DENVER – The routine administration of oxygen to terminally ill patients who are near death is unwarranted, according to the results of a randomized, double-blind trial.

"I would suggest that we always use the patient in respiratory distress as their own control in an n-of-1 trial of oxygen. If oxygen does reduce their distress, then that patient should have oxygen, but if it does not – if there’s no change in patient distress – then that oxygen can be discontinued, or certainly not initiated in the first place," Mary L. Campbell, Ph.D., declared at the annual meeting of the American Academy of Hospice and Palliative Care Medicine.

Oxygen has well-established benefits in hypoxemic patients with acute or chronic exacerbations of an underlying pulmonary condition, but without ever having been subjected to scientific scrutiny, oxygen administration has become routine for patients who are near death, asserted Dr. Campbell of Wayne State University, Detroit.

"Oxygen has become almost an iconic intervention at the end of life – as common as golf clubs on a Wednesday afternoon," she said.

And oxygen support is not a benign intervention. It’s expensive, particularly in home care, where it requires additional personnel and materials in the home, including a noisy, intrusive concentrator at the bedside. It also causes nasal drying and nosebleeds as well as feelings of suffocation, Dr. Campbell said.

["Comfort Seldom Comes from Cannula" -- Commentary, Hospitalist News, 4/6/12]

To assess the value of routine oxygen administration, she conducted a double-blind, randomized, crossover study involving 32 terminally ill patients. None was in respiratory distress at baseline, but all were at high risk for distress because of underlying COPD, heart failure, pneumonia, or lung cancer. All participants had a Palliative Performance Scale score of 30 or less, which is associated with a median 9- to 14-day survival.

Each patient received a capnoline – that is, a nasal cannula with a piece of plastic hanging down over the patient’s mouth to capture exhaled carbon dioxide. Next, randomly alternating 10-minute intervals of oxygen, medical air, and no flow were administered for 90 minutes.

The key finding: 29 of 32 patients experienced no distress during the 90-minute protocol, indicating that they didn’t need the oxygen. Yet, at enrollment, 27 patients had oxygen flowing, reflecting this widespread clinical practice at the end of life, Dr. Campbell said.

The remaining three patients rapidly became hypoxemic and distressed when crossed over from oxygen to no flow. They were returned to baseline oxygen and respiratory comfort.

As many of the study participants were unconscious or cognitively impaired and couldn’t self report their distress, the Respiratory Distress Observation Scale was assessed at baseline and for 10 minutes after every flow change. A score of 4 or less on the 0-16 scale indicates little or no distress; the average baseline score was 1.47, and it didn’t vary significantly during the different flow conditions, she reported.

The average oxygen saturation at baseline was 93.6%, and it didn’t change significantly during the 90-minute protocol.

Dr. Campbell said that she determines the need for oxygen in an end-of-life patient by taking the patient off oxygen for 10 minutes and watching for distress.

Several audience members predicted that the patient’s family is likely to object to this approach because oxygen has become an expected part of end-of-life care. Dr. Campbell responded that the solution to that problem is simply good communication.

"I think if you explain to families that this is a treatment that can be helpful but has side effects, and we always take away the things that aren’t helping when they’re no longer helping, you won’t have pushback from family members," she said.

Dr. Campbell’s study was funded by the Blue Cross/Blue Shield of Michigan Foundation. She reported having no financial conflicts.

DENVER – The routine administration of oxygen to terminally ill patients who are near death is unwarranted, according to the results of a randomized, double-blind trial.

"I would suggest that we always use the patient in respiratory distress as their own control in an n-of-1 trial of oxygen. If oxygen does reduce their distress, then that patient should have oxygen, but if it does not – if there’s no change in patient distress – then that oxygen can be discontinued, or certainly not initiated in the first place," Mary L. Campbell, Ph.D., declared at the annual meeting of the American Academy of Hospice and Palliative Care Medicine.

Oxygen has well-established benefits in hypoxemic patients with acute or chronic exacerbations of an underlying pulmonary condition, but without ever having been subjected to scientific scrutiny, oxygen administration has become routine for patients who are near death, asserted Dr. Campbell of Wayne State University, Detroit.

"Oxygen has become almost an iconic intervention at the end of life – as common as golf clubs on a Wednesday afternoon," she said.

And oxygen support is not a benign intervention. It’s expensive, particularly in home care, where it requires additional personnel and materials in the home, including a noisy, intrusive concentrator at the bedside. It also causes nasal drying and nosebleeds as well as feelings of suffocation, Dr. Campbell said.

["Comfort Seldom Comes from Cannula" -- Commentary, Hospitalist News, 4/6/12]

To assess the value of routine oxygen administration, she conducted a double-blind, randomized, crossover study involving 32 terminally ill patients. None was in respiratory distress at baseline, but all were at high risk for distress because of underlying COPD, heart failure, pneumonia, or lung cancer. All participants had a Palliative Performance Scale score of 30 or less, which is associated with a median 9- to 14-day survival.

Each patient received a capnoline – that is, a nasal cannula with a piece of plastic hanging down over the patient’s mouth to capture exhaled carbon dioxide. Next, randomly alternating 10-minute intervals of oxygen, medical air, and no flow were administered for 90 minutes.

The key finding: 29 of 32 patients experienced no distress during the 90-minute protocol, indicating that they didn’t need the oxygen. Yet, at enrollment, 27 patients had oxygen flowing, reflecting this widespread clinical practice at the end of life, Dr. Campbell said.

The remaining three patients rapidly became hypoxemic and distressed when crossed over from oxygen to no flow. They were returned to baseline oxygen and respiratory comfort.

As many of the study participants were unconscious or cognitively impaired and couldn’t self report their distress, the Respiratory Distress Observation Scale was assessed at baseline and for 10 minutes after every flow change. A score of 4 or less on the 0-16 scale indicates little or no distress; the average baseline score was 1.47, and it didn’t vary significantly during the different flow conditions, she reported.

The average oxygen saturation at baseline was 93.6%, and it didn’t change significantly during the 90-minute protocol.

Dr. Campbell said that she determines the need for oxygen in an end-of-life patient by taking the patient off oxygen for 10 minutes and watching for distress.

Several audience members predicted that the patient’s family is likely to object to this approach because oxygen has become an expected part of end-of-life care. Dr. Campbell responded that the solution to that problem is simply good communication.

"I think if you explain to families that this is a treatment that can be helpful but has side effects, and we always take away the things that aren’t helping when they’re no longer helping, you won’t have pushback from family members," she said.

Dr. Campbell’s study was funded by the Blue Cross/Blue Shield of Michigan Foundation. She reported having no financial conflicts.

DENVER – The routine administration of oxygen to terminally ill patients who are near death is unwarranted, according to the results of a randomized, double-blind trial.

"I would suggest that we always use the patient in respiratory distress as their own control in an n-of-1 trial of oxygen. If oxygen does reduce their distress, then that patient should have oxygen, but if it does not – if there’s no change in patient distress – then that oxygen can be discontinued, or certainly not initiated in the first place," Mary L. Campbell, Ph.D., declared at the annual meeting of the American Academy of Hospice and Palliative Care Medicine.

Oxygen has well-established benefits in hypoxemic patients with acute or chronic exacerbations of an underlying pulmonary condition, but without ever having been subjected to scientific scrutiny, oxygen administration has become routine for patients who are near death, asserted Dr. Campbell of Wayne State University, Detroit.

"Oxygen has become almost an iconic intervention at the end of life – as common as golf clubs on a Wednesday afternoon," she said.

And oxygen support is not a benign intervention. It’s expensive, particularly in home care, where it requires additional personnel and materials in the home, including a noisy, intrusive concentrator at the bedside. It also causes nasal drying and nosebleeds as well as feelings of suffocation, Dr. Campbell said.

["Comfort Seldom Comes from Cannula" -- Commentary, Hospitalist News, 4/6/12]

To assess the value of routine oxygen administration, she conducted a double-blind, randomized, crossover study involving 32 terminally ill patients. None was in respiratory distress at baseline, but all were at high risk for distress because of underlying COPD, heart failure, pneumonia, or lung cancer. All participants had a Palliative Performance Scale score of 30 or less, which is associated with a median 9- to 14-day survival.

Each patient received a capnoline – that is, a nasal cannula with a piece of plastic hanging down over the patient’s mouth to capture exhaled carbon dioxide. Next, randomly alternating 10-minute intervals of oxygen, medical air, and no flow were administered for 90 minutes.

The key finding: 29 of 32 patients experienced no distress during the 90-minute protocol, indicating that they didn’t need the oxygen. Yet, at enrollment, 27 patients had oxygen flowing, reflecting this widespread clinical practice at the end of life, Dr. Campbell said.

The remaining three patients rapidly became hypoxemic and distressed when crossed over from oxygen to no flow. They were returned to baseline oxygen and respiratory comfort.

As many of the study participants were unconscious or cognitively impaired and couldn’t self report their distress, the Respiratory Distress Observation Scale was assessed at baseline and for 10 minutes after every flow change. A score of 4 or less on the 0-16 scale indicates little or no distress; the average baseline score was 1.47, and it didn’t vary significantly during the different flow conditions, she reported.

The average oxygen saturation at baseline was 93.6%, and it didn’t change significantly during the 90-minute protocol.

Dr. Campbell said that she determines the need for oxygen in an end-of-life patient by taking the patient off oxygen for 10 minutes and watching for distress.

Several audience members predicted that the patient’s family is likely to object to this approach because oxygen has become an expected part of end-of-life care. Dr. Campbell responded that the solution to that problem is simply good communication.

"I think if you explain to families that this is a treatment that can be helpful but has side effects, and we always take away the things that aren’t helping when they’re no longer helping, you won’t have pushback from family members," she said.

Dr. Campbell’s study was funded by the Blue Cross/Blue Shield of Michigan Foundation. She reported having no financial conflicts.

People who receive a cancer diagnosis are at markedly increased risk for suicide and for fatal cardiovascular events in the following weeks, according to a large Swedish cohort study reported in the April 5 issue of the New England Journal of Medicine.

"This spike in risk was particularly prominent among patients in whom cancers with a poor prognosis were diagnosed, and was not explained by preexisting psychiatric or cardiovascular conditions," said Dr. Fang Fang of the department of medical epidemiology and biostatistics, Karolinska Institutet, Stockholm, and her associates.

The dramatic increase in mortality risk from suicide or cardiovascular causes also cannot be attributed to cancer treatment or cancer progression, since it peaks during the first week after diagnosis and declined over time rather than increasing as treatment intensified or disease worsened, they noted.

Previous studies have demonstrated that cancer patients are at increased risk for suicide and CV events, but most have attributed it to "the burden of living with a progressing cancer." Very few have explored the period immediately following a cancer diagnosis, Dr. Fang and her colleagues said.

They examined this time period using data from a Swedish national registry of cancers and causes of death, both of which must be reported by law in Sweden. The study period, 1991 through 2006, covered more than 6 million Swedes aged 30 and older at baseline.

A total of 534,154 people received a first cancer diagnosis during this interval, including 95,786 with prostate cancer, 74,977 with breast cancer (among women), 62,719 with colorectal cancer, 47,169 with skin cancer, 36,648 with lymphatic or hematopoietic cancer, 34,743 with lung cancer, and 13,447 with CNS cancer. Another 26,335 patients were pooled in a single category of "highly fatal cancers of the esophagus, liver, and pancreas," and the remaining 142,330 patients had other types of cancer.

During follow-up, there were 786 completed suicides among patients with any type of cancer, for a rate of 0.36 per 1,000 person-years. This was double the rate among Swedish adults who did not have cancer: 13,284 completed suicides for a rate of 0.18 per 1,000 person-years (N. Engl. J. Med. 2012;366:1310-8).

The rate of completed suicides peaked during the first week after cancer diagnosis, at 2.50 per 1,000 person-years.

"We found a relative risk of 4.8 during the first 12 weeks after diagnosis (110 patients; incidence rate, 0.95 per 1,000 person-years), with the highest relative risk observed for highly fatal cancers of the esophagus, liver, or pancreas, followed by lung cancer," they added.

The magnitude of elevated risk dropped rapidly after that, but remained higher than average beyond the first year for all cancers.

"Focusing on the first 52 weeks after a diagnosis of any cancer, we found a relative risk of 3.1 for suicide (260 patients; incidence rate, 0.60 per 1,000 person-years). The expected number of suicides, adjusted for all demographic factors, during these 52 weeks was 87, leaving 173 cases associated with cancer diagnoses," the researchers said.

The relative risks of suicide were stronger among patients who had no concomitant psychiatric disorders than among those with psychiatric disorders.

Turning to fatal cardiovascular events, there were 48,991 CV deaths among people who received a diagnosis of any cancer, for an incidence of 23.10 per 1,000 person-years. This rate is approximately three times higher than that for people who did not have cancer (543,144 deaths; incidence rate, 7.53 per 1,000 person-years.

As with suicide, the highest relative risk of CV death (5.6) peaked during the first week after diagnosis (1,318 patients; incidence rate, 116.8 per 1,000 person-years). The risk elevation was highest for central nervous system cancers, followed by highly fatal cancers of the esophagus, liver, or pancreas, and then by lung cancer.

Also as with suicide, the magnitude of the increased risk of CV death dropped rapidly after the first several weeks. It did not persist beyond the first year after diagnosis.

"Focusing on the first 4 weeks after a diagnosis of any cancer but CNS tumors, we found a relative risk of 3.3 for cardiovascular death (2,641 patients; incidence rate, 65.81 per 1,000 person-years). The adjusted expected number of CV deaths was 766 during these 4 weeks, leaving 1,875 deaths associated with a cancer diagnosis," the investigators said.

Of note was the finding that the increased hazards were seen in both men and women.

To adjust for unmeasured confounders, the researchers performed an additional case-crossover analysis among all cancer patients in the cohort who died from suicide or CV causes. The results "further allayed the concern" that there may be some alternative explanation for the observed associations, such as an unknown factor that causes cancer, suicide, and CV death.

Dr. Fang and her associates emphasized that their study "focused on hard outcomes alone, and thus probably did not capture the full extent of the psychological burden among patients with newly diagnosed cancer. Other potentially relevant outcomes, such as attempted suicide and severe but nonfatal CV events, remain to be explored," they noted.

In addition, this study involved only adults aged 30 years and older. Further studies are warranted to examine the immediate after-effects of a cancer diagnosis in children, adolescents, and young adults.

Most importantly, now that these elevated risks have been identified, future research must address prevention strategies, they said.

This study was supported by the Swedish Council for Working Life and Social Research, the Swedish Research Council, Hjärnfonden, and Svenska Sällskapet för Medicinsk Forskning. No financial conflicts of interest were reported.

People who receive a cancer diagnosis are at markedly increased risk for suicide and for fatal cardiovascular events in the following weeks, according to a large Swedish cohort study reported in the April 5 issue of the New England Journal of Medicine.

"This spike in risk was particularly prominent among patients in whom cancers with a poor prognosis were diagnosed, and was not explained by preexisting psychiatric or cardiovascular conditions," said Dr. Fang Fang of the department of medical epidemiology and biostatistics, Karolinska Institutet, Stockholm, and her associates.

The dramatic increase in mortality risk from suicide or cardiovascular causes also cannot be attributed to cancer treatment or cancer progression, since it peaks during the first week after diagnosis and declined over time rather than increasing as treatment intensified or disease worsened, they noted.

Previous studies have demonstrated that cancer patients are at increased risk for suicide and CV events, but most have attributed it to "the burden of living with a progressing cancer." Very few have explored the period immediately following a cancer diagnosis, Dr. Fang and her colleagues said.

They examined this time period using data from a Swedish national registry of cancers and causes of death, both of which must be reported by law in Sweden. The study period, 1991 through 2006, covered more than 6 million Swedes aged 30 and older at baseline.

A total of 534,154 people received a first cancer diagnosis during this interval, including 95,786 with prostate cancer, 74,977 with breast cancer (among women), 62,719 with colorectal cancer, 47,169 with skin cancer, 36,648 with lymphatic or hematopoietic cancer, 34,743 with lung cancer, and 13,447 with CNS cancer. Another 26,335 patients were pooled in a single category of "highly fatal cancers of the esophagus, liver, and pancreas," and the remaining 142,330 patients had other types of cancer.

During follow-up, there were 786 completed suicides among patients with any type of cancer, for a rate of 0.36 per 1,000 person-years. This was double the rate among Swedish adults who did not have cancer: 13,284 completed suicides for a rate of 0.18 per 1,000 person-years (N. Engl. J. Med. 2012;366:1310-8).

The rate of completed suicides peaked during the first week after cancer diagnosis, at 2.50 per 1,000 person-years.

"We found a relative risk of 4.8 during the first 12 weeks after diagnosis (110 patients; incidence rate, 0.95 per 1,000 person-years), with the highest relative risk observed for highly fatal cancers of the esophagus, liver, or pancreas, followed by lung cancer," they added.

The magnitude of elevated risk dropped rapidly after that, but remained higher than average beyond the first year for all cancers.

"Focusing on the first 52 weeks after a diagnosis of any cancer, we found a relative risk of 3.1 for suicide (260 patients; incidence rate, 0.60 per 1,000 person-years). The expected number of suicides, adjusted for all demographic factors, during these 52 weeks was 87, leaving 173 cases associated with cancer diagnoses," the researchers said.

The relative risks of suicide were stronger among patients who had no concomitant psychiatric disorders than among those with psychiatric disorders.

Turning to fatal cardiovascular events, there were 48,991 CV deaths among people who received a diagnosis of any cancer, for an incidence of 23.10 per 1,000 person-years. This rate is approximately three times higher than that for people who did not have cancer (543,144 deaths; incidence rate, 7.53 per 1,000 person-years.

As with suicide, the highest relative risk of CV death (5.6) peaked during the first week after diagnosis (1,318 patients; incidence rate, 116.8 per 1,000 person-years). The risk elevation was highest for central nervous system cancers, followed by highly fatal cancers of the esophagus, liver, or pancreas, and then by lung cancer.

Also as with suicide, the magnitude of the increased risk of CV death dropped rapidly after the first several weeks. It did not persist beyond the first year after diagnosis.

"Focusing on the first 4 weeks after a diagnosis of any cancer but CNS tumors, we found a relative risk of 3.3 for cardiovascular death (2,641 patients; incidence rate, 65.81 per 1,000 person-years). The adjusted expected number of CV deaths was 766 during these 4 weeks, leaving 1,875 deaths associated with a cancer diagnosis," the investigators said.

Of note was the finding that the increased hazards were seen in both men and women.

To adjust for unmeasured confounders, the researchers performed an additional case-crossover analysis among all cancer patients in the cohort who died from suicide or CV causes. The results "further allayed the concern" that there may be some alternative explanation for the observed associations, such as an unknown factor that causes cancer, suicide, and CV death.

Dr. Fang and her associates emphasized that their study "focused on hard outcomes alone, and thus probably did not capture the full extent of the psychological burden among patients with newly diagnosed cancer. Other potentially relevant outcomes, such as attempted suicide and severe but nonfatal CV events, remain to be explored," they noted.

In addition, this study involved only adults aged 30 years and older. Further studies are warranted to examine the immediate after-effects of a cancer diagnosis in children, adolescents, and young adults.

Most importantly, now that these elevated risks have been identified, future research must address prevention strategies, they said.

This study was supported by the Swedish Council for Working Life and Social Research, the Swedish Research Council, Hjärnfonden, and Svenska Sällskapet för Medicinsk Forskning. No financial conflicts of interest were reported.

People who receive a cancer diagnosis are at markedly increased risk for suicide and for fatal cardiovascular events in the following weeks, according to a large Swedish cohort study reported in the April 5 issue of the New England Journal of Medicine.

"This spike in risk was particularly prominent among patients in whom cancers with a poor prognosis were diagnosed, and was not explained by preexisting psychiatric or cardiovascular conditions," said Dr. Fang Fang of the department of medical epidemiology and biostatistics, Karolinska Institutet, Stockholm, and her associates.

The dramatic increase in mortality risk from suicide or cardiovascular causes also cannot be attributed to cancer treatment or cancer progression, since it peaks during the first week after diagnosis and declined over time rather than increasing as treatment intensified or disease worsened, they noted.

Previous studies have demonstrated that cancer patients are at increased risk for suicide and CV events, but most have attributed it to "the burden of living with a progressing cancer." Very few have explored the period immediately following a cancer diagnosis, Dr. Fang and her colleagues said.

They examined this time period using data from a Swedish national registry of cancers and causes of death, both of which must be reported by law in Sweden. The study period, 1991 through 2006, covered more than 6 million Swedes aged 30 and older at baseline.

A total of 534,154 people received a first cancer diagnosis during this interval, including 95,786 with prostate cancer, 74,977 with breast cancer (among women), 62,719 with colorectal cancer, 47,169 with skin cancer, 36,648 with lymphatic or hematopoietic cancer, 34,743 with lung cancer, and 13,447 with CNS cancer. Another 26,335 patients were pooled in a single category of "highly fatal cancers of the esophagus, liver, and pancreas," and the remaining 142,330 patients had other types of cancer.

During follow-up, there were 786 completed suicides among patients with any type of cancer, for a rate of 0.36 per 1,000 person-years. This was double the rate among Swedish adults who did not have cancer: 13,284 completed suicides for a rate of 0.18 per 1,000 person-years (N. Engl. J. Med. 2012;366:1310-8).

The rate of completed suicides peaked during the first week after cancer diagnosis, at 2.50 per 1,000 person-years.

"We found a relative risk of 4.8 during the first 12 weeks after diagnosis (110 patients; incidence rate, 0.95 per 1,000 person-years), with the highest relative risk observed for highly fatal cancers of the esophagus, liver, or pancreas, followed by lung cancer," they added.

The magnitude of elevated risk dropped rapidly after that, but remained higher than average beyond the first year for all cancers.

"Focusing on the first 52 weeks after a diagnosis of any cancer, we found a relative risk of 3.1 for suicide (260 patients; incidence rate, 0.60 per 1,000 person-years). The expected number of suicides, adjusted for all demographic factors, during these 52 weeks was 87, leaving 173 cases associated with cancer diagnoses," the researchers said.

The relative risks of suicide were stronger among patients who had no concomitant psychiatric disorders than among those with psychiatric disorders.

Turning to fatal cardiovascular events, there were 48,991 CV deaths among people who received a diagnosis of any cancer, for an incidence of 23.10 per 1,000 person-years. This rate is approximately three times higher than that for people who did not have cancer (543,144 deaths; incidence rate, 7.53 per 1,000 person-years.

As with suicide, the highest relative risk of CV death (5.6) peaked during the first week after diagnosis (1,318 patients; incidence rate, 116.8 per 1,000 person-years). The risk elevation was highest for central nervous system cancers, followed by highly fatal cancers of the esophagus, liver, or pancreas, and then by lung cancer.

Also as with suicide, the magnitude of the increased risk of CV death dropped rapidly after the first several weeks. It did not persist beyond the first year after diagnosis.

"Focusing on the first 4 weeks after a diagnosis of any cancer but CNS tumors, we found a relative risk of 3.3 for cardiovascular death (2,641 patients; incidence rate, 65.81 per 1,000 person-years). The adjusted expected number of CV deaths was 766 during these 4 weeks, leaving 1,875 deaths associated with a cancer diagnosis," the investigators said.

Of note was the finding that the increased hazards were seen in both men and women.

To adjust for unmeasured confounders, the researchers performed an additional case-crossover analysis among all cancer patients in the cohort who died from suicide or CV causes. The results "further allayed the concern" that there may be some alternative explanation for the observed associations, such as an unknown factor that causes cancer, suicide, and CV death.

Dr. Fang and her associates emphasized that their study "focused on hard outcomes alone, and thus probably did not capture the full extent of the psychological burden among patients with newly diagnosed cancer. Other potentially relevant outcomes, such as attempted suicide and severe but nonfatal CV events, remain to be explored," they noted.

In addition, this study involved only adults aged 30 years and older. Further studies are warranted to examine the immediate after-effects of a cancer diagnosis in children, adolescents, and young adults.

Most importantly, now that these elevated risks have been identified, future research must address prevention strategies, they said.

This study was supported by the Swedish Council for Working Life and Social Research, the Swedish Research Council, Hjärnfonden, and Svenska Sällskapet för Medicinsk Forskning. No financial conflicts of interest were reported.

DENVER – Low-dose adjunctive benzodiazepines are effective in combination with opioids for dyspnea in palliative care patients who don’t respond to opioids alone, according to Dr. Patama Gomutbutra.

When opioids alone aren’t bringing significant improvement, adding a benzodiazepine is worthwhile, she said. The question of whether benzodiazepines alone are effective in the management of dyspnea must await answers from randomized clinical trials.

Dr. Gomutbutra conducted a retrospective chart review of 303 inpatients with dyspnea evaluated by members of the University of California, San Francisco, palliative care program. These were seriously ill patients: Twenty-three percent had primary lung cancer, 32% had cancer outside the lung, 12% had heart failure, and 7% had chronic obstructive pulmonary disease. Of these patients, 47% died in the hospital and 25% were discharged to hospice.

At baseline, physicians rated dyspnea as severe in 19% of patients, moderate in 28%, and mild in 53%. At baseline, 49% of patients were already on opioids at a median dose of 52 mg/day; 87% of these patients remained on opioids at 24 hours, with a bump up in dose to a median of 60 mg/day. Of the patients not initially taking an opioid, 41% were placed on the medication at a median dose of 22 mg/day.

"Our results should not dissuade people from using opioids as the first-line treatment."

At baseline, 17% of patients were on a benzodiazepine at a median dose of 1 mg/day of oral lorazepam or its equivalent. At 24 hours, 24% of patients were on a benzodiazepine, again at a median daily dose of 1 mg.

At follow-up 24 hours after adjustment of dosages or addition of an opioid or a benzodiazepine, the population with severe dyspnea had fallen from 19% to 4%. Dyspnea was rated moderate in 18% and mild in 44%, and was absent in 34%.

Overall, 57% of patients had a clinically meaningful improvement in dyspnea of one severity grade or more, 37% remained the same, and the rest became worse, according to Dr. Gomutbutra of Chiang Mai (Thailand) University.

Taking an opioid and a benzodiazepine at follow-up was independently associated with a 2.1-fold increased likelihood of significant improvement in dyspnea. Having moderate or severe dyspnea at baseline was associated with 4.1- and 4.5-fold increased likelihoods of improvement, respectively.

Surprisingly, being on an opioid at baseline wasn’t associated with significant improvement at follow-up, even though opioids are guideline-recommended therapy for dyspnea.

Dr. Gomutbutra cautioned against overinterpretation of this finding, given that her study was retrospective and thus vulnerable to confounding. For example, she noted, the respiratory rate typically slows near death, so affected patients may not have received continued or increased doses of opioids.

"Our results should not dissuade people from using opioids as the first-line treatment," Dr. Gomutbutra emphasized.

Dr. Gomutbutra carried out this study after observing big differences in how dyspnea is managed in palliative care settings in the United States, compared with Thailand. While the median daily dose of opioids at baseline in the San Francisco study was 52 mg/day, a typical dose in Thailand would be 6 mg/day. And benzodiazepines are far more widely used in treating dyspnea there, she added.

She reported having no financial conflicts.

DENVER – Low-dose adjunctive benzodiazepines are effective in combination with opioids for dyspnea in palliative care patients who don’t respond to opioids alone, according to Dr. Patama Gomutbutra.

When opioids alone aren’t bringing significant improvement, adding a benzodiazepine is worthwhile, she said. The question of whether benzodiazepines alone are effective in the management of dyspnea must await answers from randomized clinical trials.

Dr. Gomutbutra conducted a retrospective chart review of 303 inpatients with dyspnea evaluated by members of the University of California, San Francisco, palliative care program. These were seriously ill patients: Twenty-three percent had primary lung cancer, 32% had cancer outside the lung, 12% had heart failure, and 7% had chronic obstructive pulmonary disease. Of these patients, 47% died in the hospital and 25% were discharged to hospice.

At baseline, physicians rated dyspnea as severe in 19% of patients, moderate in 28%, and mild in 53%. At baseline, 49% of patients were already on opioids at a median dose of 52 mg/day; 87% of these patients remained on opioids at 24 hours, with a bump up in dose to a median of 60 mg/day. Of the patients not initially taking an opioid, 41% were placed on the medication at a median dose of 22 mg/day.

"Our results should not dissuade people from using opioids as the first-line treatment."

At baseline, 17% of patients were on a benzodiazepine at a median dose of 1 mg/day of oral lorazepam or its equivalent. At 24 hours, 24% of patients were on a benzodiazepine, again at a median daily dose of 1 mg.

At follow-up 24 hours after adjustment of dosages or addition of an opioid or a benzodiazepine, the population with severe dyspnea had fallen from 19% to 4%. Dyspnea was rated moderate in 18% and mild in 44%, and was absent in 34%.

Overall, 57% of patients had a clinically meaningful improvement in dyspnea of one severity grade or more, 37% remained the same, and the rest became worse, according to Dr. Gomutbutra of Chiang Mai (Thailand) University.

Taking an opioid and a benzodiazepine at follow-up was independently associated with a 2.1-fold increased likelihood of significant improvement in dyspnea. Having moderate or severe dyspnea at baseline was associated with 4.1- and 4.5-fold increased likelihoods of improvement, respectively.

Surprisingly, being on an opioid at baseline wasn’t associated with significant improvement at follow-up, even though opioids are guideline-recommended therapy for dyspnea.

Dr. Gomutbutra cautioned against overinterpretation of this finding, given that her study was retrospective and thus vulnerable to confounding. For example, she noted, the respiratory rate typically slows near death, so affected patients may not have received continued or increased doses of opioids.

"Our results should not dissuade people from using opioids as the first-line treatment," Dr. Gomutbutra emphasized.

Dr. Gomutbutra carried out this study after observing big differences in how dyspnea is managed in palliative care settings in the United States, compared with Thailand. While the median daily dose of opioids at baseline in the San Francisco study was 52 mg/day, a typical dose in Thailand would be 6 mg/day. And benzodiazepines are far more widely used in treating dyspnea there, she added.

She reported having no financial conflicts.

DENVER – Low-dose adjunctive benzodiazepines are effective in combination with opioids for dyspnea in palliative care patients who don’t respond to opioids alone, according to Dr. Patama Gomutbutra.

When opioids alone aren’t bringing significant improvement, adding a benzodiazepine is worthwhile, she said. The question of whether benzodiazepines alone are effective in the management of dyspnea must await answers from randomized clinical trials.

Dr. Gomutbutra conducted a retrospective chart review of 303 inpatients with dyspnea evaluated by members of the University of California, San Francisco, palliative care program. These were seriously ill patients: Twenty-three percent had primary lung cancer, 32% had cancer outside the lung, 12% had heart failure, and 7% had chronic obstructive pulmonary disease. Of these patients, 47% died in the hospital and 25% were discharged to hospice.

At baseline, physicians rated dyspnea as severe in 19% of patients, moderate in 28%, and mild in 53%. At baseline, 49% of patients were already on opioids at a median dose of 52 mg/day; 87% of these patients remained on opioids at 24 hours, with a bump up in dose to a median of 60 mg/day. Of the patients not initially taking an opioid, 41% were placed on the medication at a median dose of 22 mg/day.

"Our results should not dissuade people from using opioids as the first-line treatment."

At baseline, 17% of patients were on a benzodiazepine at a median dose of 1 mg/day of oral lorazepam or its equivalent. At 24 hours, 24% of patients were on a benzodiazepine, again at a median daily dose of 1 mg.

At follow-up 24 hours after adjustment of dosages or addition of an opioid or a benzodiazepine, the population with severe dyspnea had fallen from 19% to 4%. Dyspnea was rated moderate in 18% and mild in 44%, and was absent in 34%.

Overall, 57% of patients had a clinically meaningful improvement in dyspnea of one severity grade or more, 37% remained the same, and the rest became worse, according to Dr. Gomutbutra of Chiang Mai (Thailand) University.

Taking an opioid and a benzodiazepine at follow-up was independently associated with a 2.1-fold increased likelihood of significant improvement in dyspnea. Having moderate or severe dyspnea at baseline was associated with 4.1- and 4.5-fold increased likelihoods of improvement, respectively.

Surprisingly, being on an opioid at baseline wasn’t associated with significant improvement at follow-up, even though opioids are guideline-recommended therapy for dyspnea.

Dr. Gomutbutra cautioned against overinterpretation of this finding, given that her study was retrospective and thus vulnerable to confounding. For example, she noted, the respiratory rate typically slows near death, so affected patients may not have received continued or increased doses of opioids.

"Our results should not dissuade people from using opioids as the first-line treatment," Dr. Gomutbutra emphasized.

Dr. Gomutbutra carried out this study after observing big differences in how dyspnea is managed in palliative care settings in the United States, compared with Thailand. While the median daily dose of opioids at baseline in the San Francisco study was 52 mg/day, a typical dose in Thailand would be 6 mg/day. And benzodiazepines are far more widely used in treating dyspnea there, she added.

She reported having no financial conflicts.

Peginesatide, a long-acting erythropoiesis-stimulating agent, has been approved as a treatment for anemia caused by chronic kidney disease in adults who are on dialysis, the Food and Drug Administration announced March 27.

This is the first erythropoiesis-stimulating agent (ESA) approved for this indication since 2001, Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in a statement. The product "offers patients and health care providers the convenience of receiving ESA therapy just once per month instead of more frequent injections," he noted.

The FDA approved the drug with a Risk Evaluation and Mitigation Strategy (REMS) that consists of educational elements for health care professionals and a requirement to assess data on how the drug is used, the statement said. The FDA can require a REMS for a product when the agency determines certain measures are needed to ensure that a drug’s benefits outweigh its risks.

Peginesatide is not approved for treating anemia in patients with chronic kidney disease (CKD) who are not on dialysis, for patients who are being treated for cancer and whose anemia is not caused by CKD, or for use instead of a red blood cell transfusion in patients who require immediate correction of anemia – which are approved indications for other ESAs. The label also states that treatment with peginesatide has not been shown to "improve symptoms, physical functioning, or health-related quality of life."

Peginesatide, which will be marketed as Omontys by Affymax Inc., is administered once a month, intravenously or subcutaneously. Treatment is started when the hemoglobin level is below 10 g/dL, according to the prescribing information.

Approval was based on two randomized open-label studies of 1,608 patients with CKD who were on dialysis, who, after their hemoglobin levels were stabilized with epoetin, were randomized to continue treatment with epoetin or peginesatide. Treatment with peginesatide was "as safe and effective as epoetin in maintaining hemoglobin levels within the studies’ prespecified range of 10 to 12 g/dL," according to the FDA statement. Diarrhea, vomiting, hypertension, and arthralgias were among the most common adverse effects reported in 10% or more of the patients on dialysis treated with peginesatide.

At a meeting in December 2011, the majority of an FDA advisory panel voted that peginesatide had a favorable risk-benefit profile for the approved indication. At that meeting, panelists were concerned about the higher rate of serious adverse events in patients treated with peginesatide, compared with those treated with darbepoetin, in studies of patients with anemia from CKD who were not on dialysis. But in the two studies of patients on dialysis, panelists agreed that the safety and efficacy of peginesatide were comparable with epoetin and cited the convenience of once-a-month dosing for patients.

Darbepoetin alfa, marketed as Aranesp, and epoetin alfa, marketed as Epogen and Procrit, are the ESAs approved in the United States; they are administered as often as one to three times per week. A pegylated epoetin beta (Mircera) is not available in the United States.

Like the other ESAs, the peginesatide prescribing information includes a boxed warning about the increased risks of deaths and serious cardiovascular events when higher hemoglobin levels are targeted, and the recommendation to use the lowest dose needed to reduce the need for transfusions.

Peginesatide, a long-acting erythropoiesis-stimulating agent, has been approved as a treatment for anemia caused by chronic kidney disease in adults who are on dialysis, the Food and Drug Administration announced March 27.

This is the first erythropoiesis-stimulating agent (ESA) approved for this indication since 2001, Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in a statement. The product "offers patients and health care providers the convenience of receiving ESA therapy just once per month instead of more frequent injections," he noted.

The FDA approved the drug with a Risk Evaluation and Mitigation Strategy (REMS) that consists of educational elements for health care professionals and a requirement to assess data on how the drug is used, the statement said. The FDA can require a REMS for a product when the agency determines certain measures are needed to ensure that a drug’s benefits outweigh its risks.

Peginesatide is not approved for treating anemia in patients with chronic kidney disease (CKD) who are not on dialysis, for patients who are being treated for cancer and whose anemia is not caused by CKD, or for use instead of a red blood cell transfusion in patients who require immediate correction of anemia – which are approved indications for other ESAs. The label also states that treatment with peginesatide has not been shown to "improve symptoms, physical functioning, or health-related quality of life."

Peginesatide, which will be marketed as Omontys by Affymax Inc., is administered once a month, intravenously or subcutaneously. Treatment is started when the hemoglobin level is below 10 g/dL, according to the prescribing information.

Approval was based on two randomized open-label studies of 1,608 patients with CKD who were on dialysis, who, after their hemoglobin levels were stabilized with epoetin, were randomized to continue treatment with epoetin or peginesatide. Treatment with peginesatide was "as safe and effective as epoetin in maintaining hemoglobin levels within the studies’ prespecified range of 10 to 12 g/dL," according to the FDA statement. Diarrhea, vomiting, hypertension, and arthralgias were among the most common adverse effects reported in 10% or more of the patients on dialysis treated with peginesatide.

At a meeting in December 2011, the majority of an FDA advisory panel voted that peginesatide had a favorable risk-benefit profile for the approved indication. At that meeting, panelists were concerned about the higher rate of serious adverse events in patients treated with peginesatide, compared with those treated with darbepoetin, in studies of patients with anemia from CKD who were not on dialysis. But in the two studies of patients on dialysis, panelists agreed that the safety and efficacy of peginesatide were comparable with epoetin and cited the convenience of once-a-month dosing for patients.

Darbepoetin alfa, marketed as Aranesp, and epoetin alfa, marketed as Epogen and Procrit, are the ESAs approved in the United States; they are administered as often as one to three times per week. A pegylated epoetin beta (Mircera) is not available in the United States.

Like the other ESAs, the peginesatide prescribing information includes a boxed warning about the increased risks of deaths and serious cardiovascular events when higher hemoglobin levels are targeted, and the recommendation to use the lowest dose needed to reduce the need for transfusions.

Peginesatide, a long-acting erythropoiesis-stimulating agent, has been approved as a treatment for anemia caused by chronic kidney disease in adults who are on dialysis, the Food and Drug Administration announced March 27.

This is the first erythropoiesis-stimulating agent (ESA) approved for this indication since 2001, Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in a statement. The product "offers patients and health care providers the convenience of receiving ESA therapy just once per month instead of more frequent injections," he noted.

The FDA approved the drug with a Risk Evaluation and Mitigation Strategy (REMS) that consists of educational elements for health care professionals and a requirement to assess data on how the drug is used, the statement said. The FDA can require a REMS for a product when the agency determines certain measures are needed to ensure that a drug’s benefits outweigh its risks.

Peginesatide is not approved for treating anemia in patients with chronic kidney disease (CKD) who are not on dialysis, for patients who are being treated for cancer and whose anemia is not caused by CKD, or for use instead of a red blood cell transfusion in patients who require immediate correction of anemia – which are approved indications for other ESAs. The label also states that treatment with peginesatide has not been shown to "improve symptoms, physical functioning, or health-related quality of life."

Peginesatide, which will be marketed as Omontys by Affymax Inc., is administered once a month, intravenously or subcutaneously. Treatment is started when the hemoglobin level is below 10 g/dL, according to the prescribing information.

Approval was based on two randomized open-label studies of 1,608 patients with CKD who were on dialysis, who, after their hemoglobin levels were stabilized with epoetin, were randomized to continue treatment with epoetin or peginesatide. Treatment with peginesatide was "as safe and effective as epoetin in maintaining hemoglobin levels within the studies’ prespecified range of 10 to 12 g/dL," according to the FDA statement. Diarrhea, vomiting, hypertension, and arthralgias were among the most common adverse effects reported in 10% or more of the patients on dialysis treated with peginesatide.

At a meeting in December 2011, the majority of an FDA advisory panel voted that peginesatide had a favorable risk-benefit profile for the approved indication. At that meeting, panelists were concerned about the higher rate of serious adverse events in patients treated with peginesatide, compared with those treated with darbepoetin, in studies of patients with anemia from CKD who were not on dialysis. But in the two studies of patients on dialysis, panelists agreed that the safety and efficacy of peginesatide were comparable with epoetin and cited the convenience of once-a-month dosing for patients.

Darbepoetin alfa, marketed as Aranesp, and epoetin alfa, marketed as Epogen and Procrit, are the ESAs approved in the United States; they are administered as often as one to three times per week. A pegylated epoetin beta (Mircera) is not available in the United States.

Like the other ESAs, the peginesatide prescribing information includes a boxed warning about the increased risks of deaths and serious cardiovascular events when higher hemoglobin levels are targeted, and the recommendation to use the lowest dose needed to reduce the need for transfusions.

DENVER – Electrocutaneous direct nerve stimulation via a device that scrambles "pain" and "no pain" signals reduced pain scores in preliminary studies involving patients with refractory chemotherapy-induced peripheral neuropathy, post-herpetic neuralgia, and other forms of chronic, disabling neuropathic pain.

"What I saw in our pilot study in patients with chemotherapy-induced peripheral neuropathy was about a 60% reduction in pain, and you knew right away – within the first 3 days – whether it was going to work," said Dr. Thomas J. Smith, professor of oncology and director of palliative care at Johns Hopkins University, Baltimore.

The device, known as the MC5-A Calmare Scrambler, received Food and Drug Administration clearance in February 2009 and has a Medicare payment code. The Scrambler has been used worldwide to treat more than 4,000 patients with no reported serious side effects. Yet few American physicians have heard of the therapy because Medicare fixed the payment so low (at $44) that there is little financial incentive to adopt it, according to Dr. Smith.

"There’s not much you can do in the hospital outpatient setting for $44. That barely covers the cost of the electrodes and maybe a technician’s time," he said at the annual meeting of the American Academy of Hospice and Palliative Care Medicine. "They set the reimbursement so low that it’s almost guaranteed not to be accepted by physicians until we get more evidence. But there are a significant number of studies in the works."

Chemotherapy-induced peripheral neuropathy affects up to 30%-40% of treated cancer patients. Dr. Smith’s pilot study involved 16 patients with refractory chemotherapy-induced peripheral neuropathy that lasted from 3 months to 8 years. The most common drugs involved were taxanes, platinum-based agents, and bortezomib (Velcade). Patients received hour-long Scrambler sessions daily on 10 consecutive working days.

Pain scores fell from a mean baseline score of 5.8 on a 10-point scale to 2.4 at the end of 10 days. Four patients had a pain score of 0, and 15 of the 16 patients had at least a 20% reduction in their pain score on day 10. There was no toxicity (J. Pain Symptom Manage. 2010;40:883-91).

"When you see that sort of effect size, you can’t believe it’s real," Dr. Smith observed. "That’s in fact what the first reviewer said of the article. He said, ‘I’ve never heard of this therapy, and I don’t believe it.’ I volunteered to give him the case reports."

Neuropathic pain reductions in the 60% range are what are seen with permanent implanted spinal cord stimulation devices, a therapy that runs about $40,000, he added.

Dr. Smith’s Scrambler pilot study results were confirmed in an Italian study involving 40 patients with refractory cancer and 33 with non–cancer-related pain. Their mean pretreatment pain scale score was 6.2, plunging to 1.6 after the 10th day of treatment, and rebounding to 2.9 at follow-up 2 weeks after the final treatment session. Again, there were no side effects (Support Care Cancer. 2012;20:405-12).

Separately, a group led by the Scrambler’s inventor, Giuseppe Marineo, Ph.D., of the University of Rome Tor Vergata, reported on a randomized but unblinded trial involving 52 patients with chronic failed back syndrome, post-herpetic neuralgia, or spinal cord stenosis. Subjects assigned to the control arm received pharmacotherapy according to European Federation of Neurological Societies guidelines (Eur. J. Neurol. 2010;17:1113-e88), while the intervention arm received 10 daily Scrambler sessions.

The pretreatment mean visual analog pain score fell in 1 month from 8.1 in a control group and 8.0 in a group treated with the Scrambler to 5.8 in controls and to 0.7 in the Scrambler group. At 2 and 3 months of follow-up, the mean pain scores were 1.4 and 2.0 points, respectively, in the Scrambler group but were still 5.7 and 5.9 points in controls. A marked and persistent reduction in allodynia was also documented in response to Scrambler therapy (J. Pain Symptom Manage. 2012;43:87-95).

With regard to post-herpetic neuralgia, Dr. Smith presented a series of 10 treated patients. Their mean pain scores dropped from 8 at baseline to less than 1 at 1 month, holding steady with a score of 2 at 2 and 3 months’ follow-up.

The Scrambler entails application of 16 ECG-like electrode pads placed along the dermatome above and below the site of pain. The Scrambler machine is designed to feed 16 different nerve potentials in rapid sequence, essentially in order to confuse a firing nerve. The electrical charge is individually adjusted to patient tolerance. It feels like a bee sting, according to Dr. Smith. The mechanism of benefit isn’t well defined as yet.

"It’s likely acting like direct spinal cord stimulation, raising the gate threshold," he continued. "My hypothesis – and the inventor’s hypothesis as well – is that the therapy resets the damaged nerves at several sites. You see some effect within the first 30 minutes, and that rapid onset suggests biochemical change. And the long-lasting nature of the pain relief suggests remodeling as well as adaptation to the pain."

Clearly, further studies need to be done – free of industry sponsorship, on larger numbers of patients, and with sham-treated controls – in order to fully assess the Scrambler therapy’s efficacy, mechanism of action, and optimal schedule.

"The Scrambler is one of several neurocutaneous direct nerve stimulation techniques that are interesting but absolutely require further testing," Dr. Smith said.

Dr. Charles L. Loprinzi, professor of oncology at the Mayo Clinic, Rochester, Minn., has started such studies, he noted. "He was at least as skeptical of this as I was, and he’s been impressed with results from this machine," Dr. Smith said, adding that Dr. Loprinzi’s research team is expected to present data later this year at the annual meeting of the American Society of Clinical Oncology.

Competitive Technologies Inc., based in Fairfield, Conn., has worldwide rights to the device. Dr. Smith reported having no financial conflicts.

DENVER – Electrocutaneous direct nerve stimulation via a device that scrambles "pain" and "no pain" signals reduced pain scores in preliminary studies involving patients with refractory chemotherapy-induced peripheral neuropathy, post-herpetic neuralgia, and other forms of chronic, disabling neuropathic pain.

"What I saw in our pilot study in patients with chemotherapy-induced peripheral neuropathy was about a 60% reduction in pain, and you knew right away – within the first 3 days – whether it was going to work," said Dr. Thomas J. Smith, professor of oncology and director of palliative care at Johns Hopkins University, Baltimore.

The device, known as the MC5-A Calmare Scrambler, received Food and Drug Administration clearance in February 2009 and has a Medicare payment code. The Scrambler has been used worldwide to treat more than 4,000 patients with no reported serious side effects. Yet few American physicians have heard of the therapy because Medicare fixed the payment so low (at $44) that there is little financial incentive to adopt it, according to Dr. Smith.

"There’s not much you can do in the hospital outpatient setting for $44. That barely covers the cost of the electrodes and maybe a technician’s time," he said at the annual meeting of the American Academy of Hospice and Palliative Care Medicine. "They set the reimbursement so low that it’s almost guaranteed not to be accepted by physicians until we get more evidence. But there are a significant number of studies in the works."

Chemotherapy-induced peripheral neuropathy affects up to 30%-40% of treated cancer patients. Dr. Smith’s pilot study involved 16 patients with refractory chemotherapy-induced peripheral neuropathy that lasted from 3 months to 8 years. The most common drugs involved were taxanes, platinum-based agents, and bortezomib (Velcade). Patients received hour-long Scrambler sessions daily on 10 consecutive working days.

Pain scores fell from a mean baseline score of 5.8 on a 10-point scale to 2.4 at the end of 10 days. Four patients had a pain score of 0, and 15 of the 16 patients had at least a 20% reduction in their pain score on day 10. There was no toxicity (J. Pain Symptom Manage. 2010;40:883-91).

"When you see that sort of effect size, you can’t believe it’s real," Dr. Smith observed. "That’s in fact what the first reviewer said of the article. He said, ‘I’ve never heard of this therapy, and I don’t believe it.’ I volunteered to give him the case reports."

Neuropathic pain reductions in the 60% range are what are seen with permanent implanted spinal cord stimulation devices, a therapy that runs about $40,000, he added.

Dr. Smith’s Scrambler pilot study results were confirmed in an Italian study involving 40 patients with refractory cancer and 33 with non–cancer-related pain. Their mean pretreatment pain scale score was 6.2, plunging to 1.6 after the 10th day of treatment, and rebounding to 2.9 at follow-up 2 weeks after the final treatment session. Again, there were no side effects (Support Care Cancer. 2012;20:405-12).

Separately, a group led by the Scrambler’s inventor, Giuseppe Marineo, Ph.D., of the University of Rome Tor Vergata, reported on a randomized but unblinded trial involving 52 patients with chronic failed back syndrome, post-herpetic neuralgia, or spinal cord stenosis. Subjects assigned to the control arm received pharmacotherapy according to European Federation of Neurological Societies guidelines (Eur. J. Neurol. 2010;17:1113-e88), while the intervention arm received 10 daily Scrambler sessions.

The pretreatment mean visual analog pain score fell in 1 month from 8.1 in a control group and 8.0 in a group treated with the Scrambler to 5.8 in controls and to 0.7 in the Scrambler group. At 2 and 3 months of follow-up, the mean pain scores were 1.4 and 2.0 points, respectively, in the Scrambler group but were still 5.7 and 5.9 points in controls. A marked and persistent reduction in allodynia was also documented in response to Scrambler therapy (J. Pain Symptom Manage. 2012;43:87-95).

With regard to post-herpetic neuralgia, Dr. Smith presented a series of 10 treated patients. Their mean pain scores dropped from 8 at baseline to less than 1 at 1 month, holding steady with a score of 2 at 2 and 3 months’ follow-up.

The Scrambler entails application of 16 ECG-like electrode pads placed along the dermatome above and below the site of pain. The Scrambler machine is designed to feed 16 different nerve potentials in rapid sequence, essentially in order to confuse a firing nerve. The electrical charge is individually adjusted to patient tolerance. It feels like a bee sting, according to Dr. Smith. The mechanism of benefit isn’t well defined as yet.

"It’s likely acting like direct spinal cord stimulation, raising the gate threshold," he continued. "My hypothesis – and the inventor’s hypothesis as well – is that the therapy resets the damaged nerves at several sites. You see some effect within the first 30 minutes, and that rapid onset suggests biochemical change. And the long-lasting nature of the pain relief suggests remodeling as well as adaptation to the pain."

Clearly, further studies need to be done – free of industry sponsorship, on larger numbers of patients, and with sham-treated controls – in order to fully assess the Scrambler therapy’s efficacy, mechanism of action, and optimal schedule.

"The Scrambler is one of several neurocutaneous direct nerve stimulation techniques that are interesting but absolutely require further testing," Dr. Smith said.

Dr. Charles L. Loprinzi, professor of oncology at the Mayo Clinic, Rochester, Minn., has started such studies, he noted. "He was at least as skeptical of this as I was, and he’s been impressed with results from this machine," Dr. Smith said, adding that Dr. Loprinzi’s research team is expected to present data later this year at the annual meeting of the American Society of Clinical Oncology.

Competitive Technologies Inc., based in Fairfield, Conn., has worldwide rights to the device. Dr. Smith reported having no financial conflicts.

DENVER – Electrocutaneous direct nerve stimulation via a device that scrambles "pain" and "no pain" signals reduced pain scores in preliminary studies involving patients with refractory chemotherapy-induced peripheral neuropathy, post-herpetic neuralgia, and other forms of chronic, disabling neuropathic pain.

"What I saw in our pilot study in patients with chemotherapy-induced peripheral neuropathy was about a 60% reduction in pain, and you knew right away – within the first 3 days – whether it was going to work," said Dr. Thomas J. Smith, professor of oncology and director of palliative care at Johns Hopkins University, Baltimore.

The device, known as the MC5-A Calmare Scrambler, received Food and Drug Administration clearance in February 2009 and has a Medicare payment code. The Scrambler has been used worldwide to treat more than 4,000 patients with no reported serious side effects. Yet few American physicians have heard of the therapy because Medicare fixed the payment so low (at $44) that there is little financial incentive to adopt it, according to Dr. Smith.

"There’s not much you can do in the hospital outpatient setting for $44. That barely covers the cost of the electrodes and maybe a technician’s time," he said at the annual meeting of the American Academy of Hospice and Palliative Care Medicine. "They set the reimbursement so low that it’s almost guaranteed not to be accepted by physicians until we get more evidence. But there are a significant number of studies in the works."

Chemotherapy-induced peripheral neuropathy affects up to 30%-40% of treated cancer patients. Dr. Smith’s pilot study involved 16 patients with refractory chemotherapy-induced peripheral neuropathy that lasted from 3 months to 8 years. The most common drugs involved were taxanes, platinum-based agents, and bortezomib (Velcade). Patients received hour-long Scrambler sessions daily on 10 consecutive working days.

Pain scores fell from a mean baseline score of 5.8 on a 10-point scale to 2.4 at the end of 10 days. Four patients had a pain score of 0, and 15 of the 16 patients had at least a 20% reduction in their pain score on day 10. There was no toxicity (J. Pain Symptom Manage. 2010;40:883-91).

"When you see that sort of effect size, you can’t believe it’s real," Dr. Smith observed. "That’s in fact what the first reviewer said of the article. He said, ‘I’ve never heard of this therapy, and I don’t believe it.’ I volunteered to give him the case reports."

Neuropathic pain reductions in the 60% range are what are seen with permanent implanted spinal cord stimulation devices, a therapy that runs about $40,000, he added.

Dr. Smith’s Scrambler pilot study results were confirmed in an Italian study involving 40 patients with refractory cancer and 33 with non–cancer-related pain. Their mean pretreatment pain scale score was 6.2, plunging to 1.6 after the 10th day of treatment, and rebounding to 2.9 at follow-up 2 weeks after the final treatment session. Again, there were no side effects (Support Care Cancer. 2012;20:405-12).

Separately, a group led by the Scrambler’s inventor, Giuseppe Marineo, Ph.D., of the University of Rome Tor Vergata, reported on a randomized but unblinded trial involving 52 patients with chronic failed back syndrome, post-herpetic neuralgia, or spinal cord stenosis. Subjects assigned to the control arm received pharmacotherapy according to European Federation of Neurological Societies guidelines (Eur. J. Neurol. 2010;17:1113-e88), while the intervention arm received 10 daily Scrambler sessions.

The pretreatment mean visual analog pain score fell in 1 month from 8.1 in a control group and 8.0 in a group treated with the Scrambler to 5.8 in controls and to 0.7 in the Scrambler group. At 2 and 3 months of follow-up, the mean pain scores were 1.4 and 2.0 points, respectively, in the Scrambler group but were still 5.7 and 5.9 points in controls. A marked and persistent reduction in allodynia was also documented in response to Scrambler therapy (J. Pain Symptom Manage. 2012;43:87-95).

With regard to post-herpetic neuralgia, Dr. Smith presented a series of 10 treated patients. Their mean pain scores dropped from 8 at baseline to less than 1 at 1 month, holding steady with a score of 2 at 2 and 3 months’ follow-up.

The Scrambler entails application of 16 ECG-like electrode pads placed along the dermatome above and below the site of pain. The Scrambler machine is designed to feed 16 different nerve potentials in rapid sequence, essentially in order to confuse a firing nerve. The electrical charge is individually adjusted to patient tolerance. It feels like a bee sting, according to Dr. Smith. The mechanism of benefit isn’t well defined as yet.

"It’s likely acting like direct spinal cord stimulation, raising the gate threshold," he continued. "My hypothesis – and the inventor’s hypothesis as well – is that the therapy resets the damaged nerves at several sites. You see some effect within the first 30 minutes, and that rapid onset suggests biochemical change. And the long-lasting nature of the pain relief suggests remodeling as well as adaptation to the pain."

Clearly, further studies need to be done – free of industry sponsorship, on larger numbers of patients, and with sham-treated controls – in order to fully assess the Scrambler therapy’s efficacy, mechanism of action, and optimal schedule.

"The Scrambler is one of several neurocutaneous direct nerve stimulation techniques that are interesting but absolutely require further testing," Dr. Smith said.

Dr. Charles L. Loprinzi, professor of oncology at the Mayo Clinic, Rochester, Minn., has started such studies, he noted. "He was at least as skeptical of this as I was, and he’s been impressed with results from this machine," Dr. Smith said, adding that Dr. Loprinzi’s research team is expected to present data later this year at the annual meeting of the American Society of Clinical Oncology.

Competitive Technologies Inc., based in Fairfield, Conn., has worldwide rights to the device. Dr. Smith reported having no financial conflicts.