should not prompt one to bypass an entire algorithm, go straight to amputation, do not pass “Go” or “collect $200” (although the professional fee for a toe amputation is probably around $200). With a multidisciplinary and multimodal approach, and vested patients, salvage is possible in the majority of cases.
 

References

1. Diabetologia. 2018 Mar;61(3):626-35.

2. Diabet Foot Ankle. 2016 Jul 12. doi: 10.3402/dfa.v7.30079.

3. Int J Technol Assess Health Care. 2008 Spring;24(2):178-83.
 

Dr. Issam Koleilat is assistant professor and associate program director, Vascular Surgery Residency and Fellowship, Division of Vascular Surgery, Albert Einstein College of Medicine/Montefiore Medical Center, New York. He had no relevant disclosures.

Amputation: Often the best option

For many years there has been debate about the best management strategy for diabetic foot infection including osteomyelitis. The principles of appropriate antibiotics, surgical debridement, good wound care, and proper offloading will always remain. There are no randomized controlled trials of medical vs. surgical management of diabetic foot ulceration with osteomyelitis.

We now have a number of widely accepted ways to define wounds including Wagner and the SVS-adopted WIFI score. Historical papers are somewhat plagued by heterogeneity in the wounds included. This is even more apparent with any attempted meta-analyses. I think everyone would agree that the superficial toe wound with minimal cellulitis is best managed medically. The issue at hand is the profoundly neuropathic diabetic often with underlying anatomic abnormality and osteomyelitis. My esteemed colleague would suggest that we are too quick to pull a trigger and amputate a toe with underlying osteomyelitis.

I think the initial item for debate is the technique of diagnosis of osteomyelitis. We have multiple ways this is reported. Plain x-ray, bone scan, MRI, and “clinical osteomyelitis” are among the alternative ways osteomyelitis is diagnosed. The reliability of the last is the most variable because clinical osteomyelitis ranges from “probes close to bone” to exposed bone visible protruding from the wound bed. Given the variability of diagnostic techniques, the literature is an amalgam of clinical scenarios and difficult to navigate in a way to affect treatment decisions.

In addition, the medical treatment for osteomyelitis is highly variable. This commonly involves tunneled catheter insertion and 6 weeks to 3 months of IV antibiotics. In some institutions antibiotics are tailored to “wound culture.” Several of our infectious disease specialists prefer bone culture and pathology of bone demonstrating an acute destructive process. Obviously, this often requires surgical debridement to obtain a specimen. Antibiotic duration recommendations may vary from 1 week (if all infected bone is resected) to 90 days if a standalone antibiotic management is selected. Chronic osteomyelitis has a reinfection rate of up to 30%.¹

Medical management is not without risk. These risks include recurring infection with resistant organisms, wound deterioration, gastrointestinal complications (Clostridium difficile), catheter-related complications, and acute kidney injury. A recent paper found over 30% of patients treated medically for osteomyelitis developed acute kidney injury. These patients had more frequent hospitalization, recurring ulceration, and infection.² We have all experienced the patient with multiple hospitalizations and episodic AKI that culminates in ESRD requiring hemodialysis.

If the argument is with good follow-up these patients will ultimately experience preservation of the toe, I would take the stance that in our patient population of diabetics presenting with foot ulcer and osteomyelitis the average hemoglobin A1c is over 9. Although this is not only related to patient compliance, in many instances this is a large piece of the puzzle. It is hard to infer that suddenly with biopsy-proven osteomyelitis the patient will become compliant with medical management of the disease process. Certainly, in some circumstances, this is the case. There are a number of studies with a wide range of findings on HbA^1c as it relates to predictive value of wound healing.

There are various studies comparing surgical to medical management for osteomyelitis. Limb salvage is contingent upon location (forefoot, midfoot, hindfoot), the extent of infection, and patient comorbidities. The conclusion of the majority of these studies is that a standalone antibiotic treatment algorithm results in greater limb loss. Patients with peripheral occlusive disease and preadmission antibiotic use have been shown to have decreased wound healing. Minor amputation has been shown to be protective from mortality, risk of major amputation, and unfavorable discharge in patients admitted with a diagnosis of osteomyelitis.³ The major limb amputation rate for antibiotics alone is 20%-30% according to two trials with duration of antibiotics of 3 months.^4,5 The available randomized trials tend to exclude patients with severe infection (poorly defined), those with PAD, or those with severe comorbid conditions.

Cost of treatment is even more poorly delineated. Obviously, surgical treatment is not without cost to the health care system. Toe amputation especially when including the metatarsal head shifts pressure points and in the neuropathic patient may lead to recurrent ulceration. The average outpatient cost per patient per ulcer is often over $30,000. The goal of surgical treatment can be defined as trying to maintain the greatest degree of function with the least risk. Removing infected bone (i.e., minor amputation) limits exposure to prolonged antibiotic treatment and hopefully lessens recurring ulceration and hospitalization. This is only one piece of the puzzle, however. A multidisciplinary approach with endocrinology, infectious disease, and orthotics for offloading are keys to decrease future ulceration.

Although I do not advocate for widespread toe carnage as suggested by Dr. Koleilat, I do think liberal application of minor amputation to limit hospital stay, limit antibiotic duration and its inherent risk, and possibly affect readmission is often in the best interest of the patient and the system as a whole. Obviously, based on the variable reports in the literature there cannot be a single approach to these patients and the treatment must be individualized based on extent of infection, compliance of the patient, access to multidisciplinary care, and comorbid conditions.
 

References

1. World J Diabetes. 2017 Apr 15;8(4):135-42.

2. Diabetes Res Clin Pract. 2018 Jan;135:58-64.

3. Ann Surg. 2005;241(6):885-94.

4. Am J Med. 1987 Oct;83(4):653-60.

5. Am J Med.1989 Jun;86(6 Pt 2):801-8.

Dr. Mark P. Androes is division chief, vascular surgery, Greenville (S.C.) Health System. He had no relevant disclosures.

Amputation: Resistance is not futile!

What’s in a toe you may ask? Why worry about saving it? Just amputate and move on ...

Not so! I implore you to resist the desire. We vascular surgeons are accustomed to cutting off toes, even feet and legs. But when it comes to diabetic feet please reconsider. Just because there is osteomyelitis, I argue that does not necessitate amputation.

We all agree that ischemic gangrene and black mummified digits are beyond salvage. That’s not what my concern is. My focus is nonhealing ulcers with underlying osteomyelitis. Whether ischemic in etiology or neuropathic (or both), give salvage a try.

Why is this so important? My opponent will try to convince you that it’s not. He’ll try to sell you on how well people walk after amputation and that functional outcomes are great. But think beyond that for a second.

Amputation changes the foot architecture and weight distribution. In a person with neuropathy, this only predisposes them to more ulcers. More ulcers will mean more infection, which will lead to more amputations. This finally culminates in a major amputation.

In one reported study,¹ researchers followed more than 200,000 diabetics from 2010 until 2013. While the risk of amputation overall was relatively small (0.36% for major and 0.56% for minor amputations), prior minor amputation increased the risk of major amputation 10-fold and increased the risk of another minor (below-ankle) amputation 20-fold. Of those who had a major amputation, 57% died over the 3 years. This is not insignificant.

This does not also consider the morbidity and impact on lifestyle and quality of life for these patients. Many may not walk. Some will be relegated to nursing homes. Some will suffer from phantom limb pain. Many may never return to work. Even more will have difficulty with their daily lives, not to mention the psychological recovery also required.

The foot seems to be the only place where amputation as first-line therapy for osteomyelitis is accepted. We don’t do a hip disarticulation for ischial pressure sores with osteomyelitis. Calvarial osteomyelitis is also treated with antibiotics. I implore you: Don’t treat toes like vestigial organs.

Granted, there are subsets of patients who would benefit from amputations. A patient with painful Charcot foot may elect to have a below-knee amputation and move on with life. Another who has lost jobs or significant time due to recurrence of osteomyelitis may progress. A patient with severe sepsis and infection into a joint may need amputation.

But what other treatment options are there? I’m glad you inquired.

I primarily treat diabetic feet by treating the soft tissue envelope. Even if a patient presents with midfoot infection or necrotizing soft tissue infection, I treat it like a good old-fashioned abscess or necrotizing fasciitis:

1) Drain pus

2) Resect the dead stuff

3) Supportive care (antibiotics, fluids, aggressive wound care, etc.)

I try to leave the bones intact. When bone is exposed I take biopsies for culture and pathology. Any bone destroyed by the infection is focally debrided. I also take a specimen of the “bone margin” that I’m leaving behind and I send this to pathology looking for residual acute osteomyelitis. These steps are important as they dictate duration and choice of antibiotic therapy. This is in keeping with the consensus recommendations published in 2016.²

Even chronic wounds get a similar approach. If there is granulation, let it granulate and see if it will fill the wound. “Just because osteomyelitis is there, it doesn’t mean that for the toe we won’t care!”

There are exceptions of course. If the soft tissue is severely affected so the phalynx protrudes like something from the movie “Coco,” probably that should be amputated. Repeat offenders also may progress to amputation. But otherwise, hold off and give it a chance.

For the inpatient, aggressive irrigation of the wounds using the Veraflo system promotes granulation, even for short hospital stays of 1 week or less. Any ischemic component is worked up and addressed with percutaneous or open revascularization. We treat with prolonged antibiotics, and in questionable cases err on the side of giving long-term courses. These wounds need to be offloaded for tasks of daily living (going to the bathroom, making a sandwich, etc.) but otherwise we instruct patients to be effectively non–weight-bearing on that limb.

We also refer patients for hyperbaric therapy frequently. Now if you’re done groaning, I assure you this is not phony medicine. There is growing evidence to support not only improved rates of healing, but also significant cost savings and improved quality of life.³

In young patients or those with large defects, we also involve plastic and reconstructive surgery for secondary closure approaches (free flaps, adjacent tissue transfers, local autogenous or prosthetic grafting [Integra, Stravix, Dermacell, etc.] or other advanced techniques). This is particularly important in plantar wounds that will need to bear weight in the future, or in young patients for improved functional and cosmetic outcomes. For smaller wounds, we often use dermal/subdermal graft substitutes ourselves.

Even still, in nonambulatory or chronically debilitated and medically high-risk patients, maybe a different option is palliative wound care with or without antibiotics. A nonoperative approach to allow individuals to live the rest of their remaining days without undergoing a morbid and disfiguring amputation is not unreasonable. Many families are thankful for this option when given it. In the absence of refractory pain or overwhelming sepsis, we just let the wound do what it will do, understanding that someday the plan may change. This allows patients to continue to treat the wound without escalation to surgery or resorting to amputation.

In the end, just like we vascular surgeons tailor our “holistic” approach to the needs and desires of a single particular patient, we should approach wounds with a similar attitude. The presence of osteomyelitis in and of itself should not prompt one to bypass an entire algorithm, go straight to amputation, do not pass “Go” or “collect $200” (although the professional fee for a toe amputation is probably around $200). With a multidisciplinary and multimodal approach, and vested patients, salvage is possible in the majority of cases.
 

References

1. Diabetologia. 2018 Mar;61(3):626-35.

2. Diabet Foot Ankle. 2016 Jul 12. doi: 10.3402/dfa.v7.30079.

3. Int J Technol Assess Health Care. 2008 Spring;24(2):178-83.
 

Dr. Issam Koleilat is assistant professor and associate program director, Vascular Surgery Residency and Fellowship, Division of Vascular Surgery, Albert Einstein College of Medicine/Montefiore Medical Center, New York. He had no relevant disclosures.

Amputation: Often the best option

For many years there has been debate about the best management strategy for diabetic foot infection including osteomyelitis. The principles of appropriate antibiotics, surgical debridement, good wound care, and proper offloading will always remain. There are no randomized controlled trials of medical vs. surgical management of diabetic foot ulceration with osteomyelitis.

We now have a number of widely accepted ways to define wounds including Wagner and the SVS-adopted WIFI score. Historical papers are somewhat plagued by heterogeneity in the wounds included. This is even more apparent with any attempted meta-analyses. I think everyone would agree that the superficial toe wound with minimal cellulitis is best managed medically. The issue at hand is the profoundly neuropathic diabetic often with underlying anatomic abnormality and osteomyelitis. My esteemed colleague would suggest that we are too quick to pull a trigger and amputate a toe with underlying osteomyelitis.

I think the initial item for debate is the technique of diagnosis of osteomyelitis. We have multiple ways this is reported. Plain x-ray, bone scan, MRI, and “clinical osteomyelitis” are among the alternative ways osteomyelitis is diagnosed. The reliability of the last is the most variable because clinical osteomyelitis ranges from “probes close to bone” to exposed bone visible protruding from the wound bed. Given the variability of diagnostic techniques, the literature is an amalgam of clinical scenarios and difficult to navigate in a way to affect treatment decisions.

In addition, the medical treatment for osteomyelitis is highly variable. This commonly involves tunneled catheter insertion and 6 weeks to 3 months of IV antibiotics. In some institutions antibiotics are tailored to “wound culture.” Several of our infectious disease specialists prefer bone culture and pathology of bone demonstrating an acute destructive process. Obviously, this often requires surgical debridement to obtain a specimen. Antibiotic duration recommendations may vary from 1 week (if all infected bone is resected) to 90 days if a standalone antibiotic management is selected. Chronic osteomyelitis has a reinfection rate of up to 30%.¹

Medical management is not without risk. These risks include recurring infection with resistant organisms, wound deterioration, gastrointestinal complications (Clostridium difficile), catheter-related complications, and acute kidney injury. A recent paper found over 30% of patients treated medically for osteomyelitis developed acute kidney injury. These patients had more frequent hospitalization, recurring ulceration, and infection.² We have all experienced the patient with multiple hospitalizations and episodic AKI that culminates in ESRD requiring hemodialysis.

If the argument is with good follow-up these patients will ultimately experience preservation of the toe, I would take the stance that in our patient population of diabetics presenting with foot ulcer and osteomyelitis the average hemoglobin A1c is over 9. Although this is not only related to patient compliance, in many instances this is a large piece of the puzzle. It is hard to infer that suddenly with biopsy-proven osteomyelitis the patient will become compliant with medical management of the disease process. Certainly, in some circumstances, this is the case. There are a number of studies with a wide range of findings on HbA^1c as it relates to predictive value of wound healing.

There are various studies comparing surgical to medical management for osteomyelitis. Limb salvage is contingent upon location (forefoot, midfoot, hindfoot), the extent of infection, and patient comorbidities. The conclusion of the majority of these studies is that a standalone antibiotic treatment algorithm results in greater limb loss. Patients with peripheral occlusive disease and preadmission antibiotic use have been shown to have decreased wound healing. Minor amputation has been shown to be protective from mortality, risk of major amputation, and unfavorable discharge in patients admitted with a diagnosis of osteomyelitis.³ The major limb amputation rate for antibiotics alone is 20%-30% according to two trials with duration of antibiotics of 3 months.^4,5 The available randomized trials tend to exclude patients with severe infection (poorly defined), those with PAD, or those with severe comorbid conditions.

Cost of treatment is even more poorly delineated. Obviously, surgical treatment is not without cost to the health care system. Toe amputation especially when including the metatarsal head shifts pressure points and in the neuropathic patient may lead to recurrent ulceration. The average outpatient cost per patient per ulcer is often over $30,000. The goal of surgical treatment can be defined as trying to maintain the greatest degree of function with the least risk. Removing infected bone (i.e., minor amputation) limits exposure to prolonged antibiotic treatment and hopefully lessens recurring ulceration and hospitalization. This is only one piece of the puzzle, however. A multidisciplinary approach with endocrinology, infectious disease, and orthotics for offloading are keys to decrease future ulceration.

Although I do not advocate for widespread toe carnage as suggested by Dr. Koleilat, I do think liberal application of minor amputation to limit hospital stay, limit antibiotic duration and its inherent risk, and possibly affect readmission is often in the best interest of the patient and the system as a whole. Obviously, based on the variable reports in the literature there cannot be a single approach to these patients and the treatment must be individualized based on extent of infection, compliance of the patient, access to multidisciplinary care, and comorbid conditions.
 

References

1. World J Diabetes. 2017 Apr 15;8(4):135-42.

2. Diabetes Res Clin Pract. 2018 Jan;135:58-64.

3. Ann Surg. 2005;241(6):885-94.

4. Am J Med. 1987 Oct;83(4):653-60.

5. Am J Med.1989 Jun;86(6 Pt 2):801-8.

Dr. Mark P. Androes is division chief, vascular surgery, Greenville (S.C.) Health System. He had no relevant disclosures.

Amputation: Resistance is not futile!

What’s in a toe you may ask? Why worry about saving it? Just amputate and move on ...

Not so! I implore you to resist the desire. We vascular surgeons are accustomed to cutting off toes, even feet and legs. But when it comes to diabetic feet please reconsider. Just because there is osteomyelitis, I argue that does not necessitate amputation.

We all agree that ischemic gangrene and black mummified digits are beyond salvage. That’s not what my concern is. My focus is nonhealing ulcers with underlying osteomyelitis. Whether ischemic in etiology or neuropathic (or both), give salvage a try.

Why is this so important? My opponent will try to convince you that it’s not. He’ll try to sell you on how well people walk after amputation and that functional outcomes are great. But think beyond that for a second.

Amputation changes the foot architecture and weight distribution. In a person with neuropathy, this only predisposes them to more ulcers. More ulcers will mean more infection, which will lead to more amputations. This finally culminates in a major amputation.

In one reported study,¹ researchers followed more than 200,000 diabetics from 2010 until 2013. While the risk of amputation overall was relatively small (0.36% for major and 0.56% for minor amputations), prior minor amputation increased the risk of major amputation 10-fold and increased the risk of another minor (below-ankle) amputation 20-fold. Of those who had a major amputation, 57% died over the 3 years. This is not insignificant.

This does not also consider the morbidity and impact on lifestyle and quality of life for these patients. Many may not walk. Some will be relegated to nursing homes. Some will suffer from phantom limb pain. Many may never return to work. Even more will have difficulty with their daily lives, not to mention the psychological recovery also required.

The foot seems to be the only place where amputation as first-line therapy for osteomyelitis is accepted. We don’t do a hip disarticulation for ischial pressure sores with osteomyelitis. Calvarial osteomyelitis is also treated with antibiotics. I implore you: Don’t treat toes like vestigial organs.

Granted, there are subsets of patients who would benefit from amputations. A patient with painful Charcot foot may elect to have a below-knee amputation and move on with life. Another who has lost jobs or significant time due to recurrence of osteomyelitis may progress. A patient with severe sepsis and infection into a joint may need amputation.

But what other treatment options are there? I’m glad you inquired.

I primarily treat diabetic feet by treating the soft tissue envelope. Even if a patient presents with midfoot infection or necrotizing soft tissue infection, I treat it like a good old-fashioned abscess or necrotizing fasciitis:

1) Drain pus

2) Resect the dead stuff

3) Supportive care (antibiotics, fluids, aggressive wound care, etc.)

I try to leave the bones intact. When bone is exposed I take biopsies for culture and pathology. Any bone destroyed by the infection is focally debrided. I also take a specimen of the “bone margin” that I’m leaving behind and I send this to pathology looking for residual acute osteomyelitis. These steps are important as they dictate duration and choice of antibiotic therapy. This is in keeping with the consensus recommendations published in 2016.²

Even chronic wounds get a similar approach. If there is granulation, let it granulate and see if it will fill the wound. “Just because osteomyelitis is there, it doesn’t mean that for the toe we won’t care!”

There are exceptions of course. If the soft tissue is severely affected so the phalynx protrudes like something from the movie “Coco,” probably that should be amputated. Repeat offenders also may progress to amputation. But otherwise, hold off and give it a chance.

For the inpatient, aggressive irrigation of the wounds using the Veraflo system promotes granulation, even for short hospital stays of 1 week or less. Any ischemic component is worked up and addressed with percutaneous or open revascularization. We treat with prolonged antibiotics, and in questionable cases err on the side of giving long-term courses. These wounds need to be offloaded for tasks of daily living (going to the bathroom, making a sandwich, etc.) but otherwise we instruct patients to be effectively non–weight-bearing on that limb.

We also refer patients for hyperbaric therapy frequently. Now if you’re done groaning, I assure you this is not phony medicine. There is growing evidence to support not only improved rates of healing, but also significant cost savings and improved quality of life.³

In young patients or those with large defects, we also involve plastic and reconstructive surgery for secondary closure approaches (free flaps, adjacent tissue transfers, local autogenous or prosthetic grafting [Integra, Stravix, Dermacell, etc.] or other advanced techniques). This is particularly important in plantar wounds that will need to bear weight in the future, or in young patients for improved functional and cosmetic outcomes. For smaller wounds, we often use dermal/subdermal graft substitutes ourselves.

Even still, in nonambulatory or chronically debilitated and medically high-risk patients, maybe a different option is palliative wound care with or without antibiotics. A nonoperative approach to allow individuals to live the rest of their remaining days without undergoing a morbid and disfiguring amputation is not unreasonable. Many families are thankful for this option when given it. In the absence of refractory pain or overwhelming sepsis, we just let the wound do what it will do, understanding that someday the plan may change. This allows patients to continue to treat the wound without escalation to surgery or resorting to amputation.

In the end, just like we vascular surgeons tailor our “holistic” approach to the needs and desires of a single particular patient, we should approach wounds with a similar attitude. The presence of osteomyelitis in and of itself should not prompt one to bypass an entire algorithm, go straight to amputation, do not pass “Go” or “collect $200” (although the professional fee for a toe amputation is probably around $200). With a multidisciplinary and multimodal approach, and vested patients, salvage is possible in the majority of cases.
 

References

1. Diabetologia. 2018 Mar;61(3):626-35.

2. Diabet Foot Ankle. 2016 Jul 12. doi: 10.3402/dfa.v7.30079.

3. Int J Technol Assess Health Care. 2008 Spring;24(2):178-83.
 

Dr. Issam Koleilat is assistant professor and associate program director, Vascular Surgery Residency and Fellowship, Division of Vascular Surgery, Albert Einstein College of Medicine/Montefiore Medical Center, New York. He had no relevant disclosures.

Amputation: Often the best option

For many years there has been debate about the best management strategy for diabetic foot infection including osteomyelitis. The principles of appropriate antibiotics, surgical debridement, good wound care, and proper offloading will always remain. There are no randomized controlled trials of medical vs. surgical management of diabetic foot ulceration with osteomyelitis.

We now have a number of widely accepted ways to define wounds including Wagner and the SVS-adopted WIFI score. Historical papers are somewhat plagued by heterogeneity in the wounds included. This is even more apparent with any attempted meta-analyses. I think everyone would agree that the superficial toe wound with minimal cellulitis is best managed medically. The issue at hand is the profoundly neuropathic diabetic often with underlying anatomic abnormality and osteomyelitis. My esteemed colleague would suggest that we are too quick to pull a trigger and amputate a toe with underlying osteomyelitis.

I think the initial item for debate is the technique of diagnosis of osteomyelitis. We have multiple ways this is reported. Plain x-ray, bone scan, MRI, and “clinical osteomyelitis” are among the alternative ways osteomyelitis is diagnosed. The reliability of the last is the most variable because clinical osteomyelitis ranges from “probes close to bone” to exposed bone visible protruding from the wound bed. Given the variability of diagnostic techniques, the literature is an amalgam of clinical scenarios and difficult to navigate in a way to affect treatment decisions.

In addition, the medical treatment for osteomyelitis is highly variable. This commonly involves tunneled catheter insertion and 6 weeks to 3 months of IV antibiotics. In some institutions antibiotics are tailored to “wound culture.” Several of our infectious disease specialists prefer bone culture and pathology of bone demonstrating an acute destructive process. Obviously, this often requires surgical debridement to obtain a specimen. Antibiotic duration recommendations may vary from 1 week (if all infected bone is resected) to 90 days if a standalone antibiotic management is selected. Chronic osteomyelitis has a reinfection rate of up to 30%.¹

Medical management is not without risk. These risks include recurring infection with resistant organisms, wound deterioration, gastrointestinal complications (Clostridium difficile), catheter-related complications, and acute kidney injury. A recent paper found over 30% of patients treated medically for osteomyelitis developed acute kidney injury. These patients had more frequent hospitalization, recurring ulceration, and infection.² We have all experienced the patient with multiple hospitalizations and episodic AKI that culminates in ESRD requiring hemodialysis.

If the argument is with good follow-up these patients will ultimately experience preservation of the toe, I would take the stance that in our patient population of diabetics presenting with foot ulcer and osteomyelitis the average hemoglobin A1c is over 9. Although this is not only related to patient compliance, in many instances this is a large piece of the puzzle. It is hard to infer that suddenly with biopsy-proven osteomyelitis the patient will become compliant with medical management of the disease process. Certainly, in some circumstances, this is the case. There are a number of studies with a wide range of findings on HbA^1c as it relates to predictive value of wound healing.

There are various studies comparing surgical to medical management for osteomyelitis. Limb salvage is contingent upon location (forefoot, midfoot, hindfoot), the extent of infection, and patient comorbidities. The conclusion of the majority of these studies is that a standalone antibiotic treatment algorithm results in greater limb loss. Patients with peripheral occlusive disease and preadmission antibiotic use have been shown to have decreased wound healing. Minor amputation has been shown to be protective from mortality, risk of major amputation, and unfavorable discharge in patients admitted with a diagnosis of osteomyelitis.³ The major limb amputation rate for antibiotics alone is 20%-30% according to two trials with duration of antibiotics of 3 months.^4,5 The available randomized trials tend to exclude patients with severe infection (poorly defined), those with PAD, or those with severe comorbid conditions.

Cost of treatment is even more poorly delineated. Obviously, surgical treatment is not without cost to the health care system. Toe amputation especially when including the metatarsal head shifts pressure points and in the neuropathic patient may lead to recurrent ulceration. The average outpatient cost per patient per ulcer is often over $30,000. The goal of surgical treatment can be defined as trying to maintain the greatest degree of function with the least risk. Removing infected bone (i.e., minor amputation) limits exposure to prolonged antibiotic treatment and hopefully lessens recurring ulceration and hospitalization. This is only one piece of the puzzle, however. A multidisciplinary approach with endocrinology, infectious disease, and orthotics for offloading are keys to decrease future ulceration.

Although I do not advocate for widespread toe carnage as suggested by Dr. Koleilat, I do think liberal application of minor amputation to limit hospital stay, limit antibiotic duration and its inherent risk, and possibly affect readmission is often in the best interest of the patient and the system as a whole. Obviously, based on the variable reports in the literature there cannot be a single approach to these patients and the treatment must be individualized based on extent of infection, compliance of the patient, access to multidisciplinary care, and comorbid conditions.
 

References

1. World J Diabetes. 2017 Apr 15;8(4):135-42.

2. Diabetes Res Clin Pract. 2018 Jan;135:58-64.

3. Ann Surg. 2005;241(6):885-94.

4. Am J Med. 1987 Oct;83(4):653-60.

5. Am J Med.1989 Jun;86(6 Pt 2):801-8.

Dr. Mark P. Androes is division chief, vascular surgery, Greenville (S.C.) Health System. He had no relevant disclosures.

Using data from the Million Veteran Program (MVP), researchers found people with mutations for PDE3B, PCSK9, and ANGPTL4 had better cholesterol and triglyceride levels than did those without the mutations.

The PDE3B mutation seems to protect against heart disease. A PCSK9 mutation may reduce the risk not only of heart disease, but also abdominal aortic aneurysm. The ANGPTL4 mutation was linked to lower risk of type 2 DM.

MVP, 1 of the world’s largest databases of health and genomic information, partners with veterans receiving care in the VHA to study how genes affect health. It has enrolled > 700,000 veterans to date.

Using data from the Million Veteran Program (MVP), researchers found people with mutations for PDE3B, PCSK9, and ANGPTL4 had better cholesterol and triglyceride levels than did those without the mutations.

The PDE3B mutation seems to protect against heart disease. A PCSK9 mutation may reduce the risk not only of heart disease, but also abdominal aortic aneurysm. The ANGPTL4 mutation was linked to lower risk of type 2 DM.

MVP, 1 of the world’s largest databases of health and genomic information, partners with veterans receiving care in the VHA to study how genes affect health. It has enrolled > 700,000 veterans to date.

Using data from the Million Veteran Program (MVP), researchers found people with mutations for PDE3B, PCSK9, and ANGPTL4 had better cholesterol and triglyceride levels than did those without the mutations.

The PDE3B mutation seems to protect against heart disease. A PCSK9 mutation may reduce the risk not only of heart disease, but also abdominal aortic aneurysm. The ANGPTL4 mutation was linked to lower risk of type 2 DM.

MVP, 1 of the world’s largest databases of health and genomic information, partners with veterans receiving care in the VHA to study how genes affect health. It has enrolled > 700,000 veterans to date.

Click to Read the Supplement.

Based on material presented at the 2018 Metabolic & Endocrine Disease Summit (MEDS), this CME supplement to Clinician Reviews provides an overview of evidence and best practices for individualizing and intensifying antihyperglycemic therapy using current basal insulin options to achieve patient-centered goals in individuals with type 2 diabetes mellitus (T2DM). Physician assistants, nurse practitioners and nurses will have the opportunity to complete pre- and post-assessment questions to earn a maximum of 1.5 free CME/CE credits.
 
Dr. Vanita Aroda and Ms. Davida Kruger walk readers through the following learning objectives: 

• Explain the role/usage of ultralong-acting basal insulins for addressing the underlying pathophysiology of T2DM
• Compare ultralong-acting and other basal insulins regarding therapeutic characteristics, including pharmacokinetic/pharmacodynamic profiles, efficacy, safety, and dosing
• Develop patient-centered treatment regimens that include ultralong-acting insulins to minimize barriers to successful use of basal insulin therapy
  
   

Click to Read the Supplement.

Click to Read the Supplement.

Based on material presented at the 2018 Metabolic & Endocrine Disease Summit (MEDS), this CME supplement to Clinician Reviews provides an overview of evidence and best practices for individualizing and intensifying antihyperglycemic therapy using current basal insulin options to achieve patient-centered goals in individuals with type 2 diabetes mellitus (T2DM). Physician assistants, nurse practitioners and nurses will have the opportunity to complete pre- and post-assessment questions to earn a maximum of 1.5 free CME/CE credits.
 
Dr. Vanita Aroda and Ms. Davida Kruger walk readers through the following learning objectives: 

• Explain the role/usage of ultralong-acting basal insulins for addressing the underlying pathophysiology of T2DM
• Compare ultralong-acting and other basal insulins regarding therapeutic characteristics, including pharmacokinetic/pharmacodynamic profiles, efficacy, safety, and dosing
• Develop patient-centered treatment regimens that include ultralong-acting insulins to minimize barriers to successful use of basal insulin therapy
  
   

Click to Read the Supplement.

Click to Read the Supplement.

Based on material presented at the 2018 Metabolic & Endocrine Disease Summit (MEDS), this CME supplement to Clinician Reviews provides an overview of evidence and best practices for individualizing and intensifying antihyperglycemic therapy using current basal insulin options to achieve patient-centered goals in individuals with type 2 diabetes mellitus (T2DM). Physician assistants, nurse practitioners and nurses will have the opportunity to complete pre- and post-assessment questions to earn a maximum of 1.5 free CME/CE credits.
 
Dr. Vanita Aroda and Ms. Davida Kruger walk readers through the following learning objectives: 

• Explain the role/usage of ultralong-acting basal insulins for addressing the underlying pathophysiology of T2DM
• Compare ultralong-acting and other basal insulins regarding therapeutic characteristics, including pharmacokinetic/pharmacodynamic profiles, efficacy, safety, and dosing
• Develop patient-centered treatment regimens that include ultralong-acting insulins to minimize barriers to successful use of basal insulin therapy
  
   

Click to Read the Supplement.

Comorbid symptoms of anxiety and depression are associated with twice the risk of developing type 2 diabetes, according to a research paper published in the Journal of Affective Disorders.

The researchers sampled 78,025 Dutch adults aged 30-75 years from the Lifelines Cohort Study and assessed them for depressive and anxious symptoms using the Mini-International Neuropsychiatric Interview before sorting them into groups based on whether they had both, depressive symptoms alone, anxious symptoms alone, or neither.

Compared with participants with no symptoms, those with depressive and anxious symptoms had an unadjusted odds ratio of 2.05 (95% confidence interval, 1.40-3.00) of developing type 2 diabetes, reported Sonya S. Deschênes, PhD, of the department of psychiatry at McGill University, Montreal, and her associates. Furthermore, in an analysis that adjusted for sociodemographic and lifestyle factors and a family history of diabetes, Dr. Deschênes and her associates found that the participants with both kinds of symptoms had an OR of 1.93 (95% CI, 1.21-3.07) of developing type 2 diabetes. Those with only depressive or anxious symptoms alone did not have a statistically significant risk of developing type 2 diabetes.

A limitation cited by the researchers is that a screening tool was used to assess depressive and anxiety symptoms. Also, glycosylated hemoglobin data were available only for a subset of the participants.

Nevertheless, Dr. Deschênes and her associates wrote, the “study extends ... prior findings and suggests that having co-occurring symptoms of [depression] and anxiety is most strongly associated with an increased risk of [type 2 diabetes]. This study also provides further support for the notion that depression with comorbid anxiety symptoms might represent a group with distinct features.”

cpalmer@mdedge.com

SOURCE: Deschênes SS et al. J Affect Disorder. 2018 Oct 1. doi: 10.1016/j.jad.2018.05.029.

Comorbid symptoms of anxiety and depression are associated with twice the risk of developing type 2 diabetes, according to a research paper published in the Journal of Affective Disorders.

The researchers sampled 78,025 Dutch adults aged 30-75 years from the Lifelines Cohort Study and assessed them for depressive and anxious symptoms using the Mini-International Neuropsychiatric Interview before sorting them into groups based on whether they had both, depressive symptoms alone, anxious symptoms alone, or neither.

Compared with participants with no symptoms, those with depressive and anxious symptoms had an unadjusted odds ratio of 2.05 (95% confidence interval, 1.40-3.00) of developing type 2 diabetes, reported Sonya S. Deschênes, PhD, of the department of psychiatry at McGill University, Montreal, and her associates. Furthermore, in an analysis that adjusted for sociodemographic and lifestyle factors and a family history of diabetes, Dr. Deschênes and her associates found that the participants with both kinds of symptoms had an OR of 1.93 (95% CI, 1.21-3.07) of developing type 2 diabetes. Those with only depressive or anxious symptoms alone did not have a statistically significant risk of developing type 2 diabetes.

A limitation cited by the researchers is that a screening tool was used to assess depressive and anxiety symptoms. Also, glycosylated hemoglobin data were available only for a subset of the participants.

Nevertheless, Dr. Deschênes and her associates wrote, the “study extends ... prior findings and suggests that having co-occurring symptoms of [depression] and anxiety is most strongly associated with an increased risk of [type 2 diabetes]. This study also provides further support for the notion that depression with comorbid anxiety symptoms might represent a group with distinct features.”

cpalmer@mdedge.com

SOURCE: Deschênes SS et al. J Affect Disorder. 2018 Oct 1. doi: 10.1016/j.jad.2018.05.029.

Comorbid symptoms of anxiety and depression are associated with twice the risk of developing type 2 diabetes, according to a research paper published in the Journal of Affective Disorders.

The researchers sampled 78,025 Dutch adults aged 30-75 years from the Lifelines Cohort Study and assessed them for depressive and anxious symptoms using the Mini-International Neuropsychiatric Interview before sorting them into groups based on whether they had both, depressive symptoms alone, anxious symptoms alone, or neither.

Compared with participants with no symptoms, those with depressive and anxious symptoms had an unadjusted odds ratio of 2.05 (95% confidence interval, 1.40-3.00) of developing type 2 diabetes, reported Sonya S. Deschênes, PhD, of the department of psychiatry at McGill University, Montreal, and her associates. Furthermore, in an analysis that adjusted for sociodemographic and lifestyle factors and a family history of diabetes, Dr. Deschênes and her associates found that the participants with both kinds of symptoms had an OR of 1.93 (95% CI, 1.21-3.07) of developing type 2 diabetes. Those with only depressive or anxious symptoms alone did not have a statistically significant risk of developing type 2 diabetes.

A limitation cited by the researchers is that a screening tool was used to assess depressive and anxiety symptoms. Also, glycosylated hemoglobin data were available only for a subset of the participants.

Nevertheless, Dr. Deschênes and her associates wrote, the “study extends ... prior findings and suggests that having co-occurring symptoms of [depression] and anxiety is most strongly associated with an increased risk of [type 2 diabetes]. This study also provides further support for the notion that depression with comorbid anxiety symptoms might represent a group with distinct features.”

cpalmer@mdedge.com

SOURCE: Deschênes SS et al. J Affect Disorder. 2018 Oct 1. doi: 10.1016/j.jad.2018.05.029.

BERLIN – A significant reduction in severe hypoglycemia was seen within the first year of using continuous glucose monitoring in a registry study of more than 3,000 children with type 1 diabetes mellitus.

Prior to continuous glucose monitoring (CGM) use, 3.9% of 3,171 individuals, aged a median of 12 years, had hypoglycemia events requiring external help. After 6 months of using CGM, however, the rate of severe hypoglycemia had fallen to 1.2% (P = .10), which remained at 1.2% at 12 months (P = .002). The event rate (events per 100 patient-years) was 10.6 at baseline, 7.8 at 6 months, and 6.1 at 12 months.

Fewer hypoglycemia events leading to coma or convulsion were seen with CGM over time, with 1.3%, 0.6%, and 0.7% of patients reporting at least one event at baseline, 6 months (P = .08), and 12 months (P = .15), respectively. Corresponding event rates were 2.5, 1.6, and 1.7 per 100 patient-years.

“The use of continuous glucose monitoring systems has increased considerably in the past years in individuals with type 1 diabetes,” noted Julia Hermann, a PhD student at Ulm University (Germany), at the annual meeting of the European Association for the Study of Diabetes. “In Germany, for example, CGM use rose considerably when reimbursement by health insurance for CGM started in the summer of 2016.”

Ms. Hermann noted that there were studies showing improved metabolic control with CGM but that clinical studies were often limited by the population of patients studied, restricting treatment to selected patients who may have been adhering better to the use of CGM because they were in a trial.

The aim of the present study was to assess metabolic control and acute complications associated with CGM use in children during its first year of use in a real-world population. Anonymized patient records from the prospective German-Austrian-Luxembourg diabetes patient follow-up (DPV) registry were used.

The DPV database is a standardized, computed-based registry of more than 500,000 adult and pediatric patients with all types of diabetes. It was established in 1995 and receives data from 471 diabetes clinics in Germany, Austria, Luxembourg, and Switzerland.

For the current analysis patients had to be aged under 18 years, have had type 1 diabetes mellitus for at least 1 year, have data available for the months prior to starting CGM, and have at least 1 year of follow-up. For inclusion there also had to be documented use of CMG for at least half of the observation time.

The reduction of severe hypoglycemia observed was not accompanied by any deterioration in metabolic control, Ms. Hermann reported. The median baseline glycosylated hemoglobin (HbA1c) was 7.6% (59 mmol/mol) and this did not noticeably change at either the 6- or 12-month follow-up time point. Furthermore, the percentage of patients achieving a target HbA1c of less than 7.5% was 52% at baseline, 55% at 6 months, and 52% at 12 months.

The rate of diabetic ketoacidosis (DKA), defined as a pH of less than 7.3, also did not change significantly from baseline to the two follow-up points, with event rates of 1.5, 1.4, and 1.1, and the percentage of patients with at least one event being 0.8%, 0.5%, and 0.4%.

“We analyzed an overall well-controlled group of pediatric individuals with type 1 diabetes,” Ms. Hermann said. “We observed a significant reduction of severe hypoglycemia. We observed no improvements in HbA1c, but the overall HbA1c remained stable. We observed no statistically significant change in DKA.”

Future research will try to address some of the limitations that the current data may have, such as looking at a longer follow-up period and other endpoints such as hospitalization, Dr. Hermann suggested. Subgroup analyses are also planned.

“Large databases like the DPV registry ... provide a contemporary picture of diabetes treatment and how the use of diabetes technology has changed over the years and also how diabetes outcomes have improved over the years,” Ms. Hermann said. “It has yet to be seen how most recent changes and advances in diabetes technology will affect these long-term trends.”

The work was partially funded by the German Center for Diabetes Research, the German Diabetes Society, Abbott, and Sanofi. Dr. Hermann reported no personal conflicts of interest.
 

SOURCE: Hermann J et al. EASD 2018, Abstract 149.

BERLIN – A significant reduction in severe hypoglycemia was seen within the first year of using continuous glucose monitoring in a registry study of more than 3,000 children with type 1 diabetes mellitus.

Prior to continuous glucose monitoring (CGM) use, 3.9% of 3,171 individuals, aged a median of 12 years, had hypoglycemia events requiring external help. After 6 months of using CGM, however, the rate of severe hypoglycemia had fallen to 1.2% (P = .10), which remained at 1.2% at 12 months (P = .002). The event rate (events per 100 patient-years) was 10.6 at baseline, 7.8 at 6 months, and 6.1 at 12 months.

Fewer hypoglycemia events leading to coma or convulsion were seen with CGM over time, with 1.3%, 0.6%, and 0.7% of patients reporting at least one event at baseline, 6 months (P = .08), and 12 months (P = .15), respectively. Corresponding event rates were 2.5, 1.6, and 1.7 per 100 patient-years.

“The use of continuous glucose monitoring systems has increased considerably in the past years in individuals with type 1 diabetes,” noted Julia Hermann, a PhD student at Ulm University (Germany), at the annual meeting of the European Association for the Study of Diabetes. “In Germany, for example, CGM use rose considerably when reimbursement by health insurance for CGM started in the summer of 2016.”

Ms. Hermann noted that there were studies showing improved metabolic control with CGM but that clinical studies were often limited by the population of patients studied, restricting treatment to selected patients who may have been adhering better to the use of CGM because they were in a trial.

The aim of the present study was to assess metabolic control and acute complications associated with CGM use in children during its first year of use in a real-world population. Anonymized patient records from the prospective German-Austrian-Luxembourg diabetes patient follow-up (DPV) registry were used.

The DPV database is a standardized, computed-based registry of more than 500,000 adult and pediatric patients with all types of diabetes. It was established in 1995 and receives data from 471 diabetes clinics in Germany, Austria, Luxembourg, and Switzerland.

For the current analysis patients had to be aged under 18 years, have had type 1 diabetes mellitus for at least 1 year, have data available for the months prior to starting CGM, and have at least 1 year of follow-up. For inclusion there also had to be documented use of CMG for at least half of the observation time.

The reduction of severe hypoglycemia observed was not accompanied by any deterioration in metabolic control, Ms. Hermann reported. The median baseline glycosylated hemoglobin (HbA1c) was 7.6% (59 mmol/mol) and this did not noticeably change at either the 6- or 12-month follow-up time point. Furthermore, the percentage of patients achieving a target HbA1c of less than 7.5% was 52% at baseline, 55% at 6 months, and 52% at 12 months.

The rate of diabetic ketoacidosis (DKA), defined as a pH of less than 7.3, also did not change significantly from baseline to the two follow-up points, with event rates of 1.5, 1.4, and 1.1, and the percentage of patients with at least one event being 0.8%, 0.5%, and 0.4%.

“We analyzed an overall well-controlled group of pediatric individuals with type 1 diabetes,” Ms. Hermann said. “We observed a significant reduction of severe hypoglycemia. We observed no improvements in HbA1c, but the overall HbA1c remained stable. We observed no statistically significant change in DKA.”

Future research will try to address some of the limitations that the current data may have, such as looking at a longer follow-up period and other endpoints such as hospitalization, Dr. Hermann suggested. Subgroup analyses are also planned.

“Large databases like the DPV registry ... provide a contemporary picture of diabetes treatment and how the use of diabetes technology has changed over the years and also how diabetes outcomes have improved over the years,” Ms. Hermann said. “It has yet to be seen how most recent changes and advances in diabetes technology will affect these long-term trends.”

The work was partially funded by the German Center for Diabetes Research, the German Diabetes Society, Abbott, and Sanofi. Dr. Hermann reported no personal conflicts of interest.
 

SOURCE: Hermann J et al. EASD 2018, Abstract 149.

BERLIN – A significant reduction in severe hypoglycemia was seen within the first year of using continuous glucose monitoring in a registry study of more than 3,000 children with type 1 diabetes mellitus.

Prior to continuous glucose monitoring (CGM) use, 3.9% of 3,171 individuals, aged a median of 12 years, had hypoglycemia events requiring external help. After 6 months of using CGM, however, the rate of severe hypoglycemia had fallen to 1.2% (P = .10), which remained at 1.2% at 12 months (P = .002). The event rate (events per 100 patient-years) was 10.6 at baseline, 7.8 at 6 months, and 6.1 at 12 months.

Fewer hypoglycemia events leading to coma or convulsion were seen with CGM over time, with 1.3%, 0.6%, and 0.7% of patients reporting at least one event at baseline, 6 months (P = .08), and 12 months (P = .15), respectively. Corresponding event rates were 2.5, 1.6, and 1.7 per 100 patient-years.

“The use of continuous glucose monitoring systems has increased considerably in the past years in individuals with type 1 diabetes,” noted Julia Hermann, a PhD student at Ulm University (Germany), at the annual meeting of the European Association for the Study of Diabetes. “In Germany, for example, CGM use rose considerably when reimbursement by health insurance for CGM started in the summer of 2016.”

Ms. Hermann noted that there were studies showing improved metabolic control with CGM but that clinical studies were often limited by the population of patients studied, restricting treatment to selected patients who may have been adhering better to the use of CGM because they were in a trial.

The aim of the present study was to assess metabolic control and acute complications associated with CGM use in children during its first year of use in a real-world population. Anonymized patient records from the prospective German-Austrian-Luxembourg diabetes patient follow-up (DPV) registry were used.

The DPV database is a standardized, computed-based registry of more than 500,000 adult and pediatric patients with all types of diabetes. It was established in 1995 and receives data from 471 diabetes clinics in Germany, Austria, Luxembourg, and Switzerland.

For the current analysis patients had to be aged under 18 years, have had type 1 diabetes mellitus for at least 1 year, have data available for the months prior to starting CGM, and have at least 1 year of follow-up. For inclusion there also had to be documented use of CMG for at least half of the observation time.

The reduction of severe hypoglycemia observed was not accompanied by any deterioration in metabolic control, Ms. Hermann reported. The median baseline glycosylated hemoglobin (HbA1c) was 7.6% (59 mmol/mol) and this did not noticeably change at either the 6- or 12-month follow-up time point. Furthermore, the percentage of patients achieving a target HbA1c of less than 7.5% was 52% at baseline, 55% at 6 months, and 52% at 12 months.

The rate of diabetic ketoacidosis (DKA), defined as a pH of less than 7.3, also did not change significantly from baseline to the two follow-up points, with event rates of 1.5, 1.4, and 1.1, and the percentage of patients with at least one event being 0.8%, 0.5%, and 0.4%.

“We analyzed an overall well-controlled group of pediatric individuals with type 1 diabetes,” Ms. Hermann said. “We observed a significant reduction of severe hypoglycemia. We observed no improvements in HbA1c, but the overall HbA1c remained stable. We observed no statistically significant change in DKA.”

Future research will try to address some of the limitations that the current data may have, such as looking at a longer follow-up period and other endpoints such as hospitalization, Dr. Hermann suggested. Subgroup analyses are also planned.

“Large databases like the DPV registry ... provide a contemporary picture of diabetes treatment and how the use of diabetes technology has changed over the years and also how diabetes outcomes have improved over the years,” Ms. Hermann said. “It has yet to be seen how most recent changes and advances in diabetes technology will affect these long-term trends.”

The work was partially funded by the German Center for Diabetes Research, the German Diabetes Society, Abbott, and Sanofi. Dr. Hermann reported no personal conflicts of interest.
 

SOURCE: Hermann J et al. EASD 2018, Abstract 149.

Researchers from Harvard and Brigham and Women’s Hospital say their study is the first to fully evaluate the link between mutations in sodium glucose co-transporter-1 (SGLT-1)—the gene responsible for absorbing glucose in the gut—and cardiometabolic disease.

The researchers used genetic data from 8,478 participants in the 25-year Atherosclerosis Risk In Communities (ARIC) study. The participants who carried the mutation (6%) had a lower risk of type 2 diabetes, were less obese, had a lower incidence of heart failure, and a lower mortality rate than did those without the mutation, regardless of dietary intake.

The researchers suggest that their findings “open the door to improved therapies” for cardiometabolic diseases.

Researchers from Harvard and Brigham and Women’s Hospital say their study is the first to fully evaluate the link between mutations in sodium glucose co-transporter-1 (SGLT-1)—the gene responsible for absorbing glucose in the gut—and cardiometabolic disease.

The researchers used genetic data from 8,478 participants in the 25-year Atherosclerosis Risk In Communities (ARIC) study. The participants who carried the mutation (6%) had a lower risk of type 2 diabetes, were less obese, had a lower incidence of heart failure, and a lower mortality rate than did those without the mutation, regardless of dietary intake.

The researchers suggest that their findings “open the door to improved therapies” for cardiometabolic diseases.

Researchers from Harvard and Brigham and Women’s Hospital say their study is the first to fully evaluate the link between mutations in sodium glucose co-transporter-1 (SGLT-1)—the gene responsible for absorbing glucose in the gut—and cardiometabolic disease.

The researchers used genetic data from 8,478 participants in the 25-year Atherosclerosis Risk In Communities (ARIC) study. The participants who carried the mutation (6%) had a lower risk of type 2 diabetes, were less obese, had a lower incidence of heart failure, and a lower mortality rate than did those without the mutation, regardless of dietary intake.

The researchers suggest that their findings “open the door to improved therapies” for cardiometabolic diseases.

BERLIN – A dry-powder nasal formulation of glucagon was as good as intramuscular delivery for the reversal of severe hypoglycemia in patients with type 1 diabetes mellitus (T1DM) in a randomized controlled trial.

Sara Freeman/MDedge News

A 100% treatment success rate (n = 66) was seen for both nasal glucagon and intramuscular glucagon, defined as an increase in plasma glucose to 70 mg/dL (3.9 mmol/L or greater) or more or an increase of 20 mg/L (1.1 mmol/L) or more from the glucose nadir within 30 minutes of administration.

Furthermore, slightly more than 97% of patients achieved treatment success within 15 minutes in both treatment groups, with mean times of 11.4 minutes for the nasal formulation and 9.8 minutes for intramuscular administration.

Similar glucose responses were observed within 40 minutes of glucagon administration, study investigator Leona Plum-Mörschel, MD, PhD, reported at the annual meeting of the European Association for the Study of Diabetes. Dr. Plum-Mörschel is the CEO of the clinical research organization Profil Mainz (Germany), which helped Eli Lilly conduct the trial.

“We are all aware and fully agree that severe hypoglycemia is a serious and potentially life-threatening complication of diabetes treatment with insulin and the sulfonylureas,” said Dr. Plum-Mörschel. At least one in three patients with diabetes reports one hypoglycemic episode per year, she added. While this is quite prevalent in patients with T1DM, it’s not uncommon for those with type 2 diabetes mellitus (T2DM) to experience hypoglycemic episodes.

“Outside of a hospital or emergency room setting, injectable glucagon is currently the only option to treat severe hypoglycemia,” Dr. Plum-Mörschel reminded delegates. “Thankfully, the available injectable glucagon emergency kits are highly effective for the treatment of hypoglycemic events,” she added.

However, for untrained caregivers they can be “really challenging to use,” according to Dr. Plum-Mörschel. This is because the available kits involve multiple steps, including reconstitution, before being ready to inject. A severe hypoglycemic event is stressful enough without them worrying about getting things right, she suggested.

This is where a nasal formulation would be advantageous, and it is something that’s been touted to be on the horizon for a few years. Studies have previously shown that nasal glucagon is comparable to intramuscular glucagon in both adult and pediatric populations. Turning the formulation used in those studies into a commercial product however, has meant more clinical testing before being licensed by the regulatory authorities.

The nasal formulation consists of a dry power containing 3 mg glucagon that is provided in a single-use, compact, and thus, portable, device. It’s been designed to be stored at room temperature and is ready to use immediately. Pressing the plunger on the device releases the fine powder that does not require inhalation to work, which means it can be given easily to an unconscious patient with severe hypoglycemia.

“The aim of the present study was to compare the efficacy and safety of commercially manufactured nasal glucagon with intramuscular glucagon for the treatment of insulin-induced hypoglycemia in adults with type 1 diabetes,” Dr. Plum-Mörschel said.

It was a randomized, single-dose, crossover study involving 70 adult patients with T1DM with hypoglycemia artificially induced by an intravenous insulin infusion during the two dosing visits. Five minutes after stopping insulin, nasal glucagon (3 mg) or intramuscular (1 mg) was given, with multiple plasma glucose measurements taken for up to 90 minutes.

The mean age of participants was 41.7 years old, 61% were male, the mean duration of diabetes was 19.8 years, with a baseline glycated hemoglobin (HbA_1c) of 7.3%.

As for safety, Dr. Plum-Mörschel noted that nasal glucagon had a safety profile that was acceptable for emergency treatment. There was no difference between the nasal or intramuscular glucagon treatment groups in the percentages of patients experiencing treatment-emergent adverse events (at least 5% frequency): nausea was seen in 22% and 29%, vomiting in 10% and 12%, and headache in 12% and 7%, respectively.

Asking patients who had been treated with nasal glucagon about specific symptoms related to nasal administration showed around 63% had watery eyes, 49% nasal itching, 39% nasal congestion, 37% a runny nose, 24% sneezing, 20% itchy eyes, and 12.9% itchy throat. “All of these events were transient, generally mild or moderate in nature, and none were serious. Indeed, there were no deaths in the study and no other serious AEs [adverse events] occurred.”

Dr. Plum-Mörschel concluded: “These results support nasal glucagon as a viable alternative to intramuscular glucagon for the treatment of severe hypoglycemia.

“I personally would expect that, due to its simplicity of use, nasal glucagon will create a greater community who can render quick aid in a rescue situation.”

The study was funded by Eli Lilly. Dr. Plum-Mörschel is an employee of Profil Mainz and has received travel grants and speaker honoraria from Eli Lilly and Novo Nordisk.
 

SOURCE: Suico J et al. EASD 2018, Abstract 150.

BERLIN – A dry-powder nasal formulation of glucagon was as good as intramuscular delivery for the reversal of severe hypoglycemia in patients with type 1 diabetes mellitus (T1DM) in a randomized controlled trial.

Sara Freeman/MDedge News

A 100% treatment success rate (n = 66) was seen for both nasal glucagon and intramuscular glucagon, defined as an increase in plasma glucose to 70 mg/dL (3.9 mmol/L or greater) or more or an increase of 20 mg/L (1.1 mmol/L) or more from the glucose nadir within 30 minutes of administration.

Furthermore, slightly more than 97% of patients achieved treatment success within 15 minutes in both treatment groups, with mean times of 11.4 minutes for the nasal formulation and 9.8 minutes for intramuscular administration.

Similar glucose responses were observed within 40 minutes of glucagon administration, study investigator Leona Plum-Mörschel, MD, PhD, reported at the annual meeting of the European Association for the Study of Diabetes. Dr. Plum-Mörschel is the CEO of the clinical research organization Profil Mainz (Germany), which helped Eli Lilly conduct the trial.

“We are all aware and fully agree that severe hypoglycemia is a serious and potentially life-threatening complication of diabetes treatment with insulin and the sulfonylureas,” said Dr. Plum-Mörschel. At least one in three patients with diabetes reports one hypoglycemic episode per year, she added. While this is quite prevalent in patients with T1DM, it’s not uncommon for those with type 2 diabetes mellitus (T2DM) to experience hypoglycemic episodes.

“Outside of a hospital or emergency room setting, injectable glucagon is currently the only option to treat severe hypoglycemia,” Dr. Plum-Mörschel reminded delegates. “Thankfully, the available injectable glucagon emergency kits are highly effective for the treatment of hypoglycemic events,” she added.

However, for untrained caregivers they can be “really challenging to use,” according to Dr. Plum-Mörschel. This is because the available kits involve multiple steps, including reconstitution, before being ready to inject. A severe hypoglycemic event is stressful enough without them worrying about getting things right, she suggested.

This is where a nasal formulation would be advantageous, and it is something that’s been touted to be on the horizon for a few years. Studies have previously shown that nasal glucagon is comparable to intramuscular glucagon in both adult and pediatric populations. Turning the formulation used in those studies into a commercial product however, has meant more clinical testing before being licensed by the regulatory authorities.

The nasal formulation consists of a dry power containing 3 mg glucagon that is provided in a single-use, compact, and thus, portable, device. It’s been designed to be stored at room temperature and is ready to use immediately. Pressing the plunger on the device releases the fine powder that does not require inhalation to work, which means it can be given easily to an unconscious patient with severe hypoglycemia.

“The aim of the present study was to compare the efficacy and safety of commercially manufactured nasal glucagon with intramuscular glucagon for the treatment of insulin-induced hypoglycemia in adults with type 1 diabetes,” Dr. Plum-Mörschel said.

It was a randomized, single-dose, crossover study involving 70 adult patients with T1DM with hypoglycemia artificially induced by an intravenous insulin infusion during the two dosing visits. Five minutes after stopping insulin, nasal glucagon (3 mg) or intramuscular (1 mg) was given, with multiple plasma glucose measurements taken for up to 90 minutes.

The mean age of participants was 41.7 years old, 61% were male, the mean duration of diabetes was 19.8 years, with a baseline glycated hemoglobin (HbA_1c) of 7.3%.

As for safety, Dr. Plum-Mörschel noted that nasal glucagon had a safety profile that was acceptable for emergency treatment. There was no difference between the nasal or intramuscular glucagon treatment groups in the percentages of patients experiencing treatment-emergent adverse events (at least 5% frequency): nausea was seen in 22% and 29%, vomiting in 10% and 12%, and headache in 12% and 7%, respectively.

Asking patients who had been treated with nasal glucagon about specific symptoms related to nasal administration showed around 63% had watery eyes, 49% nasal itching, 39% nasal congestion, 37% a runny nose, 24% sneezing, 20% itchy eyes, and 12.9% itchy throat. “All of these events were transient, generally mild or moderate in nature, and none were serious. Indeed, there were no deaths in the study and no other serious AEs [adverse events] occurred.”

Dr. Plum-Mörschel concluded: “These results support nasal glucagon as a viable alternative to intramuscular glucagon for the treatment of severe hypoglycemia.

“I personally would expect that, due to its simplicity of use, nasal glucagon will create a greater community who can render quick aid in a rescue situation.”

The study was funded by Eli Lilly. Dr. Plum-Mörschel is an employee of Profil Mainz and has received travel grants and speaker honoraria from Eli Lilly and Novo Nordisk.
 

SOURCE: Suico J et al. EASD 2018, Abstract 150.

BERLIN – A dry-powder nasal formulation of glucagon was as good as intramuscular delivery for the reversal of severe hypoglycemia in patients with type 1 diabetes mellitus (T1DM) in a randomized controlled trial.

Sara Freeman/MDedge News

A 100% treatment success rate (n = 66) was seen for both nasal glucagon and intramuscular glucagon, defined as an increase in plasma glucose to 70 mg/dL (3.9 mmol/L or greater) or more or an increase of 20 mg/L (1.1 mmol/L) or more from the glucose nadir within 30 minutes of administration.

Furthermore, slightly more than 97% of patients achieved treatment success within 15 minutes in both treatment groups, with mean times of 11.4 minutes for the nasal formulation and 9.8 minutes for intramuscular administration.

Similar glucose responses were observed within 40 minutes of glucagon administration, study investigator Leona Plum-Mörschel, MD, PhD, reported at the annual meeting of the European Association for the Study of Diabetes. Dr. Plum-Mörschel is the CEO of the clinical research organization Profil Mainz (Germany), which helped Eli Lilly conduct the trial.

“We are all aware and fully agree that severe hypoglycemia is a serious and potentially life-threatening complication of diabetes treatment with insulin and the sulfonylureas,” said Dr. Plum-Mörschel. At least one in three patients with diabetes reports one hypoglycemic episode per year, she added. While this is quite prevalent in patients with T1DM, it’s not uncommon for those with type 2 diabetes mellitus (T2DM) to experience hypoglycemic episodes.

“Outside of a hospital or emergency room setting, injectable glucagon is currently the only option to treat severe hypoglycemia,” Dr. Plum-Mörschel reminded delegates. “Thankfully, the available injectable glucagon emergency kits are highly effective for the treatment of hypoglycemic events,” she added.

However, for untrained caregivers they can be “really challenging to use,” according to Dr. Plum-Mörschel. This is because the available kits involve multiple steps, including reconstitution, before being ready to inject. A severe hypoglycemic event is stressful enough without them worrying about getting things right, she suggested.

This is where a nasal formulation would be advantageous, and it is something that’s been touted to be on the horizon for a few years. Studies have previously shown that nasal glucagon is comparable to intramuscular glucagon in both adult and pediatric populations. Turning the formulation used in those studies into a commercial product however, has meant more clinical testing before being licensed by the regulatory authorities.

The nasal formulation consists of a dry power containing 3 mg glucagon that is provided in a single-use, compact, and thus, portable, device. It’s been designed to be stored at room temperature and is ready to use immediately. Pressing the plunger on the device releases the fine powder that does not require inhalation to work, which means it can be given easily to an unconscious patient with severe hypoglycemia.

“The aim of the present study was to compare the efficacy and safety of commercially manufactured nasal glucagon with intramuscular glucagon for the treatment of insulin-induced hypoglycemia in adults with type 1 diabetes,” Dr. Plum-Mörschel said.

It was a randomized, single-dose, crossover study involving 70 adult patients with T1DM with hypoglycemia artificially induced by an intravenous insulin infusion during the two dosing visits. Five minutes after stopping insulin, nasal glucagon (3 mg) or intramuscular (1 mg) was given, with multiple plasma glucose measurements taken for up to 90 minutes.

The mean age of participants was 41.7 years old, 61% were male, the mean duration of diabetes was 19.8 years, with a baseline glycated hemoglobin (HbA_1c) of 7.3%.

As for safety, Dr. Plum-Mörschel noted that nasal glucagon had a safety profile that was acceptable for emergency treatment. There was no difference between the nasal or intramuscular glucagon treatment groups in the percentages of patients experiencing treatment-emergent adverse events (at least 5% frequency): nausea was seen in 22% and 29%, vomiting in 10% and 12%, and headache in 12% and 7%, respectively.

Asking patients who had been treated with nasal glucagon about specific symptoms related to nasal administration showed around 63% had watery eyes, 49% nasal itching, 39% nasal congestion, 37% a runny nose, 24% sneezing, 20% itchy eyes, and 12.9% itchy throat. “All of these events were transient, generally mild or moderate in nature, and none were serious. Indeed, there were no deaths in the study and no other serious AEs [adverse events] occurred.”

Dr. Plum-Mörschel concluded: “These results support nasal glucagon as a viable alternative to intramuscular glucagon for the treatment of severe hypoglycemia.

“I personally would expect that, due to its simplicity of use, nasal glucagon will create a greater community who can render quick aid in a rescue situation.”

The study was funded by Eli Lilly. Dr. Plum-Mörschel is an employee of Profil Mainz and has received travel grants and speaker honoraria from Eli Lilly and Novo Nordisk.
 

SOURCE: Suico J et al. EASD 2018, Abstract 150.