Pain

Another randomized trial, on the heels of the recently published SAMSON, has concluded – many would say confirmed – that statin therapy is no more likely than placebo to “cause” muscle pain in most patients who report such symptoms while taking the drugs.

Affected patients who sorely doubt that conclusion might possibly embrace statins, researchers say, if the new trial’s creative methodology could somehow be applied to them in clinical practice.

The recent SAMSON trial made waves in November 2020 by concluding, with some caveats, that about 90% of the burden of muscle symptoms reported by patients on statins may be attributable to a nocebo effect; that is, they are attributed to the drugs – perhaps because of negative expectations – but not actually caused by them.

The new trial, StatinWISE (Statin Web-based Investigation of Side Effects), triple the size but similar in design and conducted parallel to SAMSON, similarly saw no important differences in patient-reported muscle symptom prevalence or severity during administration of atorvastatin 20 mg/day or placebo, in withdrawal from the study because of such symptoms, or in patient quality of life.

The findings also support years of observational evidence that argues against a statin effect on muscle symptoms except in rare cases of confirmed myopathy, as well as results from randomized trials like ODYSSEY ALTERNATIVE and GAUSS-3, in which significant muscle symptoms in “statin-intolerant” patients were unusual, note StatinWISE investigators in their report, published online Feb. 24 in BMJ, with lead author Emily Herrett, MSc, PhD, London School of Hygiene and Tropical Medicine.

“I’m hoping it can change minds a bit and reassure people. That was part of the reason we did it, to inform this debate about harms and benefits of statins,” principal investigator Liam Smeeth, MBChB, MSc, PhD, from the same institution, said during a virtual press conference on the trial conducted by the U.K. nonprofit Science Media Centre.

“In thinking through whether to take a statin or not, people can be reassured that these muscle symptoms are rare; they aren’t common. Aches and pains are common, but are not caused by statins,” said Dr. Smeeth, who is senior author on the trial publication.

Another goal of the 200-patient study, he said, was to explore whether patients who had experienced muscle symptoms on a statin but were willing to explore whether the statin was to blame could be convinced – depending on what they learned in the trial – to stay on the drugs.

It seemed to work; two-thirds of the participants who finished the study “decided that they would actually want to try starting statins again, which was quite amazing.”

But there was a “slight caveat,” Dr. Smeeth observed. “To join our trial, yes, you had to have had a bad experience with statins, but you probably had to be a little bit open to the idea of trying them again. So, I can’t claim that that two-thirds would apply to everybody in the population.”

Because StatinWISE entered only patients who had reported severe muscle symptoms on a statin but hadn’t showed significant enzymatic evidence of myopathy, all had either taken themselves off the statin or were “considering” it. And the study had excluded anyone with “persistent, generalized, unexplained muscle pain” regardless of any statin therapy.

“This was very deliberately a select group of people who had serious problems taking statins. This was not a random sample by any means,” Dr. Smeeth said.

“The patients in the study were willing to participate and take statins again,” suggesting they “may not be completely representative of all those who believe they experience side effects with statins, as anyone who refused to take statins ever again would not have been recruited,” observed Tim Chico, MBChB, MD, University of Sheffield (England) in a Science Media Centre press release on StatinWISE.

Still, even among this “supersaturated group of people” selected for having had muscle symptoms on statins, Dr. Smeeth said at the briefing, “in almost all cases, their pains and aches were no worse on statins than they were on placebo. We’re not saying that anyone is making up their aches and pains. These are real aches and pains. What we’re showing very clearly is that those aches and pains are no worse on statins than they are on placebo.”
 

Rechallenge is possible

Some people are more likely than others to experience adverse reactions to any drug, “and that’s true of statins,” Neil J. Stone, MD, Northwestern University, Chicago, told this news organization. But StatinWISE underscores that many patients with muscle symptoms on the drugs can be convinced to continue with them rather than stop them entirely.

“The study didn’t say that everybody who has symptoms on a statin is having a nocebo effect,” said Dr. Stone, vice chair for the multisociety 2018 Guideline on the Management of Blood Cholesterol, who was not involved with StatinWISE.

“It simply said,” allowing for some caveats, “that a significant number of patients may have symptoms that don’t preclude them from being rechallenged with a statin again, once they understand what this nocebo effect is.”

And, Dr. Stone said, “it amplifies the 2018 guidelines, with their emphasis on the clinician-patient discussion before starting therapy,” by showing that statin-associated muscle pain isn’t necessarily caused by the drugs and isn’t a reason to stop them.

“That there is a second study confirming SAMSON is helpful, and the results are helpful because they say many of these patients, once they are shown the results, can be rechallenged and will then tolerate statins,” Steven E. Nissen, MD, Cleveland Clinic, said in an interview.

“They were able to get two-thirds of those completing the trial into long-term treatment, which I think is obviously very admirable and very important,” said Dr. Nissen, who was GAUSS-3 principal investigator but not associated with StatinWISE.

“I think it is important, however, that we not completely dismiss patients who complain of adverse effects. Because, in fact, there probably are some people who do have muscle-related symptoms,” he said. “But you know, to really call somebody statin intolerant, they really should fail three statins, which would be a very good standard.”

In his experience, said Patrick M. Moriarty, MD, who directs the Atherosclerosis & Lipoprotein-Apheresis Center at the University of Kansas Medical Center, Kansas City, perhaps 80%-90% of patients who believe they are statin intolerant because of muscle symptoms are actually not statin intolerant at all.

“I think a massive amount of it is supratentorial,” Dr. Moriarty, who was not part of StatinWISE, told this news organization. It comes directly from “what they heard, what they read, or what they were told – and at their age, they’re going to have aches and pains.”
 

Value of the n-of-1 trial

Dr. Smeeth and colleagues framed StatinWISE in part as a test of a strategy for overcoming nocebo-based aversion to statins. One goal was to see whether these methods might be helpful in practice for convincing patients who want to reject statins because of muscle symptoms to give the drugs another chance.

In StatinWISE, patients were individually assigned to take atorvastatin or placebo in randomized order with multiple blinding during each of six successive 2-month periods, so that they were on one or the other agent half the time. They rated their symptoms at the end of each period.

So the trial in composite was, as the publication states, “a series of randomized, placebo-controlled n-of-1 trials.” SAMSON followed a similar scheme, except – as previously reported – it had specified 4 months of atorvastatin, 4 months of placebo, and 4 months with patients on neither statin nor placebo.

StatinWISE “provides a useful approach (the n = 1 study) that could be used in real life to help patients understand the cause of their own possible side effects, which could also be applied to medications other than statins,” Dr. Chico added in the Science Media Centre release.

“I often encounter people who have a firmly held view that statins cause muscle pains, even when they haven’t taken these medications themselves, and I hope that this study may help change this view and make them willing to try such an ‘experiment,’ ” he said.

Others aren’t sure an experiment resembling an n-of-1 trial would be practical or effective when conducted in routine practice.

More efficient and useful, Dr. Moriarty noted, would be for physicians to nurture a close relationship with patients, one that could help transform their negative feelings about statins into a willingness to accept the drugs. “This is a trust you have to build; these are human beings.”

He said getting the patient’s confidence is critical. “You have to explain the pluses and minuses of getting treatment, of the 30% reduction in cardiovascular events that occur with the statin. You don’t go ‘testing this and that.’ I think it’s more about getting them on board.”
 

No statin effect on muscle symptoms

Patients in StatinWISE were recruited from 50 primary care practices in England and Wales from December 2016 to April 2018, the report notes; their mean age was 69 years, and 58% were men. Of the 200 patients, 151 recorded muscle-symptom scores for at least one statin period and one placebo period, and so were included in the primary-endpoint assessment.

The mean muscle symptom score was lower on statin therapy than on placebo (1.68 vs. 2.57), but there was no significant difference in adjusted analysis (mean difference, –0.11 (95% confidence interval, –0.36 to 0.14; P = .40).

Statins showed no significant effect on development of muscle symptoms overall, it was reported, with an odds ratio of 1.11 (99% confidence interval, 0.62-1.99). Nor was there an effect on “muscle symptoms that could not be attributed to another cause,” (OR, 1.22; 95% CI, 0.77-1.94).

Of the 80 withdrawals during the study for any reason, 43% occurred when the patient was on the statin, 49% when the patient was on placebo, and 9% after randomization but before either statin or placebo had been initiated. Of those, 33 were because of “intolerable muscle symptoms,” says the report. But withdrawal occurred about as often on statin therapy as off the drug – 9% and 7%, respectively – throughout the 1-year study.

“This study provides further evidence through the lived experience of individuals that muscle pains often attributed to statins are not due to the drug,” said Sir Nilesh J. Samani, MBChB, MD, medical director for the British Heart Foundation, as quoted in the Science Media Centre press release.

“The use of each patient as their own control in the trial provides a powerful way of distinguishing the effect of a statin from that of taking a pill,” he said. “The findings should give confidence to patients who may be concerned about taking statins.”

StatinWISE was funded by the National Institute for Health Research-Health Technology Program and sponsored by the London School of Hygiene and Tropical Medicine. The authors declare that they have “no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.” Dr. Smeeth reports receiving grants from GlaxoSmithKline, and personal fees for advisory work from AstraZeneca and GlaxoSmithKline. Dr. Stone reports no industry relationships or other disclosures. Dr. Nissen reports that his center has received funding for clinical trials from AbbVie, Amgen, AstraZeneca, Cerenis, Eli Lilly, Esperion, Medtronic, MyoKardia, Novartis, Orexigen, Pfizer, Takeda, The Medicines Company, and Silence Therapeutics; that he is involved in these trials but receives no personal remuneration; and that he consults for many pharmaceutical companies but requires them to donate all honoraria or fees directly to charity so that he receives neither income nor a tax deduction. Dr. Chico had no conflicts. Dr. Moriarty declared no relevant conflicts of interest. Dr. Samani had no disclosures.

A version of this article first appeared on Medscape.com.

Another randomized trial, on the heels of the recently published SAMSON, has concluded – many would say confirmed – that statin therapy is no more likely than placebo to “cause” muscle pain in most patients who report such symptoms while taking the drugs.

Affected patients who sorely doubt that conclusion might possibly embrace statins, researchers say, if the new trial’s creative methodology could somehow be applied to them in clinical practice.

The recent SAMSON trial made waves in November 2020 by concluding, with some caveats, that about 90% of the burden of muscle symptoms reported by patients on statins may be attributable to a nocebo effect; that is, they are attributed to the drugs – perhaps because of negative expectations – but not actually caused by them.

The new trial, StatinWISE (Statin Web-based Investigation of Side Effects), triple the size but similar in design and conducted parallel to SAMSON, similarly saw no important differences in patient-reported muscle symptom prevalence or severity during administration of atorvastatin 20 mg/day or placebo, in withdrawal from the study because of such symptoms, or in patient quality of life.

The findings also support years of observational evidence that argues against a statin effect on muscle symptoms except in rare cases of confirmed myopathy, as well as results from randomized trials like ODYSSEY ALTERNATIVE and GAUSS-3, in which significant muscle symptoms in “statin-intolerant” patients were unusual, note StatinWISE investigators in their report, published online Feb. 24 in BMJ, with lead author Emily Herrett, MSc, PhD, London School of Hygiene and Tropical Medicine.

“I’m hoping it can change minds a bit and reassure people. That was part of the reason we did it, to inform this debate about harms and benefits of statins,” principal investigator Liam Smeeth, MBChB, MSc, PhD, from the same institution, said during a virtual press conference on the trial conducted by the U.K. nonprofit Science Media Centre.

“In thinking through whether to take a statin or not, people can be reassured that these muscle symptoms are rare; they aren’t common. Aches and pains are common, but are not caused by statins,” said Dr. Smeeth, who is senior author on the trial publication.

Another goal of the 200-patient study, he said, was to explore whether patients who had experienced muscle symptoms on a statin but were willing to explore whether the statin was to blame could be convinced – depending on what they learned in the trial – to stay on the drugs.

It seemed to work; two-thirds of the participants who finished the study “decided that they would actually want to try starting statins again, which was quite amazing.”

But there was a “slight caveat,” Dr. Smeeth observed. “To join our trial, yes, you had to have had a bad experience with statins, but you probably had to be a little bit open to the idea of trying them again. So, I can’t claim that that two-thirds would apply to everybody in the population.”

Because StatinWISE entered only patients who had reported severe muscle symptoms on a statin but hadn’t showed significant enzymatic evidence of myopathy, all had either taken themselves off the statin or were “considering” it. And the study had excluded anyone with “persistent, generalized, unexplained muscle pain” regardless of any statin therapy.

“This was very deliberately a select group of people who had serious problems taking statins. This was not a random sample by any means,” Dr. Smeeth said.

“The patients in the study were willing to participate and take statins again,” suggesting they “may not be completely representative of all those who believe they experience side effects with statins, as anyone who refused to take statins ever again would not have been recruited,” observed Tim Chico, MBChB, MD, University of Sheffield (England) in a Science Media Centre press release on StatinWISE.

Still, even among this “supersaturated group of people” selected for having had muscle symptoms on statins, Dr. Smeeth said at the briefing, “in almost all cases, their pains and aches were no worse on statins than they were on placebo. We’re not saying that anyone is making up their aches and pains. These are real aches and pains. What we’re showing very clearly is that those aches and pains are no worse on statins than they are on placebo.”
 

Rechallenge is possible

Some people are more likely than others to experience adverse reactions to any drug, “and that’s true of statins,” Neil J. Stone, MD, Northwestern University, Chicago, told this news organization. But StatinWISE underscores that many patients with muscle symptoms on the drugs can be convinced to continue with them rather than stop them entirely.

“The study didn’t say that everybody who has symptoms on a statin is having a nocebo effect,” said Dr. Stone, vice chair for the multisociety 2018 Guideline on the Management of Blood Cholesterol, who was not involved with StatinWISE.

“It simply said,” allowing for some caveats, “that a significant number of patients may have symptoms that don’t preclude them from being rechallenged with a statin again, once they understand what this nocebo effect is.”

And, Dr. Stone said, “it amplifies the 2018 guidelines, with their emphasis on the clinician-patient discussion before starting therapy,” by showing that statin-associated muscle pain isn’t necessarily caused by the drugs and isn’t a reason to stop them.

“That there is a second study confirming SAMSON is helpful, and the results are helpful because they say many of these patients, once they are shown the results, can be rechallenged and will then tolerate statins,” Steven E. Nissen, MD, Cleveland Clinic, said in an interview.

“They were able to get two-thirds of those completing the trial into long-term treatment, which I think is obviously very admirable and very important,” said Dr. Nissen, who was GAUSS-3 principal investigator but not associated with StatinWISE.

“I think it is important, however, that we not completely dismiss patients who complain of adverse effects. Because, in fact, there probably are some people who do have muscle-related symptoms,” he said. “But you know, to really call somebody statin intolerant, they really should fail three statins, which would be a very good standard.”

In his experience, said Patrick M. Moriarty, MD, who directs the Atherosclerosis & Lipoprotein-Apheresis Center at the University of Kansas Medical Center, Kansas City, perhaps 80%-90% of patients who believe they are statin intolerant because of muscle symptoms are actually not statin intolerant at all.

“I think a massive amount of it is supratentorial,” Dr. Moriarty, who was not part of StatinWISE, told this news organization. It comes directly from “what they heard, what they read, or what they were told – and at their age, they’re going to have aches and pains.”
 

Value of the n-of-1 trial

Dr. Smeeth and colleagues framed StatinWISE in part as a test of a strategy for overcoming nocebo-based aversion to statins. One goal was to see whether these methods might be helpful in practice for convincing patients who want to reject statins because of muscle symptoms to give the drugs another chance.

In StatinWISE, patients were individually assigned to take atorvastatin or placebo in randomized order with multiple blinding during each of six successive 2-month periods, so that they were on one or the other agent half the time. They rated their symptoms at the end of each period.

So the trial in composite was, as the publication states, “a series of randomized, placebo-controlled n-of-1 trials.” SAMSON followed a similar scheme, except – as previously reported – it had specified 4 months of atorvastatin, 4 months of placebo, and 4 months with patients on neither statin nor placebo.

StatinWISE “provides a useful approach (the n = 1 study) that could be used in real life to help patients understand the cause of their own possible side effects, which could also be applied to medications other than statins,” Dr. Chico added in the Science Media Centre release.

“I often encounter people who have a firmly held view that statins cause muscle pains, even when they haven’t taken these medications themselves, and I hope that this study may help change this view and make them willing to try such an ‘experiment,’ ” he said.

Others aren’t sure an experiment resembling an n-of-1 trial would be practical or effective when conducted in routine practice.

More efficient and useful, Dr. Moriarty noted, would be for physicians to nurture a close relationship with patients, one that could help transform their negative feelings about statins into a willingness to accept the drugs. “This is a trust you have to build; these are human beings.”

He said getting the patient’s confidence is critical. “You have to explain the pluses and minuses of getting treatment, of the 30% reduction in cardiovascular events that occur with the statin. You don’t go ‘testing this and that.’ I think it’s more about getting them on board.”
 

No statin effect on muscle symptoms

Patients in StatinWISE were recruited from 50 primary care practices in England and Wales from December 2016 to April 2018, the report notes; their mean age was 69 years, and 58% were men. Of the 200 patients, 151 recorded muscle-symptom scores for at least one statin period and one placebo period, and so were included in the primary-endpoint assessment.

The mean muscle symptom score was lower on statin therapy than on placebo (1.68 vs. 2.57), but there was no significant difference in adjusted analysis (mean difference, –0.11 (95% confidence interval, –0.36 to 0.14; P = .40).

Statins showed no significant effect on development of muscle symptoms overall, it was reported, with an odds ratio of 1.11 (99% confidence interval, 0.62-1.99). Nor was there an effect on “muscle symptoms that could not be attributed to another cause,” (OR, 1.22; 95% CI, 0.77-1.94).

Of the 80 withdrawals during the study for any reason, 43% occurred when the patient was on the statin, 49% when the patient was on placebo, and 9% after randomization but before either statin or placebo had been initiated. Of those, 33 were because of “intolerable muscle symptoms,” says the report. But withdrawal occurred about as often on statin therapy as off the drug – 9% and 7%, respectively – throughout the 1-year study.

“This study provides further evidence through the lived experience of individuals that muscle pains often attributed to statins are not due to the drug,” said Sir Nilesh J. Samani, MBChB, MD, medical director for the British Heart Foundation, as quoted in the Science Media Centre press release.

“The use of each patient as their own control in the trial provides a powerful way of distinguishing the effect of a statin from that of taking a pill,” he said. “The findings should give confidence to patients who may be concerned about taking statins.”

StatinWISE was funded by the National Institute for Health Research-Health Technology Program and sponsored by the London School of Hygiene and Tropical Medicine. The authors declare that they have “no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.” Dr. Smeeth reports receiving grants from GlaxoSmithKline, and personal fees for advisory work from AstraZeneca and GlaxoSmithKline. Dr. Stone reports no industry relationships or other disclosures. Dr. Nissen reports that his center has received funding for clinical trials from AbbVie, Amgen, AstraZeneca, Cerenis, Eli Lilly, Esperion, Medtronic, MyoKardia, Novartis, Orexigen, Pfizer, Takeda, The Medicines Company, and Silence Therapeutics; that he is involved in these trials but receives no personal remuneration; and that he consults for many pharmaceutical companies but requires them to donate all honoraria or fees directly to charity so that he receives neither income nor a tax deduction. Dr. Chico had no conflicts. Dr. Moriarty declared no relevant conflicts of interest. Dr. Samani had no disclosures.

A version of this article first appeared on Medscape.com.

Another randomized trial, on the heels of the recently published SAMSON, has concluded – many would say confirmed – that statin therapy is no more likely than placebo to “cause” muscle pain in most patients who report such symptoms while taking the drugs.

Affected patients who sorely doubt that conclusion might possibly embrace statins, researchers say, if the new trial’s creative methodology could somehow be applied to them in clinical practice.

The recent SAMSON trial made waves in November 2020 by concluding, with some caveats, that about 90% of the burden of muscle symptoms reported by patients on statins may be attributable to a nocebo effect; that is, they are attributed to the drugs – perhaps because of negative expectations – but not actually caused by them.

The new trial, StatinWISE (Statin Web-based Investigation of Side Effects), triple the size but similar in design and conducted parallel to SAMSON, similarly saw no important differences in patient-reported muscle symptom prevalence or severity during administration of atorvastatin 20 mg/day or placebo, in withdrawal from the study because of such symptoms, or in patient quality of life.

The findings also support years of observational evidence that argues against a statin effect on muscle symptoms except in rare cases of confirmed myopathy, as well as results from randomized trials like ODYSSEY ALTERNATIVE and GAUSS-3, in which significant muscle symptoms in “statin-intolerant” patients were unusual, note StatinWISE investigators in their report, published online Feb. 24 in BMJ, with lead author Emily Herrett, MSc, PhD, London School of Hygiene and Tropical Medicine.

“I’m hoping it can change minds a bit and reassure people. That was part of the reason we did it, to inform this debate about harms and benefits of statins,” principal investigator Liam Smeeth, MBChB, MSc, PhD, from the same institution, said during a virtual press conference on the trial conducted by the U.K. nonprofit Science Media Centre.

“In thinking through whether to take a statin or not, people can be reassured that these muscle symptoms are rare; they aren’t common. Aches and pains are common, but are not caused by statins,” said Dr. Smeeth, who is senior author on the trial publication.

Another goal of the 200-patient study, he said, was to explore whether patients who had experienced muscle symptoms on a statin but were willing to explore whether the statin was to blame could be convinced – depending on what they learned in the trial – to stay on the drugs.

It seemed to work; two-thirds of the participants who finished the study “decided that they would actually want to try starting statins again, which was quite amazing.”

But there was a “slight caveat,” Dr. Smeeth observed. “To join our trial, yes, you had to have had a bad experience with statins, but you probably had to be a little bit open to the idea of trying them again. So, I can’t claim that that two-thirds would apply to everybody in the population.”

Because StatinWISE entered only patients who had reported severe muscle symptoms on a statin but hadn’t showed significant enzymatic evidence of myopathy, all had either taken themselves off the statin or were “considering” it. And the study had excluded anyone with “persistent, generalized, unexplained muscle pain” regardless of any statin therapy.

“This was very deliberately a select group of people who had serious problems taking statins. This was not a random sample by any means,” Dr. Smeeth said.

“The patients in the study were willing to participate and take statins again,” suggesting they “may not be completely representative of all those who believe they experience side effects with statins, as anyone who refused to take statins ever again would not have been recruited,” observed Tim Chico, MBChB, MD, University of Sheffield (England) in a Science Media Centre press release on StatinWISE.

Still, even among this “supersaturated group of people” selected for having had muscle symptoms on statins, Dr. Smeeth said at the briefing, “in almost all cases, their pains and aches were no worse on statins than they were on placebo. We’re not saying that anyone is making up their aches and pains. These are real aches and pains. What we’re showing very clearly is that those aches and pains are no worse on statins than they are on placebo.”
 

Rechallenge is possible

Some people are more likely than others to experience adverse reactions to any drug, “and that’s true of statins,” Neil J. Stone, MD, Northwestern University, Chicago, told this news organization. But StatinWISE underscores that many patients with muscle symptoms on the drugs can be convinced to continue with them rather than stop them entirely.

“The study didn’t say that everybody who has symptoms on a statin is having a nocebo effect,” said Dr. Stone, vice chair for the multisociety 2018 Guideline on the Management of Blood Cholesterol, who was not involved with StatinWISE.

“It simply said,” allowing for some caveats, “that a significant number of patients may have symptoms that don’t preclude them from being rechallenged with a statin again, once they understand what this nocebo effect is.”

And, Dr. Stone said, “it amplifies the 2018 guidelines, with their emphasis on the clinician-patient discussion before starting therapy,” by showing that statin-associated muscle pain isn’t necessarily caused by the drugs and isn’t a reason to stop them.

“That there is a second study confirming SAMSON is helpful, and the results are helpful because they say many of these patients, once they are shown the results, can be rechallenged and will then tolerate statins,” Steven E. Nissen, MD, Cleveland Clinic, said in an interview.

“They were able to get two-thirds of those completing the trial into long-term treatment, which I think is obviously very admirable and very important,” said Dr. Nissen, who was GAUSS-3 principal investigator but not associated with StatinWISE.

“I think it is important, however, that we not completely dismiss patients who complain of adverse effects. Because, in fact, there probably are some people who do have muscle-related symptoms,” he said. “But you know, to really call somebody statin intolerant, they really should fail three statins, which would be a very good standard.”

In his experience, said Patrick M. Moriarty, MD, who directs the Atherosclerosis & Lipoprotein-Apheresis Center at the University of Kansas Medical Center, Kansas City, perhaps 80%-90% of patients who believe they are statin intolerant because of muscle symptoms are actually not statin intolerant at all.

“I think a massive amount of it is supratentorial,” Dr. Moriarty, who was not part of StatinWISE, told this news organization. It comes directly from “what they heard, what they read, or what they were told – and at their age, they’re going to have aches and pains.”
 

Value of the n-of-1 trial

Dr. Smeeth and colleagues framed StatinWISE in part as a test of a strategy for overcoming nocebo-based aversion to statins. One goal was to see whether these methods might be helpful in practice for convincing patients who want to reject statins because of muscle symptoms to give the drugs another chance.

In StatinWISE, patients were individually assigned to take atorvastatin or placebo in randomized order with multiple blinding during each of six successive 2-month periods, so that they were on one or the other agent half the time. They rated their symptoms at the end of each period.

So the trial in composite was, as the publication states, “a series of randomized, placebo-controlled n-of-1 trials.” SAMSON followed a similar scheme, except – as previously reported – it had specified 4 months of atorvastatin, 4 months of placebo, and 4 months with patients on neither statin nor placebo.

StatinWISE “provides a useful approach (the n = 1 study) that could be used in real life to help patients understand the cause of their own possible side effects, which could also be applied to medications other than statins,” Dr. Chico added in the Science Media Centre release.

“I often encounter people who have a firmly held view that statins cause muscle pains, even when they haven’t taken these medications themselves, and I hope that this study may help change this view and make them willing to try such an ‘experiment,’ ” he said.

Others aren’t sure an experiment resembling an n-of-1 trial would be practical or effective when conducted in routine practice.

More efficient and useful, Dr. Moriarty noted, would be for physicians to nurture a close relationship with patients, one that could help transform their negative feelings about statins into a willingness to accept the drugs. “This is a trust you have to build; these are human beings.”

He said getting the patient’s confidence is critical. “You have to explain the pluses and minuses of getting treatment, of the 30% reduction in cardiovascular events that occur with the statin. You don’t go ‘testing this and that.’ I think it’s more about getting them on board.”
 

No statin effect on muscle symptoms

Patients in StatinWISE were recruited from 50 primary care practices in England and Wales from December 2016 to April 2018, the report notes; their mean age was 69 years, and 58% were men. Of the 200 patients, 151 recorded muscle-symptom scores for at least one statin period and one placebo period, and so were included in the primary-endpoint assessment.

The mean muscle symptom score was lower on statin therapy than on placebo (1.68 vs. 2.57), but there was no significant difference in adjusted analysis (mean difference, –0.11 (95% confidence interval, –0.36 to 0.14; P = .40).

Statins showed no significant effect on development of muscle symptoms overall, it was reported, with an odds ratio of 1.11 (99% confidence interval, 0.62-1.99). Nor was there an effect on “muscle symptoms that could not be attributed to another cause,” (OR, 1.22; 95% CI, 0.77-1.94).

Of the 80 withdrawals during the study for any reason, 43% occurred when the patient was on the statin, 49% when the patient was on placebo, and 9% after randomization but before either statin or placebo had been initiated. Of those, 33 were because of “intolerable muscle symptoms,” says the report. But withdrawal occurred about as often on statin therapy as off the drug – 9% and 7%, respectively – throughout the 1-year study.

“This study provides further evidence through the lived experience of individuals that muscle pains often attributed to statins are not due to the drug,” said Sir Nilesh J. Samani, MBChB, MD, medical director for the British Heart Foundation, as quoted in the Science Media Centre press release.

“The use of each patient as their own control in the trial provides a powerful way of distinguishing the effect of a statin from that of taking a pill,” he said. “The findings should give confidence to patients who may be concerned about taking statins.”

StatinWISE was funded by the National Institute for Health Research-Health Technology Program and sponsored by the London School of Hygiene and Tropical Medicine. The authors declare that they have “no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.” Dr. Smeeth reports receiving grants from GlaxoSmithKline, and personal fees for advisory work from AstraZeneca and GlaxoSmithKline. Dr. Stone reports no industry relationships or other disclosures. Dr. Nissen reports that his center has received funding for clinical trials from AbbVie, Amgen, AstraZeneca, Cerenis, Eli Lilly, Esperion, Medtronic, MyoKardia, Novartis, Orexigen, Pfizer, Takeda, The Medicines Company, and Silence Therapeutics; that he is involved in these trials but receives no personal remuneration; and that he consults for many pharmaceutical companies but requires them to donate all honoraria or fees directly to charity so that he receives neither income nor a tax deduction. Dr. Chico had no conflicts. Dr. Moriarty declared no relevant conflicts of interest. Dr. Samani had no disclosures.

A version of this article first appeared on Medscape.com.

This patient had hand and foot psoriasis with the classic thick scale and erythema on his palms and soles. Additionally, in the area of the sole toward the heel, he had hyperpigmented macules called mahogany spots that are another hallmark of psoriasis. Pitting and distal onycholysis were also visible on his right ring finger.

This case illustrates how the painful plaques seen in hand and foot psoriasis—and other forms of psoriasis—can interfere with work and usual daily activities. UVA or narrowband UVB light therapy is a treatment option but requires 3 visits per week, which is not conducive to most people’s work schedules. Acitretin can be prescribed to decrease the abnormal proliferation of keratinocytes; however, adverse reactions can be expected, like this patient’s dry skin and itching. Furthermore, acitretin is a retinoid, like isotretinoin, which can cause severe birth defects, as well as hypertriglyceridemia and transaminitis. Pregnancy needs to be avoided for 3 years due to the teratogenicity and long washout period, so it should not be used in women with reproductive potential.¹

This patient was initially treated with topical calcipotriene (a vitamin D derivative) and clobetasol (high-potency topical steroid) bid but did not have adequate improvement. Screening lab tests showed elevated liver enzymes, precluding treatment with methotrexate (and acitretin, which he’d received previously). He was started on apremilast, an oral phosphodiesterase inhibitor, because his insurance denied adalimumab. Apremilast can cause diarrhea, depression, nausea, and headache. Other than some loose stools, the patient tolerated apremilast well and showed significant improvement in his psoriasis at his 3-month follow-up visit.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

This patient had hand and foot psoriasis with the classic thick scale and erythema on his palms and soles. Additionally, in the area of the sole toward the heel, he had hyperpigmented macules called mahogany spots that are another hallmark of psoriasis. Pitting and distal onycholysis were also visible on his right ring finger.

This case illustrates how the painful plaques seen in hand and foot psoriasis—and other forms of psoriasis—can interfere with work and usual daily activities. UVA or narrowband UVB light therapy is a treatment option but requires 3 visits per week, which is not conducive to most people’s work schedules. Acitretin can be prescribed to decrease the abnormal proliferation of keratinocytes; however, adverse reactions can be expected, like this patient’s dry skin and itching. Furthermore, acitretin is a retinoid, like isotretinoin, which can cause severe birth defects, as well as hypertriglyceridemia and transaminitis. Pregnancy needs to be avoided for 3 years due to the teratogenicity and long washout period, so it should not be used in women with reproductive potential.¹

This patient was initially treated with topical calcipotriene (a vitamin D derivative) and clobetasol (high-potency topical steroid) bid but did not have adequate improvement. Screening lab tests showed elevated liver enzymes, precluding treatment with methotrexate (and acitretin, which he’d received previously). He was started on apremilast, an oral phosphodiesterase inhibitor, because his insurance denied adalimumab. Apremilast can cause diarrhea, depression, nausea, and headache. Other than some loose stools, the patient tolerated apremilast well and showed significant improvement in his psoriasis at his 3-month follow-up visit.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

This patient had hand and foot psoriasis with the classic thick scale and erythema on his palms and soles. Additionally, in the area of the sole toward the heel, he had hyperpigmented macules called mahogany spots that are another hallmark of psoriasis. Pitting and distal onycholysis were also visible on his right ring finger.

This case illustrates how the painful plaques seen in hand and foot psoriasis—and other forms of psoriasis—can interfere with work and usual daily activities. UVA or narrowband UVB light therapy is a treatment option but requires 3 visits per week, which is not conducive to most people’s work schedules. Acitretin can be prescribed to decrease the abnormal proliferation of keratinocytes; however, adverse reactions can be expected, like this patient’s dry skin and itching. Furthermore, acitretin is a retinoid, like isotretinoin, which can cause severe birth defects, as well as hypertriglyceridemia and transaminitis. Pregnancy needs to be avoided for 3 years due to the teratogenicity and long washout period, so it should not be used in women with reproductive potential.¹

This patient was initially treated with topical calcipotriene (a vitamin D derivative) and clobetasol (high-potency topical steroid) bid but did not have adequate improvement. Screening lab tests showed elevated liver enzymes, precluding treatment with methotrexate (and acitretin, which he’d received previously). He was started on apremilast, an oral phosphodiesterase inhibitor, because his insurance denied adalimumab. Apremilast can cause diarrhea, depression, nausea, and headache. Other than some loose stools, the patient tolerated apremilast well and showed significant improvement in his psoriasis at his 3-month follow-up visit.

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

Endometriosis, which affects 1 in 10 women, is one of the most common conditions that gynecologists treat. It is known to cause pain, pelvic adhesive disease, endometriotic cyst formation, and infertility. However, even more sinister, it also increases a woman’s risk for the development of epithelial ovarian cancer (known as endometriosis-associated ovarian cancer or EAOC). A woman with endometriosis has a two- to threefold increased risk of developing epithelial ovarian cancer, compared with nonaffected women.¹ This risk appears to be concentrated in the premenopausal age group, particularly the fifth decade of life. After menopause their risk of developing cancer returns to a baseline level.

EAOC classically presents as clear cell or endometrioid adenocarcinomas, rather than high-grade serous carcinomas. However, low-grade serous carcinomas are also frequently observed in this cohort.^2,3 Unlike high-grade serous carcinoma, EAOC is more likely to be diagnosed at an early stage, with the majority at stage I or II, and prognosis is better. After matching for age and stage with cases of high-grade serous carcinoma, there is improved disease-free and overall survival observed among cases of EAOC of clear cell and endometrioid histologic cell types.⁴ The phenomenon of dual primaries (synchronous endometrial and ovarian cancer) occurs more frequently in EAOC than it does in patients with nonendometriosis-related high-grade serous cancer (25% vs. 4%).

The genomics of these endometriosis-associated cancers are quite distinct. Similar to benign endometriosis implants, EAOC is associated with genomic mutations in ARID1A, PIK3CA, and PTEN, as well as progesterone resistance.^1,2 Multiple studies have shown that the adjacent eutopic endometrium carries similar gene mutations as those found in both benign endometriotic implants and EAOC.² This may explain the higher incidence (twofold) of endometrial cancer in patients with endometriosis as well as the increased incidence of dual ovarian and endometrial cancer primaries.

Just as there are multiple theories regarding the mechanism of benign endometriosis, we have theories rather than conclusions regarding the origins of EAOC. One such theory is that it develops from malignant transformation in an existing endometriotic cyst.⁵ Endometriotic cysts provide an iron-rich environment which promotes reactive oxygen species that promote carcinogenesis by inducing gene mutations and epigenetic alterations. However, if prolonged exposure to oxidative stress within endometriotic cysts were to be the cause for EAOC, we would expect to see a progressively increasing incidence of ovarian cancer over time in patients with expectantly managed cysts. However, in cases of expectant management, an initial, early, increased risk for cancer within the first 5 years is followed by a subsequent decreasing incidence over time.⁶ This early incidence spike suggests that some endometriotic cysts may have been misclassified as benign, then rapidly declare themselves as malignant during the observation period rather than a transformation into malignancy from a benign endometrioma over time.

An alternative, and favored, theory for the origins of EAOC are that endometrial cells with carcinogenic genomic alterations reflux through the fallopian tubes during menstruation and settle onto the ovarian epithelium which itself is damaged from recent ovulation thus providing an environment that is highly suitable for oncogenesis.² Genomic analyses of both the eutopic endometrium and malignant cells in patients with EAOC have shown that both tissues contain the same genomic alterations.¹ Given that menstruation, including retrograde menstruation, ends after menopause, this mechanism supports the observation that EAOC is predominantly a malignancy of premenopausal women. Additionally, salpingectomy and hysterectomy confers a protective effect on the development of EAOC, theoretically by preventing the retrograde transfer of these mutant progenitor endometrial cells. Furthermore, the factors that increase the number of menstrual cycles (such as an early age of menarche and delayed or nonchildbearing states) increases the risk for EAOC and factors that inhibit menstruation, such as oral contraceptive pill use, appear to decrease its risk.

EAOC most commonly arises in the ovary, and not in the deep endometriosis implants of adjacent pelvic structures (such as the anterior and posterior cul de sac and pelvic peritoneum). It is suggested that the ovary itself provides a uniquely favorable environment for carcinogenesis. As stated above, it is hypothesized that refluxed endometrial cells, carrying important progenitor mutations, may become trapped in the tissues of traumatized ovarian epithelium, ripe with inflammatory changes, post ovulation.² This microenvironment may promote the development of malignancy.

Given these theories and their supporting evidence, how can we attempt to reduce the incidence of this cancer for our patients with endometriosis? Despite their increased risk for ovarian and endometrial cancers, current recommendations do not support routine cancer screening in women with endometriosis.⁷ However, risk-mitigation strategies can still be pursued. Hormonal contraceptives to decrease ovulation and menstrual cycling are protective against ovarian cancer and are also helpful in mitigating the symptoms of endometriosis. While removal of endometriotic cysts may not, in and of itself, be a strategy to prevent EAOC, it is still generally recommended because these cysts are commonly a source of pain and infertility. While they do not appear to undergo malignant transformation, it can be difficult to definitively rule out an early ovarian cancer in these complex ovarian cysts, particularly as they are often associated with tumor marker abnormalities such as elevations in CA 125. Therefore, if surgical excision of an endometriotic cyst is not performed, it should be closely followed for at least 5 years to ensure it is a benign structure. If surgery is pursued and ovarian preservation is desired, removal of the fallopian tubes and uterus can help mitigate the risk for EAOC.⁸

Endometriosis is a morbid condition for many young women. In addition to causing pain and infertility it increases a woman’s risk for ovarian and endometrial cancer, particularly ovarian clear cell, endometrioid, and low-grade serous cancers and synchronous endometrial and ovarian cancers. Endometriotic cysts should be removed or closely monitored, and clinicians should discuss treatment options that minimize frequency of ovulation and menstruation events as a preventative strategy.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Endocrinology. 2019;160(3):626-38.

2. Cancers. 2020;12(6):1676.

3. Lancet Oncol. 2012;13:385-94.

4. Gynecol Oncol. 2014;132(3):760-6.

5. Redox Rep. 2016;21:119-26.

6. Int. J Clin Oncol. 2020;25:51-8.

7. Hum Reprod. 2013;28:1552-68.

8. J Natl Cancer Inst. 2019;111:1097-103.

Endometriosis, which affects 1 in 10 women, is one of the most common conditions that gynecologists treat. It is known to cause pain, pelvic adhesive disease, endometriotic cyst formation, and infertility. However, even more sinister, it also increases a woman’s risk for the development of epithelial ovarian cancer (known as endometriosis-associated ovarian cancer or EAOC). A woman with endometriosis has a two- to threefold increased risk of developing epithelial ovarian cancer, compared with nonaffected women.¹ This risk appears to be concentrated in the premenopausal age group, particularly the fifth decade of life. After menopause their risk of developing cancer returns to a baseline level.

EAOC classically presents as clear cell or endometrioid adenocarcinomas, rather than high-grade serous carcinomas. However, low-grade serous carcinomas are also frequently observed in this cohort.^2,3 Unlike high-grade serous carcinoma, EAOC is more likely to be diagnosed at an early stage, with the majority at stage I or II, and prognosis is better. After matching for age and stage with cases of high-grade serous carcinoma, there is improved disease-free and overall survival observed among cases of EAOC of clear cell and endometrioid histologic cell types.⁴ The phenomenon of dual primaries (synchronous endometrial and ovarian cancer) occurs more frequently in EAOC than it does in patients with nonendometriosis-related high-grade serous cancer (25% vs. 4%).

The genomics of these endometriosis-associated cancers are quite distinct. Similar to benign endometriosis implants, EAOC is associated with genomic mutations in ARID1A, PIK3CA, and PTEN, as well as progesterone resistance.^1,2 Multiple studies have shown that the adjacent eutopic endometrium carries similar gene mutations as those found in both benign endometriotic implants and EAOC.² This may explain the higher incidence (twofold) of endometrial cancer in patients with endometriosis as well as the increased incidence of dual ovarian and endometrial cancer primaries.

Just as there are multiple theories regarding the mechanism of benign endometriosis, we have theories rather than conclusions regarding the origins of EAOC. One such theory is that it develops from malignant transformation in an existing endometriotic cyst.⁵ Endometriotic cysts provide an iron-rich environment which promotes reactive oxygen species that promote carcinogenesis by inducing gene mutations and epigenetic alterations. However, if prolonged exposure to oxidative stress within endometriotic cysts were to be the cause for EAOC, we would expect to see a progressively increasing incidence of ovarian cancer over time in patients with expectantly managed cysts. However, in cases of expectant management, an initial, early, increased risk for cancer within the first 5 years is followed by a subsequent decreasing incidence over time.⁶ This early incidence spike suggests that some endometriotic cysts may have been misclassified as benign, then rapidly declare themselves as malignant during the observation period rather than a transformation into malignancy from a benign endometrioma over time.

An alternative, and favored, theory for the origins of EAOC are that endometrial cells with carcinogenic genomic alterations reflux through the fallopian tubes during menstruation and settle onto the ovarian epithelium which itself is damaged from recent ovulation thus providing an environment that is highly suitable for oncogenesis.² Genomic analyses of both the eutopic endometrium and malignant cells in patients with EAOC have shown that both tissues contain the same genomic alterations.¹ Given that menstruation, including retrograde menstruation, ends after menopause, this mechanism supports the observation that EAOC is predominantly a malignancy of premenopausal women. Additionally, salpingectomy and hysterectomy confers a protective effect on the development of EAOC, theoretically by preventing the retrograde transfer of these mutant progenitor endometrial cells. Furthermore, the factors that increase the number of menstrual cycles (such as an early age of menarche and delayed or nonchildbearing states) increases the risk for EAOC and factors that inhibit menstruation, such as oral contraceptive pill use, appear to decrease its risk.

EAOC most commonly arises in the ovary, and not in the deep endometriosis implants of adjacent pelvic structures (such as the anterior and posterior cul de sac and pelvic peritoneum). It is suggested that the ovary itself provides a uniquely favorable environment for carcinogenesis. As stated above, it is hypothesized that refluxed endometrial cells, carrying important progenitor mutations, may become trapped in the tissues of traumatized ovarian epithelium, ripe with inflammatory changes, post ovulation.² This microenvironment may promote the development of malignancy.

Given these theories and their supporting evidence, how can we attempt to reduce the incidence of this cancer for our patients with endometriosis? Despite their increased risk for ovarian and endometrial cancers, current recommendations do not support routine cancer screening in women with endometriosis.⁷ However, risk-mitigation strategies can still be pursued. Hormonal contraceptives to decrease ovulation and menstrual cycling are protective against ovarian cancer and are also helpful in mitigating the symptoms of endometriosis. While removal of endometriotic cysts may not, in and of itself, be a strategy to prevent EAOC, it is still generally recommended because these cysts are commonly a source of pain and infertility. While they do not appear to undergo malignant transformation, it can be difficult to definitively rule out an early ovarian cancer in these complex ovarian cysts, particularly as they are often associated with tumor marker abnormalities such as elevations in CA 125. Therefore, if surgical excision of an endometriotic cyst is not performed, it should be closely followed for at least 5 years to ensure it is a benign structure. If surgery is pursued and ovarian preservation is desired, removal of the fallopian tubes and uterus can help mitigate the risk for EAOC.⁸

Endometriosis is a morbid condition for many young women. In addition to causing pain and infertility it increases a woman’s risk for ovarian and endometrial cancer, particularly ovarian clear cell, endometrioid, and low-grade serous cancers and synchronous endometrial and ovarian cancers. Endometriotic cysts should be removed or closely monitored, and clinicians should discuss treatment options that minimize frequency of ovulation and menstruation events as a preventative strategy.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Endocrinology. 2019;160(3):626-38.

2. Cancers. 2020;12(6):1676.

3. Lancet Oncol. 2012;13:385-94.

4. Gynecol Oncol. 2014;132(3):760-6.

5. Redox Rep. 2016;21:119-26.

6. Int. J Clin Oncol. 2020;25:51-8.

7. Hum Reprod. 2013;28:1552-68.

8. J Natl Cancer Inst. 2019;111:1097-103.

Endometriosis, which affects 1 in 10 women, is one of the most common conditions that gynecologists treat. It is known to cause pain, pelvic adhesive disease, endometriotic cyst formation, and infertility. However, even more sinister, it also increases a woman’s risk for the development of epithelial ovarian cancer (known as endometriosis-associated ovarian cancer or EAOC). A woman with endometriosis has a two- to threefold increased risk of developing epithelial ovarian cancer, compared with nonaffected women.¹ This risk appears to be concentrated in the premenopausal age group, particularly the fifth decade of life. After menopause their risk of developing cancer returns to a baseline level.

EAOC classically presents as clear cell or endometrioid adenocarcinomas, rather than high-grade serous carcinomas. However, low-grade serous carcinomas are also frequently observed in this cohort.^2,3 Unlike high-grade serous carcinoma, EAOC is more likely to be diagnosed at an early stage, with the majority at stage I or II, and prognosis is better. After matching for age and stage with cases of high-grade serous carcinoma, there is improved disease-free and overall survival observed among cases of EAOC of clear cell and endometrioid histologic cell types.⁴ The phenomenon of dual primaries (synchronous endometrial and ovarian cancer) occurs more frequently in EAOC than it does in patients with nonendometriosis-related high-grade serous cancer (25% vs. 4%).

The genomics of these endometriosis-associated cancers are quite distinct. Similar to benign endometriosis implants, EAOC is associated with genomic mutations in ARID1A, PIK3CA, and PTEN, as well as progesterone resistance.^1,2 Multiple studies have shown that the adjacent eutopic endometrium carries similar gene mutations as those found in both benign endometriotic implants and EAOC.² This may explain the higher incidence (twofold) of endometrial cancer in patients with endometriosis as well as the increased incidence of dual ovarian and endometrial cancer primaries.

Just as there are multiple theories regarding the mechanism of benign endometriosis, we have theories rather than conclusions regarding the origins of EAOC. One such theory is that it develops from malignant transformation in an existing endometriotic cyst.⁵ Endometriotic cysts provide an iron-rich environment which promotes reactive oxygen species that promote carcinogenesis by inducing gene mutations and epigenetic alterations. However, if prolonged exposure to oxidative stress within endometriotic cysts were to be the cause for EAOC, we would expect to see a progressively increasing incidence of ovarian cancer over time in patients with expectantly managed cysts. However, in cases of expectant management, an initial, early, increased risk for cancer within the first 5 years is followed by a subsequent decreasing incidence over time.⁶ This early incidence spike suggests that some endometriotic cysts may have been misclassified as benign, then rapidly declare themselves as malignant during the observation period rather than a transformation into malignancy from a benign endometrioma over time.

An alternative, and favored, theory for the origins of EAOC are that endometrial cells with carcinogenic genomic alterations reflux through the fallopian tubes during menstruation and settle onto the ovarian epithelium which itself is damaged from recent ovulation thus providing an environment that is highly suitable for oncogenesis.² Genomic analyses of both the eutopic endometrium and malignant cells in patients with EAOC have shown that both tissues contain the same genomic alterations.¹ Given that menstruation, including retrograde menstruation, ends after menopause, this mechanism supports the observation that EAOC is predominantly a malignancy of premenopausal women. Additionally, salpingectomy and hysterectomy confers a protective effect on the development of EAOC, theoretically by preventing the retrograde transfer of these mutant progenitor endometrial cells. Furthermore, the factors that increase the number of menstrual cycles (such as an early age of menarche and delayed or nonchildbearing states) increases the risk for EAOC and factors that inhibit menstruation, such as oral contraceptive pill use, appear to decrease its risk.

EAOC most commonly arises in the ovary, and not in the deep endometriosis implants of adjacent pelvic structures (such as the anterior and posterior cul de sac and pelvic peritoneum). It is suggested that the ovary itself provides a uniquely favorable environment for carcinogenesis. As stated above, it is hypothesized that refluxed endometrial cells, carrying important progenitor mutations, may become trapped in the tissues of traumatized ovarian epithelium, ripe with inflammatory changes, post ovulation.² This microenvironment may promote the development of malignancy.

Given these theories and their supporting evidence, how can we attempt to reduce the incidence of this cancer for our patients with endometriosis? Despite their increased risk for ovarian and endometrial cancers, current recommendations do not support routine cancer screening in women with endometriosis.⁷ However, risk-mitigation strategies can still be pursued. Hormonal contraceptives to decrease ovulation and menstrual cycling are protective against ovarian cancer and are also helpful in mitigating the symptoms of endometriosis. While removal of endometriotic cysts may not, in and of itself, be a strategy to prevent EAOC, it is still generally recommended because these cysts are commonly a source of pain and infertility. While they do not appear to undergo malignant transformation, it can be difficult to definitively rule out an early ovarian cancer in these complex ovarian cysts, particularly as they are often associated with tumor marker abnormalities such as elevations in CA 125. Therefore, if surgical excision of an endometriotic cyst is not performed, it should be closely followed for at least 5 years to ensure it is a benign structure. If surgery is pursued and ovarian preservation is desired, removal of the fallopian tubes and uterus can help mitigate the risk for EAOC.⁸

Endometriosis is a morbid condition for many young women. In addition to causing pain and infertility it increases a woman’s risk for ovarian and endometrial cancer, particularly ovarian clear cell, endometrioid, and low-grade serous cancers and synchronous endometrial and ovarian cancers. Endometriotic cysts should be removed or closely monitored, and clinicians should discuss treatment options that minimize frequency of ovulation and menstruation events as a preventative strategy.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Endocrinology. 2019;160(3):626-38.

2. Cancers. 2020;12(6):1676.

3. Lancet Oncol. 2012;13:385-94.

4. Gynecol Oncol. 2014;132(3):760-6.

5. Redox Rep. 2016;21:119-26.

6. Int. J Clin Oncol. 2020;25:51-8.

7. Hum Reprod. 2013;28:1552-68.

8. J Natl Cancer Inst. 2019;111:1097-103.

Prescriptions for opioids as a first-line treatment for painful diabetic peripheral neuropathy (DPN) outnumbered those for other medications between 2014 and 2018, despite the fact that the former is not recommended, new research indicates.

“We know that for any kind of chronic pain, opioids are not ideal. They’re not very effective for chronic pain in general, and they’re definitely not safe,” senior author Rozalina G. McCoy, MD, an endocrinologist and primary care clinician at the Mayo Clinic in Rochester, Minn., told this news organization.

That’s true even for severe DPN pain or painful exacerbations, she added.

“There’s a myth that opioids are the strongest pain meds possible ... For painful neuropathic pain, duloxetine [Cymbalta], pregabalin [Lyrica], and gabapentin [Neurontin] are the most effective pain medications based on multiple studies and extensive experience using them,” she explained. “But I think the public perception is that opioids are the strongest. When a patient comes with severe pain, I think there’s that kind of gut feeling that if the pain is severe, I need to give opioids.”

What’s more, she noted, “evidence is emerging for other harms, not only the potential for dependency and potential overdose, but also the potential for opioid-induced hyperalgesia. Opioids themselves can cause chronic pain. When we think about using opioids for chronic pain, we are really shooting ourselves in the foot. We’re going to harm patients.”

The American Diabetes Association DPN guidelines essentially say as much, advising opioids only as a tertiary option for refractory pain, she observed.

The new findings, from a retrospective study of Mayo Clinic electronic health data, were published online in JAMA Network Open by Jungwei Fan, PhD, also of Mayo Clinic, and colleagues.


 

Are fewer patients with DPN receiving any treatment now?

The data also reveal that, while opioid prescribing dropped over the study period, there wasn’t a comparable rise in prescriptions of recommended pain medications, suggesting that recent efforts to minimize opioid prescribing may have resulted in less overall treatment of significant pain. (The study had to be stopped in 2018 when Mayo switched to a new electronic health record system, Dr. McCoy explained.)

“The proportion of opioids among new prescriptions has been decreasing. I’m hopeful that the rates are even lower now than they were 2 years ago. What was concerning to me was the proportion of people receiving treatment overall had gone down,” Dr. McCoy noted.

“So, while it’s great that opioids aren’t being used, it’s doubtful that people with DPN are any less symptomatic. So I worry that there’s a proportion of patients who have pain who aren’t getting the treatment they need just because we don’t want to give them opioids. There are other options,” Dr. McCoy said, including nonpharmacologic approaches.
 

Opioids dominated in new-onset DPN prescribing during 2014-2018

The study involved 3,495 adults with newly diagnosed DPN from all three Mayo Clinic locations in Rochester, Minn.; Phoenix, Ariz.; and Jacksonville, Fla. during the period 2014-2018. Of those, 40.2% (1,406) were prescribed a new pain medication after diagnosis. However, that proportion dropped from 45.6% in 2014 to 35.2% in 2018.

The odds of initiating any treatment were significantly greater among patients with depression (odds ratio, 1.61), arthritis (OR, 1.21), and back pain (OR, 1.34), but decreased over time among all patients.

Among those receiving drug treatment, opioids were prescribed to 43.8%, whereas guideline-recommended medications (gabapentin, pregabalin, and serotonin norepinephrine reuptake inhibitors including duloxetine) were prescribed to 42.9%.

Another 20.6% received medications deemed “acceptable” for treating neuropathic pain, including topical analgesics, tricyclic antidepressants, and other anticonvulsants.

Males were significantly more likely than females to receive opioids (OR, 1.26), while individuals diagnosed with comorbid fibromyalgia were less likely (OR, 0.67). Those with comorbid arthritis were less likely to receive recommended DPN medications (OR, 0.76).

Use of opioids was 29% less likely in 2018, compared with 2014, although this difference did not achieve significance. Similarly, use of recommended medications was 25% more likely in 2018, compared with 2014, also not a significant difference.
 

Dr. McCoy offers clinical pearls for treating pain in DPN

Clinically, Dr. McCoy said that she individualizes treatment for painful DPN.

“I tend to use duloxetine if the patient also has a mood disorder including depression or anxiety, because it can also help with that. Gabapentin can also be helpful for radiculopathy or for chronic low-back pain. It can even help with degenerative joint disease like arthritis of the knees. So, you maximize benefit if you use one drug to treat multiple things.”

All three recommended medications are generic now, although pregabalin still tends to be more expensive, she noted. Gabapentin can cause drowsiness, which makes it ideal for a patient with insomnia but much less so for a long-haul truck driver. Duloxetine doesn’t cause sleepiness. Pregabalin can, but less so than gabapentin.  

“I think that’s why it’s so important to talk to your patient and ask how the neuropathy is affecting them. What other comorbidities do they have? What is their life like? I think you have to figure out what drug works for each individual person.”

Importantly, she advised, if one of the three doesn’t work, stop it and try another. “It doesn’t mean that none of these meds work. All three should be tried to see if they give relief.”

Nonpharmacologic measures such as cognitive behavioral therapy, acupuncture, or physical therapy may help some patients as well.

Supplements such as vitamin B₁₂ – which can also help with metformin-induced B₁₂ deficiency – or alpha-lipoic acid may also be worth a try as long as the patient is made aware of potential risks, she noted.

Dr. McCoy hopes to repeat this study using national data. “I don’t think this is isolated to Mayo ... I think it affects all practices,” she said.

Since the study, “we [Mayo Clinic] have implemented practice changes to limit use of opioids for chronic pain ... so I hope it’s getting better. It’s important to be aware of our patterns in prescribing.”

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. McCoy reported receiving grants from the AARP Quality Measure Innovation program through a collaboration with OptumLabs and the Mayo Clinic’s Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery.
 

A version of this article first appeared on Medscape.com.

Prescriptions for opioids as a first-line treatment for painful diabetic peripheral neuropathy (DPN) outnumbered those for other medications between 2014 and 2018, despite the fact that the former is not recommended, new research indicates.

“We know that for any kind of chronic pain, opioids are not ideal. They’re not very effective for chronic pain in general, and they’re definitely not safe,” senior author Rozalina G. McCoy, MD, an endocrinologist and primary care clinician at the Mayo Clinic in Rochester, Minn., told this news organization.

That’s true even for severe DPN pain or painful exacerbations, she added.

“There’s a myth that opioids are the strongest pain meds possible ... For painful neuropathic pain, duloxetine [Cymbalta], pregabalin [Lyrica], and gabapentin [Neurontin] are the most effective pain medications based on multiple studies and extensive experience using them,” she explained. “But I think the public perception is that opioids are the strongest. When a patient comes with severe pain, I think there’s that kind of gut feeling that if the pain is severe, I need to give opioids.”

What’s more, she noted, “evidence is emerging for other harms, not only the potential for dependency and potential overdose, but also the potential for opioid-induced hyperalgesia. Opioids themselves can cause chronic pain. When we think about using opioids for chronic pain, we are really shooting ourselves in the foot. We’re going to harm patients.”

The American Diabetes Association DPN guidelines essentially say as much, advising opioids only as a tertiary option for refractory pain, she observed.

The new findings, from a retrospective study of Mayo Clinic electronic health data, were published online in JAMA Network Open by Jungwei Fan, PhD, also of Mayo Clinic, and colleagues.


 

Are fewer patients with DPN receiving any treatment now?

The data also reveal that, while opioid prescribing dropped over the study period, there wasn’t a comparable rise in prescriptions of recommended pain medications, suggesting that recent efforts to minimize opioid prescribing may have resulted in less overall treatment of significant pain. (The study had to be stopped in 2018 when Mayo switched to a new electronic health record system, Dr. McCoy explained.)

“The proportion of opioids among new prescriptions has been decreasing. I’m hopeful that the rates are even lower now than they were 2 years ago. What was concerning to me was the proportion of people receiving treatment overall had gone down,” Dr. McCoy noted.

“So, while it’s great that opioids aren’t being used, it’s doubtful that people with DPN are any less symptomatic. So I worry that there’s a proportion of patients who have pain who aren’t getting the treatment they need just because we don’t want to give them opioids. There are other options,” Dr. McCoy said, including nonpharmacologic approaches.
 

Opioids dominated in new-onset DPN prescribing during 2014-2018

The study involved 3,495 adults with newly diagnosed DPN from all three Mayo Clinic locations in Rochester, Minn.; Phoenix, Ariz.; and Jacksonville, Fla. during the period 2014-2018. Of those, 40.2% (1,406) were prescribed a new pain medication after diagnosis. However, that proportion dropped from 45.6% in 2014 to 35.2% in 2018.

The odds of initiating any treatment were significantly greater among patients with depression (odds ratio, 1.61), arthritis (OR, 1.21), and back pain (OR, 1.34), but decreased over time among all patients.

Among those receiving drug treatment, opioids were prescribed to 43.8%, whereas guideline-recommended medications (gabapentin, pregabalin, and serotonin norepinephrine reuptake inhibitors including duloxetine) were prescribed to 42.9%.

Another 20.6% received medications deemed “acceptable” for treating neuropathic pain, including topical analgesics, tricyclic antidepressants, and other anticonvulsants.

Males were significantly more likely than females to receive opioids (OR, 1.26), while individuals diagnosed with comorbid fibromyalgia were less likely (OR, 0.67). Those with comorbid arthritis were less likely to receive recommended DPN medications (OR, 0.76).

Use of opioids was 29% less likely in 2018, compared with 2014, although this difference did not achieve significance. Similarly, use of recommended medications was 25% more likely in 2018, compared with 2014, also not a significant difference.
 

Dr. McCoy offers clinical pearls for treating pain in DPN

Clinically, Dr. McCoy said that she individualizes treatment for painful DPN.

“I tend to use duloxetine if the patient also has a mood disorder including depression or anxiety, because it can also help with that. Gabapentin can also be helpful for radiculopathy or for chronic low-back pain. It can even help with degenerative joint disease like arthritis of the knees. So, you maximize benefit if you use one drug to treat multiple things.”

All three recommended medications are generic now, although pregabalin still tends to be more expensive, she noted. Gabapentin can cause drowsiness, which makes it ideal for a patient with insomnia but much less so for a long-haul truck driver. Duloxetine doesn’t cause sleepiness. Pregabalin can, but less so than gabapentin.  

“I think that’s why it’s so important to talk to your patient and ask how the neuropathy is affecting them. What other comorbidities do they have? What is their life like? I think you have to figure out what drug works for each individual person.”

Importantly, she advised, if one of the three doesn’t work, stop it and try another. “It doesn’t mean that none of these meds work. All three should be tried to see if they give relief.”

Nonpharmacologic measures such as cognitive behavioral therapy, acupuncture, or physical therapy may help some patients as well.

Supplements such as vitamin B₁₂ – which can also help with metformin-induced B₁₂ deficiency – or alpha-lipoic acid may also be worth a try as long as the patient is made aware of potential risks, she noted.

Dr. McCoy hopes to repeat this study using national data. “I don’t think this is isolated to Mayo ... I think it affects all practices,” she said.

Since the study, “we [Mayo Clinic] have implemented practice changes to limit use of opioids for chronic pain ... so I hope it’s getting better. It’s important to be aware of our patterns in prescribing.”

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. McCoy reported receiving grants from the AARP Quality Measure Innovation program through a collaboration with OptumLabs and the Mayo Clinic’s Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery.
 

A version of this article first appeared on Medscape.com.

Prescriptions for opioids as a first-line treatment for painful diabetic peripheral neuropathy (DPN) outnumbered those for other medications between 2014 and 2018, despite the fact that the former is not recommended, new research indicates.

“We know that for any kind of chronic pain, opioids are not ideal. They’re not very effective for chronic pain in general, and they’re definitely not safe,” senior author Rozalina G. McCoy, MD, an endocrinologist and primary care clinician at the Mayo Clinic in Rochester, Minn., told this news organization.

That’s true even for severe DPN pain or painful exacerbations, she added.

“There’s a myth that opioids are the strongest pain meds possible ... For painful neuropathic pain, duloxetine [Cymbalta], pregabalin [Lyrica], and gabapentin [Neurontin] are the most effective pain medications based on multiple studies and extensive experience using them,” she explained. “But I think the public perception is that opioids are the strongest. When a patient comes with severe pain, I think there’s that kind of gut feeling that if the pain is severe, I need to give opioids.”

What’s more, she noted, “evidence is emerging for other harms, not only the potential for dependency and potential overdose, but also the potential for opioid-induced hyperalgesia. Opioids themselves can cause chronic pain. When we think about using opioids for chronic pain, we are really shooting ourselves in the foot. We’re going to harm patients.”

The American Diabetes Association DPN guidelines essentially say as much, advising opioids only as a tertiary option for refractory pain, she observed.

The new findings, from a retrospective study of Mayo Clinic electronic health data, were published online in JAMA Network Open by Jungwei Fan, PhD, also of Mayo Clinic, and colleagues.


 

Are fewer patients with DPN receiving any treatment now?

The data also reveal that, while opioid prescribing dropped over the study period, there wasn’t a comparable rise in prescriptions of recommended pain medications, suggesting that recent efforts to minimize opioid prescribing may have resulted in less overall treatment of significant pain. (The study had to be stopped in 2018 when Mayo switched to a new electronic health record system, Dr. McCoy explained.)

“The proportion of opioids among new prescriptions has been decreasing. I’m hopeful that the rates are even lower now than they were 2 years ago. What was concerning to me was the proportion of people receiving treatment overall had gone down,” Dr. McCoy noted.

“So, while it’s great that opioids aren’t being used, it’s doubtful that people with DPN are any less symptomatic. So I worry that there’s a proportion of patients who have pain who aren’t getting the treatment they need just because we don’t want to give them opioids. There are other options,” Dr. McCoy said, including nonpharmacologic approaches.
 

Opioids dominated in new-onset DPN prescribing during 2014-2018

The study involved 3,495 adults with newly diagnosed DPN from all three Mayo Clinic locations in Rochester, Minn.; Phoenix, Ariz.; and Jacksonville, Fla. during the period 2014-2018. Of those, 40.2% (1,406) were prescribed a new pain medication after diagnosis. However, that proportion dropped from 45.6% in 2014 to 35.2% in 2018.

The odds of initiating any treatment were significantly greater among patients with depression (odds ratio, 1.61), arthritis (OR, 1.21), and back pain (OR, 1.34), but decreased over time among all patients.

Among those receiving drug treatment, opioids were prescribed to 43.8%, whereas guideline-recommended medications (gabapentin, pregabalin, and serotonin norepinephrine reuptake inhibitors including duloxetine) were prescribed to 42.9%.

Another 20.6% received medications deemed “acceptable” for treating neuropathic pain, including topical analgesics, tricyclic antidepressants, and other anticonvulsants.

Males were significantly more likely than females to receive opioids (OR, 1.26), while individuals diagnosed with comorbid fibromyalgia were less likely (OR, 0.67). Those with comorbid arthritis were less likely to receive recommended DPN medications (OR, 0.76).

Use of opioids was 29% less likely in 2018, compared with 2014, although this difference did not achieve significance. Similarly, use of recommended medications was 25% more likely in 2018, compared with 2014, also not a significant difference.
 

Dr. McCoy offers clinical pearls for treating pain in DPN

Clinically, Dr. McCoy said that she individualizes treatment for painful DPN.

“I tend to use duloxetine if the patient also has a mood disorder including depression or anxiety, because it can also help with that. Gabapentin can also be helpful for radiculopathy or for chronic low-back pain. It can even help with degenerative joint disease like arthritis of the knees. So, you maximize benefit if you use one drug to treat multiple things.”

All three recommended medications are generic now, although pregabalin still tends to be more expensive, she noted. Gabapentin can cause drowsiness, which makes it ideal for a patient with insomnia but much less so for a long-haul truck driver. Duloxetine doesn’t cause sleepiness. Pregabalin can, but less so than gabapentin.  

“I think that’s why it’s so important to talk to your patient and ask how the neuropathy is affecting them. What other comorbidities do they have? What is their life like? I think you have to figure out what drug works for each individual person.”

Importantly, she advised, if one of the three doesn’t work, stop it and try another. “It doesn’t mean that none of these meds work. All three should be tried to see if they give relief.”

Nonpharmacologic measures such as cognitive behavioral therapy, acupuncture, or physical therapy may help some patients as well.

Supplements such as vitamin B₁₂ – which can also help with metformin-induced B₁₂ deficiency – or alpha-lipoic acid may also be worth a try as long as the patient is made aware of potential risks, she noted.

Dr. McCoy hopes to repeat this study using national data. “I don’t think this is isolated to Mayo ... I think it affects all practices,” she said.

Since the study, “we [Mayo Clinic] have implemented practice changes to limit use of opioids for chronic pain ... so I hope it’s getting better. It’s important to be aware of our patterns in prescribing.”

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. McCoy reported receiving grants from the AARP Quality Measure Innovation program through a collaboration with OptumLabs and the Mayo Clinic’s Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery.
 

A version of this article first appeared on Medscape.com.

Patients with cluster headache face a double whammy: Physicians too often fail to recognize it, and their condition is among the most severe and debilitating among headache types. In fact, a new survey of patients with cluster headache shows that they rank the pain as worse than most other painful experiences in life, including childbirth, passing of kidney stones, and pancreatitis, among others.

The study’s comparison of cluster headaches to other common painful experiences can help nonsufferers relate to the experience, said Larry Schor, PhD, a coauthor of the paper. “Headache is a terrible word. Bee stings sting, burns burn. [A cluster headache] doesn’t ache. It’s a piercing intensity like you just can’t believe,” said Dr. Schor, professor of psychology at the University of West Georgia, Carrollton, and a cluster headache patient since he first experienced an attack at the age of 21.

The study was published in the January 2021 issue of Headache.

Ranking cluster headaches as worse than experiences such as childbirth or kidney stones is “kind of eye opening, and helps to describe the experience in terms that more people can relate to. I think it helps to share the experience of cluster headache more broadly, because we’re in a situation where cluster headache remains underfunded, and we don’t have enough treatments for it. I think one way to overcome that is to spread awareness of what this problem is, and the impact it has on human life,” said Rashmi Halker Singh, MD, associate professor of neurology at the Mayo Clinic in Scottsdale, Ariz., and deputy editor of Headache. She was not involved in the study.

Dr. Schor called for physicians to consider cluster headache an emergency, because of the severity of pain and also the potential for suicidality. Treatments remain comparatively sparse, but high-flow oxygen can help some patients, and intranasal or intravenous triptans can treat acute pain. In 2018, the Food and Drug Administration approved galcanezumab (Eli Lilly) for prevention of episodic cluster headaches.

But cluster headaches are often misdiagnosed. For many patients, it takes more than a year or even as long as 5 years to get an accurate diagnosis, according to Dr. Schor. Women may be particularly vulnerable to misdiagnosis, because migraines are more common in women. It doesn’t help that many neurologists are taught that cluster headache is primarily a male disease. “Because that idea is so ingrained, I think a lot of women who have cluster headache are probably missed and told they have migraine instead. There are a lot of women who have cluster headache, and that gender difference might not be as big a difference as we were initially taught. We need to do a better job of recognizing cluster headache to better understand what the true prevalence is,” said Dr. Halker Singh.

She noted that patients with side-locked headache should be evaluated for cluster headache, and asked how long the pain lasts in the absence of medication. “Also ask about the presence of cranial autonomic symptoms, and if they occur in the context of headache pain, and if they are side-locked to the side of the headache. Those are important questions that can tease out cluster headache from other conditions,” said Dr. Halker Singh.

For the survey, the researchers asked 1,604 patients with cluster headache patients to rate pain on a scale of 1 to 10. Cluster headache ranked highest at 9.7, then labor pain (7.2), pancreatitis (7.0), and nephrolithiasis (6.9). Cluster headache pain was ranked at 10.0 by 72.1% of respondents. Those reporting maximal pain or were more likely to have cranial autonomic features in comparison with patients who reported less pain, including conjunctival injection or lacrimation (91% versus 85%), eyelid edema (77% versus 66%), forehead/facial sweating (60% versus 49%), fullness in the ear (47% versus 35%), and miosis or ptosis (85% versus 75%). They had more frequent attacks (4.0 versus 3.5 per day), higher Hopelessness Depression Symptom Questionnaire scores (24.5 versus 21.1), and reduced effectiveness of calcium channel blockers (2.2 versus 2.5 on a 5-point Likert scale). They were more often female (34% versus 24%). (P < .001 for all).

The study received funding from Autonomic Technologies and Cluster Busters. Dr. Schor and Dr. Halker Singh had no relevant financial disclosures.

Patients with cluster headache face a double whammy: Physicians too often fail to recognize it, and their condition is among the most severe and debilitating among headache types. In fact, a new survey of patients with cluster headache shows that they rank the pain as worse than most other painful experiences in life, including childbirth, passing of kidney stones, and pancreatitis, among others.

The study’s comparison of cluster headaches to other common painful experiences can help nonsufferers relate to the experience, said Larry Schor, PhD, a coauthor of the paper. “Headache is a terrible word. Bee stings sting, burns burn. [A cluster headache] doesn’t ache. It’s a piercing intensity like you just can’t believe,” said Dr. Schor, professor of psychology at the University of West Georgia, Carrollton, and a cluster headache patient since he first experienced an attack at the age of 21.

The study was published in the January 2021 issue of Headache.

Ranking cluster headaches as worse than experiences such as childbirth or kidney stones is “kind of eye opening, and helps to describe the experience in terms that more people can relate to. I think it helps to share the experience of cluster headache more broadly, because we’re in a situation where cluster headache remains underfunded, and we don’t have enough treatments for it. I think one way to overcome that is to spread awareness of what this problem is, and the impact it has on human life,” said Rashmi Halker Singh, MD, associate professor of neurology at the Mayo Clinic in Scottsdale, Ariz., and deputy editor of Headache. She was not involved in the study.

Dr. Schor called for physicians to consider cluster headache an emergency, because of the severity of pain and also the potential for suicidality. Treatments remain comparatively sparse, but high-flow oxygen can help some patients, and intranasal or intravenous triptans can treat acute pain. In 2018, the Food and Drug Administration approved galcanezumab (Eli Lilly) for prevention of episodic cluster headaches.

But cluster headaches are often misdiagnosed. For many patients, it takes more than a year or even as long as 5 years to get an accurate diagnosis, according to Dr. Schor. Women may be particularly vulnerable to misdiagnosis, because migraines are more common in women. It doesn’t help that many neurologists are taught that cluster headache is primarily a male disease. “Because that idea is so ingrained, I think a lot of women who have cluster headache are probably missed and told they have migraine instead. There are a lot of women who have cluster headache, and that gender difference might not be as big a difference as we were initially taught. We need to do a better job of recognizing cluster headache to better understand what the true prevalence is,” said Dr. Halker Singh.

She noted that patients with side-locked headache should be evaluated for cluster headache, and asked how long the pain lasts in the absence of medication. “Also ask about the presence of cranial autonomic symptoms, and if they occur in the context of headache pain, and if they are side-locked to the side of the headache. Those are important questions that can tease out cluster headache from other conditions,” said Dr. Halker Singh.

For the survey, the researchers asked 1,604 patients with cluster headache patients to rate pain on a scale of 1 to 10. Cluster headache ranked highest at 9.7, then labor pain (7.2), pancreatitis (7.0), and nephrolithiasis (6.9). Cluster headache pain was ranked at 10.0 by 72.1% of respondents. Those reporting maximal pain or were more likely to have cranial autonomic features in comparison with patients who reported less pain, including conjunctival injection or lacrimation (91% versus 85%), eyelid edema (77% versus 66%), forehead/facial sweating (60% versus 49%), fullness in the ear (47% versus 35%), and miosis or ptosis (85% versus 75%). They had more frequent attacks (4.0 versus 3.5 per day), higher Hopelessness Depression Symptom Questionnaire scores (24.5 versus 21.1), and reduced effectiveness of calcium channel blockers (2.2 versus 2.5 on a 5-point Likert scale). They were more often female (34% versus 24%). (P < .001 for all).

The study received funding from Autonomic Technologies and Cluster Busters. Dr. Schor and Dr. Halker Singh had no relevant financial disclosures.

Patients with cluster headache face a double whammy: Physicians too often fail to recognize it, and their condition is among the most severe and debilitating among headache types. In fact, a new survey of patients with cluster headache shows that they rank the pain as worse than most other painful experiences in life, including childbirth, passing of kidney stones, and pancreatitis, among others.

The study’s comparison of cluster headaches to other common painful experiences can help nonsufferers relate to the experience, said Larry Schor, PhD, a coauthor of the paper. “Headache is a terrible word. Bee stings sting, burns burn. [A cluster headache] doesn’t ache. It’s a piercing intensity like you just can’t believe,” said Dr. Schor, professor of psychology at the University of West Georgia, Carrollton, and a cluster headache patient since he first experienced an attack at the age of 21.

The study was published in the January 2021 issue of Headache.

Ranking cluster headaches as worse than experiences such as childbirth or kidney stones is “kind of eye opening, and helps to describe the experience in terms that more people can relate to. I think it helps to share the experience of cluster headache more broadly, because we’re in a situation where cluster headache remains underfunded, and we don’t have enough treatments for it. I think one way to overcome that is to spread awareness of what this problem is, and the impact it has on human life,” said Rashmi Halker Singh, MD, associate professor of neurology at the Mayo Clinic in Scottsdale, Ariz., and deputy editor of Headache. She was not involved in the study.

Dr. Schor called for physicians to consider cluster headache an emergency, because of the severity of pain and also the potential for suicidality. Treatments remain comparatively sparse, but high-flow oxygen can help some patients, and intranasal or intravenous triptans can treat acute pain. In 2018, the Food and Drug Administration approved galcanezumab (Eli Lilly) for prevention of episodic cluster headaches.

But cluster headaches are often misdiagnosed. For many patients, it takes more than a year or even as long as 5 years to get an accurate diagnosis, according to Dr. Schor. Women may be particularly vulnerable to misdiagnosis, because migraines are more common in women. It doesn’t help that many neurologists are taught that cluster headache is primarily a male disease. “Because that idea is so ingrained, I think a lot of women who have cluster headache are probably missed and told they have migraine instead. There are a lot of women who have cluster headache, and that gender difference might not be as big a difference as we were initially taught. We need to do a better job of recognizing cluster headache to better understand what the true prevalence is,” said Dr. Halker Singh.

She noted that patients with side-locked headache should be evaluated for cluster headache, and asked how long the pain lasts in the absence of medication. “Also ask about the presence of cranial autonomic symptoms, and if they occur in the context of headache pain, and if they are side-locked to the side of the headache. Those are important questions that can tease out cluster headache from other conditions,” said Dr. Halker Singh.

For the survey, the researchers asked 1,604 patients with cluster headache patients to rate pain on a scale of 1 to 10. Cluster headache ranked highest at 9.7, then labor pain (7.2), pancreatitis (7.0), and nephrolithiasis (6.9). Cluster headache pain was ranked at 10.0 by 72.1% of respondents. Those reporting maximal pain or were more likely to have cranial autonomic features in comparison with patients who reported less pain, including conjunctival injection or lacrimation (91% versus 85%), eyelid edema (77% versus 66%), forehead/facial sweating (60% versus 49%), fullness in the ear (47% versus 35%), and miosis or ptosis (85% versus 75%). They had more frequent attacks (4.0 versus 3.5 per day), higher Hopelessness Depression Symptom Questionnaire scores (24.5 versus 21.1), and reduced effectiveness of calcium channel blockers (2.2 versus 2.5 on a 5-point Likert scale). They were more often female (34% versus 24%). (P < .001 for all).

The study received funding from Autonomic Technologies and Cluster Busters. Dr. Schor and Dr. Halker Singh had no relevant financial disclosures.

Among patients with migraine who use prescription medications, the increasing use of prescription opioids is associated with chronic migraine, more severe disability, and anxiety and depression, according to an analysis published in the January issue of Headache . The use of prescription opioids also is associated with treatment-related variables such as poor acute treatment optimization and treatment in a pain clinic. The results indicate the continued need to educate patients and clinicians about the potential risks of opioids for migraineurs, according to the researchers.

A review of MAST data

Dr. Lipton and colleagues set out to identify the variables associated with the frequency of opioid use in people with migraine. Among the variables that they sought to examine were demographic characteristics, comorbidities, headache characteristics, medication use, and patterns of health care use. Dr. Lipton’s group hypothesized that migraine-related severity and burden would increase with increasing frequency of opioid use.

To conduct their research, the investigators examined data from the MAST study, a nationwide sample of American adults with migraine. They focused specifically on participants who reported receiving prescription acute medications. Participants eligible for this analysis reported 3 or more headache days in the previous 3 months and at least 1 monthly headache day in the previous month. In all, 15,133 participants met these criteria.

Dr. Lipton and colleagues categorized participants into four groups based on their frequency of opioid use. The groups had no opioid use, 3 or fewer monthly days of opioid use, 4 to 9 monthly days of opioid use, and 10 or more days of monthly opioid use. The last category is consistent with the International Classification of Headache Disorders-3 criteria for overuse of opioids in migraine.

At baseline, MAST participants provided information about variables such as gender, age, marital status, smoking status, education, and income. Participants also reported how many times in the previous 6 months they had visited a primary care doctor, a neurologist, a headache specialist, or a pain specialist. Dr. Lipton’s group calculated monthly headache days using the number of days during the previous 3 months affected by headache. The Migraine Disability Assessment (MIDAS) questionnaire was used to measure headache-related disability. The four-item Patient Health Questionnaire (PHQ-4) was used to screen for anxiety and depression, and the Migraine Treatment Optimization Questionnaire (mTOQ-4) evaluated participants’ treatment optimization.
 

Men predominated among opioid users

The investigators included 4,701 MAST participants in their analysis. The population’s mean age was 45 years, and 71.6% of participants were women. Of the entire sample, 67.5% reported no opioid use, and 32.5% reported opioid use. Of the total study population, 18.7% of patients took opioids 3 or fewer days per month, 6.5% took opioids 4 to 9 days per month, and 7.3% took opioids on 10 or more days per month.

Opioid users did not differ from nonusers on race or marital status. Men were overrepresented among all groups of opioid users, however. In addition, opioid use was more prevalent among participants with fewer than 4 years of college education (34.9%) than among participants with 4 or more years of college (30.8%). The proportion of participants with fewer than 4 years of college increased with increasing monthly opioid use. Furthermore, opioid use increased with decreasing household income. As opioid use increased, rates of employment decreased. Approximately 33% of the entire sample were obese, and the proportion of obese participants increased with increasing days per month of opioid use.

The most frequent setting during the previous 6 months for participants seeking care was primary care (49.7%). The next most frequent setting was neurology units (20.9%), pain clinics (8.3%), and headache clinics (7.7%). The prevalence of opioid use was 37.5% among participants with primary care visits, 37.3% among participants with neurologist visits, 43.0% among participants with headache clinic visits, and 53.5% with pain clinic visits.

About 15% of the population had chronic migraine. The prevalence of chronic migraine increased with increasing frequency of opioid use. About 49% of the sample had allodynia, and the prevalence of allodynia increased with increasing frequency of opioid use. Overall, disability was moderate to severe in 57.3% of participants. Participants who used opioids on 3 or fewer days per month had the lowest prevalence of moderate to severe disability (50.2%), and participants who used opioids on 10 or more days per month had the highest prevalence of moderate to severe disability (83.8%).

Approximately 21% of participants had anxiety or depression. The lowest prevalence of anxiety or depression was among participants who took opioids on 3 or fewer days per month (17.4%), and the highest prevalence was among participants who took opioids on 10 or more days per month (43.2%). About 39% of the population had very poor to poor treatment optimization. Among opioid nonusers, 35.6% had very poor to poor treatment optimization, and 59.4% of participants who used opioids on 10 or more days per month had very poor to poor treatment optimization.

Dr. Lipton and colleagues also examined the study population’s use of triptans. Overall, 51.5% of participants reported taking triptans. The prevalence of triptan use was highest among participants who did not use opioids (64.1%) and lowest among participants who used opioids on 3 or fewer days per month (20.5%). Triptan use increased as monthly days of opioid use increased.
 

Pain clinics and opioid prescription

“In the general population, women are more likely to receive opioids than men,” said Dr. Lipton. “This [finding] could reflect, in part, that women have more pain disorders than men and are more likely to seek medical care for pain than men.” In the current study, however, men with migraine were more likely to receive opioid prescriptions than were women with migraine. One potential explanation for this finding is that men with migraine are less likely to receive a migraine diagnosis, which might attenuate opioid prescribing, than women with migraine. “It may be that opioids are perceived to be serious drugs for serious pain, and that some physicians may be more likely to prescribe opioids to men because the disorder is taken more seriously in men than women,” said Dr. Lipton.

The observation that opioids were more likely to be prescribed for people treated in pain clinics “is consistent with my understanding of practice patterns,” he added. “Generally, neurologists strive to find effective acute treatment alternatives to opioids. The emergence of [drug classes known as] gepants and ditans provides a helpful set of alternatives to tritpans.”

Dr. Lipton and his colleagues plan further research into the treatment of migraineurs. “In a claims analysis, we showed that when people with migraine fail a triptan, they are most likely to get an opioid as their next drug,” he said. “Reasonable [clinicians] might disagree on the next step. The next step, in the absence of contraindications, could be a different oral triptan, a nonoral triptan, or a gepant or ditan. We are planning a randomized trial to probe this question.”
 

Why are opioids still being used?

The study’s reliance on patients’ self-report and its retrospective design are two of its weaknesses, said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. One strength, however, is that the stratified sampling methodology produced a study population that accurately reflects the demographic characteristics of the U.S. adult population, he added. Another strength is the investigators’ examination of opioid use by patient characteristics such as marital status, education, income, obesity, and smoking.

Given the harmful effects of opioids in migraine, it is hard to understand why as much as one-third of study participants using acute care medication for migraine were using opioids, said Dr. Rapoport. Using opioids for the acute treatment of migraine attacks often indicates inadequate treatment optimization, which leads to ongoing headache. As a consequence, patients may take more medication, which can increase headache frequency and lead to diagnoses of chronic migraine and medication overuse headache. Although the study found an association between the increased use of opioids and decreased household income and increased unemployment, smoking, and obesity, “it is not possible to assign causality to any of these associations, even though some would argue that decreased socioeconomic status was somehow related to more headache, disability, obesity, smoking, and unemployment,” he added.

“The paper suggests that future research should look at the risk factors for use of opioids and should determine if depression is a risk factor for or a consequence of opioid use,” said Dr. Rapoport. “Interventional studies designed to improve the acute care of migraine attacks might be able to reduce the use of opioids. I have not used opioids or butalbital-containing medication in my office for many years.”

This study was funded and sponsored by Dr. Reddy’s Laboratories group of companies, Princeton, N.J. Dr. Lipton has received grant support from the National Institutes of Health, the National Headache Foundation, and the Migraine Research Fund. He serves as a consultant, serves as an advisory board member, or has received honoraria from Alder, Allergan, American Headache Society, Autonomic Technologies, Biohaven, Dr. Reddy’s Laboratories, Eli Lilly, eNeura Therapeutics, Merck, Novartis, Pfizer, and Teva, Inc. He receives royalties from Wolff’s Headache, 8th Edition (New York: Oxford University Press, 2009) and holds stock options in eNeura Therapeutics and Biohaven.

SOURCE: Lipton RB, et al. Headache. https://doi.org/10.1111/head.14018. 2020;61(1):103-16.

Among patients with migraine who use prescription medications, the increasing use of prescription opioids is associated with chronic migraine, more severe disability, and anxiety and depression, according to an analysis published in the January issue of Headache . The use of prescription opioids also is associated with treatment-related variables such as poor acute treatment optimization and treatment in a pain clinic. The results indicate the continued need to educate patients and clinicians about the potential risks of opioids for migraineurs, according to the researchers.

A review of MAST data

Dr. Lipton and colleagues set out to identify the variables associated with the frequency of opioid use in people with migraine. Among the variables that they sought to examine were demographic characteristics, comorbidities, headache characteristics, medication use, and patterns of health care use. Dr. Lipton’s group hypothesized that migraine-related severity and burden would increase with increasing frequency of opioid use.

To conduct their research, the investigators examined data from the MAST study, a nationwide sample of American adults with migraine. They focused specifically on participants who reported receiving prescription acute medications. Participants eligible for this analysis reported 3 or more headache days in the previous 3 months and at least 1 monthly headache day in the previous month. In all, 15,133 participants met these criteria.

Dr. Lipton and colleagues categorized participants into four groups based on their frequency of opioid use. The groups had no opioid use, 3 or fewer monthly days of opioid use, 4 to 9 monthly days of opioid use, and 10 or more days of monthly opioid use. The last category is consistent with the International Classification of Headache Disorders-3 criteria for overuse of opioids in migraine.

At baseline, MAST participants provided information about variables such as gender, age, marital status, smoking status, education, and income. Participants also reported how many times in the previous 6 months they had visited a primary care doctor, a neurologist, a headache specialist, or a pain specialist. Dr. Lipton’s group calculated monthly headache days using the number of days during the previous 3 months affected by headache. The Migraine Disability Assessment (MIDAS) questionnaire was used to measure headache-related disability. The four-item Patient Health Questionnaire (PHQ-4) was used to screen for anxiety and depression, and the Migraine Treatment Optimization Questionnaire (mTOQ-4) evaluated participants’ treatment optimization.
 

Men predominated among opioid users

The investigators included 4,701 MAST participants in their analysis. The population’s mean age was 45 years, and 71.6% of participants were women. Of the entire sample, 67.5% reported no opioid use, and 32.5% reported opioid use. Of the total study population, 18.7% of patients took opioids 3 or fewer days per month, 6.5% took opioids 4 to 9 days per month, and 7.3% took opioids on 10 or more days per month.

Opioid users did not differ from nonusers on race or marital status. Men were overrepresented among all groups of opioid users, however. In addition, opioid use was more prevalent among participants with fewer than 4 years of college education (34.9%) than among participants with 4 or more years of college (30.8%). The proportion of participants with fewer than 4 years of college increased with increasing monthly opioid use. Furthermore, opioid use increased with decreasing household income. As opioid use increased, rates of employment decreased. Approximately 33% of the entire sample were obese, and the proportion of obese participants increased with increasing days per month of opioid use.

The most frequent setting during the previous 6 months for participants seeking care was primary care (49.7%). The next most frequent setting was neurology units (20.9%), pain clinics (8.3%), and headache clinics (7.7%). The prevalence of opioid use was 37.5% among participants with primary care visits, 37.3% among participants with neurologist visits, 43.0% among participants with headache clinic visits, and 53.5% with pain clinic visits.

About 15% of the population had chronic migraine. The prevalence of chronic migraine increased with increasing frequency of opioid use. About 49% of the sample had allodynia, and the prevalence of allodynia increased with increasing frequency of opioid use. Overall, disability was moderate to severe in 57.3% of participants. Participants who used opioids on 3 or fewer days per month had the lowest prevalence of moderate to severe disability (50.2%), and participants who used opioids on 10 or more days per month had the highest prevalence of moderate to severe disability (83.8%).

Approximately 21% of participants had anxiety or depression. The lowest prevalence of anxiety or depression was among participants who took opioids on 3 or fewer days per month (17.4%), and the highest prevalence was among participants who took opioids on 10 or more days per month (43.2%). About 39% of the population had very poor to poor treatment optimization. Among opioid nonusers, 35.6% had very poor to poor treatment optimization, and 59.4% of participants who used opioids on 10 or more days per month had very poor to poor treatment optimization.

Dr. Lipton and colleagues also examined the study population’s use of triptans. Overall, 51.5% of participants reported taking triptans. The prevalence of triptan use was highest among participants who did not use opioids (64.1%) and lowest among participants who used opioids on 3 or fewer days per month (20.5%). Triptan use increased as monthly days of opioid use increased.
 

Pain clinics and opioid prescription

“In the general population, women are more likely to receive opioids than men,” said Dr. Lipton. “This [finding] could reflect, in part, that women have more pain disorders than men and are more likely to seek medical care for pain than men.” In the current study, however, men with migraine were more likely to receive opioid prescriptions than were women with migraine. One potential explanation for this finding is that men with migraine are less likely to receive a migraine diagnosis, which might attenuate opioid prescribing, than women with migraine. “It may be that opioids are perceived to be serious drugs for serious pain, and that some physicians may be more likely to prescribe opioids to men because the disorder is taken more seriously in men than women,” said Dr. Lipton.

The observation that opioids were more likely to be prescribed for people treated in pain clinics “is consistent with my understanding of practice patterns,” he added. “Generally, neurologists strive to find effective acute treatment alternatives to opioids. The emergence of [drug classes known as] gepants and ditans provides a helpful set of alternatives to tritpans.”

Dr. Lipton and his colleagues plan further research into the treatment of migraineurs. “In a claims analysis, we showed that when people with migraine fail a triptan, they are most likely to get an opioid as their next drug,” he said. “Reasonable [clinicians] might disagree on the next step. The next step, in the absence of contraindications, could be a different oral triptan, a nonoral triptan, or a gepant or ditan. We are planning a randomized trial to probe this question.”
 

Why are opioids still being used?

The study’s reliance on patients’ self-report and its retrospective design are two of its weaknesses, said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. One strength, however, is that the stratified sampling methodology produced a study population that accurately reflects the demographic characteristics of the U.S. adult population, he added. Another strength is the investigators’ examination of opioid use by patient characteristics such as marital status, education, income, obesity, and smoking.

Given the harmful effects of opioids in migraine, it is hard to understand why as much as one-third of study participants using acute care medication for migraine were using opioids, said Dr. Rapoport. Using opioids for the acute treatment of migraine attacks often indicates inadequate treatment optimization, which leads to ongoing headache. As a consequence, patients may take more medication, which can increase headache frequency and lead to diagnoses of chronic migraine and medication overuse headache. Although the study found an association between the increased use of opioids and decreased household income and increased unemployment, smoking, and obesity, “it is not possible to assign causality to any of these associations, even though some would argue that decreased socioeconomic status was somehow related to more headache, disability, obesity, smoking, and unemployment,” he added.

“The paper suggests that future research should look at the risk factors for use of opioids and should determine if depression is a risk factor for or a consequence of opioid use,” said Dr. Rapoport. “Interventional studies designed to improve the acute care of migraine attacks might be able to reduce the use of opioids. I have not used opioids or butalbital-containing medication in my office for many years.”

This study was funded and sponsored by Dr. Reddy’s Laboratories group of companies, Princeton, N.J. Dr. Lipton has received grant support from the National Institutes of Health, the National Headache Foundation, and the Migraine Research Fund. He serves as a consultant, serves as an advisory board member, or has received honoraria from Alder, Allergan, American Headache Society, Autonomic Technologies, Biohaven, Dr. Reddy’s Laboratories, Eli Lilly, eNeura Therapeutics, Merck, Novartis, Pfizer, and Teva, Inc. He receives royalties from Wolff’s Headache, 8th Edition (New York: Oxford University Press, 2009) and holds stock options in eNeura Therapeutics and Biohaven.

SOURCE: Lipton RB, et al. Headache. https://doi.org/10.1111/head.14018. 2020;61(1):103-16.

Among patients with migraine who use prescription medications, the increasing use of prescription opioids is associated with chronic migraine, more severe disability, and anxiety and depression, according to an analysis published in the January issue of Headache . The use of prescription opioids also is associated with treatment-related variables such as poor acute treatment optimization and treatment in a pain clinic. The results indicate the continued need to educate patients and clinicians about the potential risks of opioids for migraineurs, according to the researchers.

A review of MAST data

Dr. Lipton and colleagues set out to identify the variables associated with the frequency of opioid use in people with migraine. Among the variables that they sought to examine were demographic characteristics, comorbidities, headache characteristics, medication use, and patterns of health care use. Dr. Lipton’s group hypothesized that migraine-related severity and burden would increase with increasing frequency of opioid use.

To conduct their research, the investigators examined data from the MAST study, a nationwide sample of American adults with migraine. They focused specifically on participants who reported receiving prescription acute medications. Participants eligible for this analysis reported 3 or more headache days in the previous 3 months and at least 1 monthly headache day in the previous month. In all, 15,133 participants met these criteria.

Dr. Lipton and colleagues categorized participants into four groups based on their frequency of opioid use. The groups had no opioid use, 3 or fewer monthly days of opioid use, 4 to 9 monthly days of opioid use, and 10 or more days of monthly opioid use. The last category is consistent with the International Classification of Headache Disorders-3 criteria for overuse of opioids in migraine.

At baseline, MAST participants provided information about variables such as gender, age, marital status, smoking status, education, and income. Participants also reported how many times in the previous 6 months they had visited a primary care doctor, a neurologist, a headache specialist, or a pain specialist. Dr. Lipton’s group calculated monthly headache days using the number of days during the previous 3 months affected by headache. The Migraine Disability Assessment (MIDAS) questionnaire was used to measure headache-related disability. The four-item Patient Health Questionnaire (PHQ-4) was used to screen for anxiety and depression, and the Migraine Treatment Optimization Questionnaire (mTOQ-4) evaluated participants’ treatment optimization.
 

Men predominated among opioid users

The investigators included 4,701 MAST participants in their analysis. The population’s mean age was 45 years, and 71.6% of participants were women. Of the entire sample, 67.5% reported no opioid use, and 32.5% reported opioid use. Of the total study population, 18.7% of patients took opioids 3 or fewer days per month, 6.5% took opioids 4 to 9 days per month, and 7.3% took opioids on 10 or more days per month.

Opioid users did not differ from nonusers on race or marital status. Men were overrepresented among all groups of opioid users, however. In addition, opioid use was more prevalent among participants with fewer than 4 years of college education (34.9%) than among participants with 4 or more years of college (30.8%). The proportion of participants with fewer than 4 years of college increased with increasing monthly opioid use. Furthermore, opioid use increased with decreasing household income. As opioid use increased, rates of employment decreased. Approximately 33% of the entire sample were obese, and the proportion of obese participants increased with increasing days per month of opioid use.

The most frequent setting during the previous 6 months for participants seeking care was primary care (49.7%). The next most frequent setting was neurology units (20.9%), pain clinics (8.3%), and headache clinics (7.7%). The prevalence of opioid use was 37.5% among participants with primary care visits, 37.3% among participants with neurologist visits, 43.0% among participants with headache clinic visits, and 53.5% with pain clinic visits.

About 15% of the population had chronic migraine. The prevalence of chronic migraine increased with increasing frequency of opioid use. About 49% of the sample had allodynia, and the prevalence of allodynia increased with increasing frequency of opioid use. Overall, disability was moderate to severe in 57.3% of participants. Participants who used opioids on 3 or fewer days per month had the lowest prevalence of moderate to severe disability (50.2%), and participants who used opioids on 10 or more days per month had the highest prevalence of moderate to severe disability (83.8%).

Approximately 21% of participants had anxiety or depression. The lowest prevalence of anxiety or depression was among participants who took opioids on 3 or fewer days per month (17.4%), and the highest prevalence was among participants who took opioids on 10 or more days per month (43.2%). About 39% of the population had very poor to poor treatment optimization. Among opioid nonusers, 35.6% had very poor to poor treatment optimization, and 59.4% of participants who used opioids on 10 or more days per month had very poor to poor treatment optimization.

Dr. Lipton and colleagues also examined the study population’s use of triptans. Overall, 51.5% of participants reported taking triptans. The prevalence of triptan use was highest among participants who did not use opioids (64.1%) and lowest among participants who used opioids on 3 or fewer days per month (20.5%). Triptan use increased as monthly days of opioid use increased.
 

Pain clinics and opioid prescription

“In the general population, women are more likely to receive opioids than men,” said Dr. Lipton. “This [finding] could reflect, in part, that women have more pain disorders than men and are more likely to seek medical care for pain than men.” In the current study, however, men with migraine were more likely to receive opioid prescriptions than were women with migraine. One potential explanation for this finding is that men with migraine are less likely to receive a migraine diagnosis, which might attenuate opioid prescribing, than women with migraine. “It may be that opioids are perceived to be serious drugs for serious pain, and that some physicians may be more likely to prescribe opioids to men because the disorder is taken more seriously in men than women,” said Dr. Lipton.

The observation that opioids were more likely to be prescribed for people treated in pain clinics “is consistent with my understanding of practice patterns,” he added. “Generally, neurologists strive to find effective acute treatment alternatives to opioids. The emergence of [drug classes known as] gepants and ditans provides a helpful set of alternatives to tritpans.”

Dr. Lipton and his colleagues plan further research into the treatment of migraineurs. “In a claims analysis, we showed that when people with migraine fail a triptan, they are most likely to get an opioid as their next drug,” he said. “Reasonable [clinicians] might disagree on the next step. The next step, in the absence of contraindications, could be a different oral triptan, a nonoral triptan, or a gepant or ditan. We are planning a randomized trial to probe this question.”
 

Why are opioids still being used?

The study’s reliance on patients’ self-report and its retrospective design are two of its weaknesses, said Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews. One strength, however, is that the stratified sampling methodology produced a study population that accurately reflects the demographic characteristics of the U.S. adult population, he added. Another strength is the investigators’ examination of opioid use by patient characteristics such as marital status, education, income, obesity, and smoking.

Given the harmful effects of opioids in migraine, it is hard to understand why as much as one-third of study participants using acute care medication for migraine were using opioids, said Dr. Rapoport. Using opioids for the acute treatment of migraine attacks often indicates inadequate treatment optimization, which leads to ongoing headache. As a consequence, patients may take more medication, which can increase headache frequency and lead to diagnoses of chronic migraine and medication overuse headache. Although the study found an association between the increased use of opioids and decreased household income and increased unemployment, smoking, and obesity, “it is not possible to assign causality to any of these associations, even though some would argue that decreased socioeconomic status was somehow related to more headache, disability, obesity, smoking, and unemployment,” he added.

“The paper suggests that future research should look at the risk factors for use of opioids and should determine if depression is a risk factor for or a consequence of opioid use,” said Dr. Rapoport. “Interventional studies designed to improve the acute care of migraine attacks might be able to reduce the use of opioids. I have not used opioids or butalbital-containing medication in my office for many years.”

This study was funded and sponsored by Dr. Reddy’s Laboratories group of companies, Princeton, N.J. Dr. Lipton has received grant support from the National Institutes of Health, the National Headache Foundation, and the Migraine Research Fund. He serves as a consultant, serves as an advisory board member, or has received honoraria from Alder, Allergan, American Headache Society, Autonomic Technologies, Biohaven, Dr. Reddy’s Laboratories, Eli Lilly, eNeura Therapeutics, Merck, Novartis, Pfizer, and Teva, Inc. He receives royalties from Wolff’s Headache, 8th Edition (New York: Oxford University Press, 2009) and holds stock options in eNeura Therapeutics and Biohaven.

SOURCE: Lipton RB, et al. Headache. https://doi.org/10.1111/head.14018. 2020;61(1):103-16.

When 42-year-old Danielle Simone Brand started having hormonal migraines, she first turned to cannabidiol (CBD) oil, eventually adding an occasional pull on a prefilled tetrahydrocannabinol (THC) vape for nighttime use. She was careful to avoid THC during work hours. A parenting and cannabis writer, Ms. Brand had more than a cursory background in cannabinoid medicine and had spent time at her local California dispensary discussing various cannabinoid components that might help alleviate her pain.

Anatoliy Sizov/Getty Images

A self-professed “do-it-yourselfer,” Ms. Brand continues to use cannabinoids for her monthly headaches, forgoing any other pain medication. “There are times for conventional medicine in partnership with your doctor, but when it comes to health and wellness, women should be empowered to make decisions and self-experiment,” she said in an interview.

Ms. Brand is not alone. Significant numbers of women are replacing or supplementing prescription medications with cannabinoids, often without consulting their primary care physician, ob.gyn., or other specialist. At times, women have tried to have these conversations, only to be met with silence or worse.

Take Linda Fuller, a 58-year-old yoga instructor from Long Island who says that she uses CBD and THC for chronic sacroiliac pain after a car accident and to alleviate stress-triggered eczema flares. “I’ve had doctors turn their backs on me; I’ve had nurse practitioners walk out on me in the middle of a sentence,” she said in an interview.

Ms. Fuller said her conversion to cannabinoid medicine is relatively new; she never used cannabis recreationally before her accident but now considers it a gift. She doesn’t keep aspirin in the house and refused pain medication immediately after she injured her back.

Diana Krach, a 34-year-old writer from Maryland, says she’s encountered roadblocks about her decision to use cannabinoids for endometriosis and for pain from Crohn’s disease. When she tried to discuss her CBD use with a gastroenterologist, he interrupted her: “Whatever pot you’re smoking isn’t going to work, you’re going on biologics.”

Ms. Krach had not been smoking anything but had turned to a CBD tincture for symptom relief after prescription pain medications failed to help.

Ms. Brand, Ms. Fuller, and Ms. Krach are the tip of the iceberg when it comes to women seeking symptom relief outside the medicine cabinet. A recent survey in the Journal of Women’s Health of almost 1,000 women show that 90% (most between the ages of 35 and 44) had used cannabis and would consider using it to treat gynecologic pain. Roughly 80% said they would consider using it for procedure-related pain or other conditions. Additionally, women have reported using cannabinoids for PTSD, sleep disturbances or insomnia, anxiety, and migraine headaches.

Observational survey data have likewise shown that 80% of women with advanced or recurrent gynecologic malignancies who were prescribed cannabis reported that it was equivalent or superior to other medications for relieving pain, neuropathy, nausea, insomnia, decreased appetite, and anxiety.

In another survey, almost half (45%) of women with gynecologic malignancies who used nonprescribed cannabis for the same symptoms reported that they had reduced their use of prescription narcotics after initiating use of cannabis.
 

The gray zone

There has been a surge in self-reported cannabis use among pregnant women in particular. The National Survey on Drug Use and Health findings for the periods 2002-2003 and 2016-2017 highlight increases in adjusted prevalence rates from 3.4% to 7% in past-month use among pregnant women overall and from 5.7% to 12.1% during the first trimester alone.

“The more that you talk to pregnant women, the more that you realize that a lot are using cannabinoids for something that is basically medicinal, for sleep, for anxiety, or for nausea,” Katrina Mark, MD, an ob.gyn. and associate professor of medicine at the University of Maryland, College Park, said in an interview. “I’m not saying it’s fine to use drugs in pregnancy, but it is a grayer conversation than a lot of colleagues want to believe. Telling women to quit seems foolish since the alternative is to be anxious, don’t sleep, don’t eat, or use a medication that also has risks to it.”

One observational study shows that pregnant women themselves are conflicted. Although the majority believe that cannabis is “natural” and “safe,” compared with prescription drugs, they aren’t entirely in the dark about potential risks. They often express frustration with practitioners’ responses when these topics are broached during office visits. An observational survey among women and practitioners published in 2020 highlights that only half of doctors openly discouraged perinatal cannabis use and that others opted out of the discussion entirely.

This is the experience of many of the women that this news organization spoke with. Ms. Krach pointed out that “there’s a big deficit in listening; the doctor is supposed to be working for our behalf, especially when it comes to reproductive health.”

Dr. Mark believed that a lot of the conversation has been clouded by the illegality of the substance but that cannabinoids deserve as much of a fair chance for discussion and consideration as other medicines, which also carry risks in pregnancy. “There’s literally no evidence that it will work in pregnancy [for these symptoms], but there’s no evidence that it doesn’t, either,” she said in an interview. “When I have this conversation with colleagues who do not share my views, I try to encourage them to look at the actual risks versus the benefits versus the alternatives.”

The ‘entourage effect’

Data supporting cannabinoids have been mostly laboratory based, case based, or observational. However, several well-designed (albeit small) trials have demonstrated efficacy for chronic pain conditions, including neuropathic and headache pain, as well as in Crohn’s disease. Most investigators have concluded that dosage is important and that there is a synergistic interaction between compounds (known as the “entourage effect”) that relates to cannabinoid efficacy or lack thereof, as well as possible adverse effects.

In addition to legality issues, the entourage effect is one of the most important factors related to the medical use of cannabinoids. “There are literally thousands of cultivars of cannabis, each with their own phytocannabinoid and terpenic profiles that may produce distinct therapeutic effects, [so] it is misguided to speak of cannabis in monolithic terms. It is like making broad claims about soup,” wrote coauthor Samoon Ahmad, MD, in Medical Marijuana: A Clinical Handbook.

Additionally, the role that reproductive hormones play is not entirely understood. Reproductive-aged women appear to be more susceptible to a “telescoping” (gender-related progression to dependence) effect in comparison with men. Ziva Cooper, PhD, director of the Cannabis Research Initiative at the University of California, Los Angeles, said in an interview. She explained that research has shown that factors such as the degree of exposure, frequency of use, and menses confound this susceptibility.
 

It’s the data

Frustration over cannabinoid therapeutics abound, especially when it comes to data, legal issues, and lack of training. “The feedback that I hear from providers is that there isn’t enough information; we just don’t know enough about it,” Dr. Mark said, “but there is information that we do have, and ignoring it is not beneficial.”

Dr. Cooper concurred. Although she readily acknowledges that data from randomized, placebo-controlled trials are mostly lacking, she says, “There are signals in the literature providing evidence for the utility of cannabis and cannabinoids for pain and some other effects.”

Other practitioners said in an interview that some patients admit to using cannabinoids but that they lack the ample information to guide these patients. By and large, many women equate “natural” with “safe,” and some will experiment on their own to see what works.

Those experiments are not without risk, which is why “it’s just as important for physicians to talk to their patients about cannabis use as it is for patients to be forthcoming about that use,” said Dr. Cooper. “It could have implications on their overall health as well as interactions with other drugs that they’re using.”

That balance from a clinical perspective on cannabis is crucial, wrote coauthor Kenneth Hill, MD, in Medical Marijuana: A Clinical Handbook. “Without it,” he wrote, “the window of opportunity for a patient to accept treatment that she needs may not be open very long.”

A version of this article first appeared on Medscape.com.

When 42-year-old Danielle Simone Brand started having hormonal migraines, she first turned to cannabidiol (CBD) oil, eventually adding an occasional pull on a prefilled tetrahydrocannabinol (THC) vape for nighttime use. She was careful to avoid THC during work hours. A parenting and cannabis writer, Ms. Brand had more than a cursory background in cannabinoid medicine and had spent time at her local California dispensary discussing various cannabinoid components that might help alleviate her pain.

Anatoliy Sizov/Getty Images

A self-professed “do-it-yourselfer,” Ms. Brand continues to use cannabinoids for her monthly headaches, forgoing any other pain medication. “There are times for conventional medicine in partnership with your doctor, but when it comes to health and wellness, women should be empowered to make decisions and self-experiment,” she said in an interview.

Ms. Brand is not alone. Significant numbers of women are replacing or supplementing prescription medications with cannabinoids, often without consulting their primary care physician, ob.gyn., or other specialist. At times, women have tried to have these conversations, only to be met with silence or worse.

Take Linda Fuller, a 58-year-old yoga instructor from Long Island who says that she uses CBD and THC for chronic sacroiliac pain after a car accident and to alleviate stress-triggered eczema flares. “I’ve had doctors turn their backs on me; I’ve had nurse practitioners walk out on me in the middle of a sentence,” she said in an interview.

Ms. Fuller said her conversion to cannabinoid medicine is relatively new; she never used cannabis recreationally before her accident but now considers it a gift. She doesn’t keep aspirin in the house and refused pain medication immediately after she injured her back.

Diana Krach, a 34-year-old writer from Maryland, says she’s encountered roadblocks about her decision to use cannabinoids for endometriosis and for pain from Crohn’s disease. When she tried to discuss her CBD use with a gastroenterologist, he interrupted her: “Whatever pot you’re smoking isn’t going to work, you’re going on biologics.”

Ms. Krach had not been smoking anything but had turned to a CBD tincture for symptom relief after prescription pain medications failed to help.

Ms. Brand, Ms. Fuller, and Ms. Krach are the tip of the iceberg when it comes to women seeking symptom relief outside the medicine cabinet. A recent survey in the Journal of Women’s Health of almost 1,000 women show that 90% (most between the ages of 35 and 44) had used cannabis and would consider using it to treat gynecologic pain. Roughly 80% said they would consider using it for procedure-related pain or other conditions. Additionally, women have reported using cannabinoids for PTSD, sleep disturbances or insomnia, anxiety, and migraine headaches.

Observational survey data have likewise shown that 80% of women with advanced or recurrent gynecologic malignancies who were prescribed cannabis reported that it was equivalent or superior to other medications for relieving pain, neuropathy, nausea, insomnia, decreased appetite, and anxiety.

In another survey, almost half (45%) of women with gynecologic malignancies who used nonprescribed cannabis for the same symptoms reported that they had reduced their use of prescription narcotics after initiating use of cannabis.
 

The gray zone

There has been a surge in self-reported cannabis use among pregnant women in particular. The National Survey on Drug Use and Health findings for the periods 2002-2003 and 2016-2017 highlight increases in adjusted prevalence rates from 3.4% to 7% in past-month use among pregnant women overall and from 5.7% to 12.1% during the first trimester alone.

“The more that you talk to pregnant women, the more that you realize that a lot are using cannabinoids for something that is basically medicinal, for sleep, for anxiety, or for nausea,” Katrina Mark, MD, an ob.gyn. and associate professor of medicine at the University of Maryland, College Park, said in an interview. “I’m not saying it’s fine to use drugs in pregnancy, but it is a grayer conversation than a lot of colleagues want to believe. Telling women to quit seems foolish since the alternative is to be anxious, don’t sleep, don’t eat, or use a medication that also has risks to it.”

One observational study shows that pregnant women themselves are conflicted. Although the majority believe that cannabis is “natural” and “safe,” compared with prescription drugs, they aren’t entirely in the dark about potential risks. They often express frustration with practitioners’ responses when these topics are broached during office visits. An observational survey among women and practitioners published in 2020 highlights that only half of doctors openly discouraged perinatal cannabis use and that others opted out of the discussion entirely.

This is the experience of many of the women that this news organization spoke with. Ms. Krach pointed out that “there’s a big deficit in listening; the doctor is supposed to be working for our behalf, especially when it comes to reproductive health.”

Dr. Mark believed that a lot of the conversation has been clouded by the illegality of the substance but that cannabinoids deserve as much of a fair chance for discussion and consideration as other medicines, which also carry risks in pregnancy. “There’s literally no evidence that it will work in pregnancy [for these symptoms], but there’s no evidence that it doesn’t, either,” she said in an interview. “When I have this conversation with colleagues who do not share my views, I try to encourage them to look at the actual risks versus the benefits versus the alternatives.”

The ‘entourage effect’

Data supporting cannabinoids have been mostly laboratory based, case based, or observational. However, several well-designed (albeit small) trials have demonstrated efficacy for chronic pain conditions, including neuropathic and headache pain, as well as in Crohn’s disease. Most investigators have concluded that dosage is important and that there is a synergistic interaction between compounds (known as the “entourage effect”) that relates to cannabinoid efficacy or lack thereof, as well as possible adverse effects.

In addition to legality issues, the entourage effect is one of the most important factors related to the medical use of cannabinoids. “There are literally thousands of cultivars of cannabis, each with their own phytocannabinoid and terpenic profiles that may produce distinct therapeutic effects, [so] it is misguided to speak of cannabis in monolithic terms. It is like making broad claims about soup,” wrote coauthor Samoon Ahmad, MD, in Medical Marijuana: A Clinical Handbook.

Additionally, the role that reproductive hormones play is not entirely understood. Reproductive-aged women appear to be more susceptible to a “telescoping” (gender-related progression to dependence) effect in comparison with men. Ziva Cooper, PhD, director of the Cannabis Research Initiative at the University of California, Los Angeles, said in an interview. She explained that research has shown that factors such as the degree of exposure, frequency of use, and menses confound this susceptibility.
 

It’s the data

Frustration over cannabinoid therapeutics abound, especially when it comes to data, legal issues, and lack of training. “The feedback that I hear from providers is that there isn’t enough information; we just don’t know enough about it,” Dr. Mark said, “but there is information that we do have, and ignoring it is not beneficial.”

Dr. Cooper concurred. Although she readily acknowledges that data from randomized, placebo-controlled trials are mostly lacking, she says, “There are signals in the literature providing evidence for the utility of cannabis and cannabinoids for pain and some other effects.”

Other practitioners said in an interview that some patients admit to using cannabinoids but that they lack the ample information to guide these patients. By and large, many women equate “natural” with “safe,” and some will experiment on their own to see what works.

Those experiments are not without risk, which is why “it’s just as important for physicians to talk to their patients about cannabis use as it is for patients to be forthcoming about that use,” said Dr. Cooper. “It could have implications on their overall health as well as interactions with other drugs that they’re using.”

That balance from a clinical perspective on cannabis is crucial, wrote coauthor Kenneth Hill, MD, in Medical Marijuana: A Clinical Handbook. “Without it,” he wrote, “the window of opportunity for a patient to accept treatment that she needs may not be open very long.”

A version of this article first appeared on Medscape.com.

When 42-year-old Danielle Simone Brand started having hormonal migraines, she first turned to cannabidiol (CBD) oil, eventually adding an occasional pull on a prefilled tetrahydrocannabinol (THC) vape for nighttime use. She was careful to avoid THC during work hours. A parenting and cannabis writer, Ms. Brand had more than a cursory background in cannabinoid medicine and had spent time at her local California dispensary discussing various cannabinoid components that might help alleviate her pain.

Anatoliy Sizov/Getty Images

A self-professed “do-it-yourselfer,” Ms. Brand continues to use cannabinoids for her monthly headaches, forgoing any other pain medication. “There are times for conventional medicine in partnership with your doctor, but when it comes to health and wellness, women should be empowered to make decisions and self-experiment,” she said in an interview.

Ms. Brand is not alone. Significant numbers of women are replacing or supplementing prescription medications with cannabinoids, often without consulting their primary care physician, ob.gyn., or other specialist. At times, women have tried to have these conversations, only to be met with silence or worse.

Take Linda Fuller, a 58-year-old yoga instructor from Long Island who says that she uses CBD and THC for chronic sacroiliac pain after a car accident and to alleviate stress-triggered eczema flares. “I’ve had doctors turn their backs on me; I’ve had nurse practitioners walk out on me in the middle of a sentence,” she said in an interview.

Ms. Fuller said her conversion to cannabinoid medicine is relatively new; she never used cannabis recreationally before her accident but now considers it a gift. She doesn’t keep aspirin in the house and refused pain medication immediately after she injured her back.

Diana Krach, a 34-year-old writer from Maryland, says she’s encountered roadblocks about her decision to use cannabinoids for endometriosis and for pain from Crohn’s disease. When she tried to discuss her CBD use with a gastroenterologist, he interrupted her: “Whatever pot you’re smoking isn’t going to work, you’re going on biologics.”

Ms. Krach had not been smoking anything but had turned to a CBD tincture for symptom relief after prescription pain medications failed to help.

Ms. Brand, Ms. Fuller, and Ms. Krach are the tip of the iceberg when it comes to women seeking symptom relief outside the medicine cabinet. A recent survey in the Journal of Women’s Health of almost 1,000 women show that 90% (most between the ages of 35 and 44) had used cannabis and would consider using it to treat gynecologic pain. Roughly 80% said they would consider using it for procedure-related pain or other conditions. Additionally, women have reported using cannabinoids for PTSD, sleep disturbances or insomnia, anxiety, and migraine headaches.

Observational survey data have likewise shown that 80% of women with advanced or recurrent gynecologic malignancies who were prescribed cannabis reported that it was equivalent or superior to other medications for relieving pain, neuropathy, nausea, insomnia, decreased appetite, and anxiety.

In another survey, almost half (45%) of women with gynecologic malignancies who used nonprescribed cannabis for the same symptoms reported that they had reduced their use of prescription narcotics after initiating use of cannabis.
 

The gray zone

There has been a surge in self-reported cannabis use among pregnant women in particular. The National Survey on Drug Use and Health findings for the periods 2002-2003 and 2016-2017 highlight increases in adjusted prevalence rates from 3.4% to 7% in past-month use among pregnant women overall and from 5.7% to 12.1% during the first trimester alone.

“The more that you talk to pregnant women, the more that you realize that a lot are using cannabinoids for something that is basically medicinal, for sleep, for anxiety, or for nausea,” Katrina Mark, MD, an ob.gyn. and associate professor of medicine at the University of Maryland, College Park, said in an interview. “I’m not saying it’s fine to use drugs in pregnancy, but it is a grayer conversation than a lot of colleagues want to believe. Telling women to quit seems foolish since the alternative is to be anxious, don’t sleep, don’t eat, or use a medication that also has risks to it.”

One observational study shows that pregnant women themselves are conflicted. Although the majority believe that cannabis is “natural” and “safe,” compared with prescription drugs, they aren’t entirely in the dark about potential risks. They often express frustration with practitioners’ responses when these topics are broached during office visits. An observational survey among women and practitioners published in 2020 highlights that only half of doctors openly discouraged perinatal cannabis use and that others opted out of the discussion entirely.

This is the experience of many of the women that this news organization spoke with. Ms. Krach pointed out that “there’s a big deficit in listening; the doctor is supposed to be working for our behalf, especially when it comes to reproductive health.”

Dr. Mark believed that a lot of the conversation has been clouded by the illegality of the substance but that cannabinoids deserve as much of a fair chance for discussion and consideration as other medicines, which also carry risks in pregnancy. “There’s literally no evidence that it will work in pregnancy [for these symptoms], but there’s no evidence that it doesn’t, either,” she said in an interview. “When I have this conversation with colleagues who do not share my views, I try to encourage them to look at the actual risks versus the benefits versus the alternatives.”

The ‘entourage effect’

Data supporting cannabinoids have been mostly laboratory based, case based, or observational. However, several well-designed (albeit small) trials have demonstrated efficacy for chronic pain conditions, including neuropathic and headache pain, as well as in Crohn’s disease. Most investigators have concluded that dosage is important and that there is a synergistic interaction between compounds (known as the “entourage effect”) that relates to cannabinoid efficacy or lack thereof, as well as possible adverse effects.

In addition to legality issues, the entourage effect is one of the most important factors related to the medical use of cannabinoids. “There are literally thousands of cultivars of cannabis, each with their own phytocannabinoid and terpenic profiles that may produce distinct therapeutic effects, [so] it is misguided to speak of cannabis in monolithic terms. It is like making broad claims about soup,” wrote coauthor Samoon Ahmad, MD, in Medical Marijuana: A Clinical Handbook.

Additionally, the role that reproductive hormones play is not entirely understood. Reproductive-aged women appear to be more susceptible to a “telescoping” (gender-related progression to dependence) effect in comparison with men. Ziva Cooper, PhD, director of the Cannabis Research Initiative at the University of California, Los Angeles, said in an interview. She explained that research has shown that factors such as the degree of exposure, frequency of use, and menses confound this susceptibility.
 

It’s the data

Frustration over cannabinoid therapeutics abound, especially when it comes to data, legal issues, and lack of training. “The feedback that I hear from providers is that there isn’t enough information; we just don’t know enough about it,” Dr. Mark said, “but there is information that we do have, and ignoring it is not beneficial.”

Dr. Cooper concurred. Although she readily acknowledges that data from randomized, placebo-controlled trials are mostly lacking, she says, “There are signals in the literature providing evidence for the utility of cannabis and cannabinoids for pain and some other effects.”

Other practitioners said in an interview that some patients admit to using cannabinoids but that they lack the ample information to guide these patients. By and large, many women equate “natural” with “safe,” and some will experiment on their own to see what works.

Those experiments are not without risk, which is why “it’s just as important for physicians to talk to their patients about cannabis use as it is for patients to be forthcoming about that use,” said Dr. Cooper. “It could have implications on their overall health as well as interactions with other drugs that they’re using.”

That balance from a clinical perspective on cannabis is crucial, wrote coauthor Kenneth Hill, MD, in Medical Marijuana: A Clinical Handbook. “Without it,” he wrote, “the window of opportunity for a patient to accept treatment that she needs may not be open very long.”

A version of this article first appeared on Medscape.com.

For decades, opioids have been a mainstay in the management of pain after total joint arthroplasty. In the past 10 years, however, opioid prescribing has come under increased scrutiny due to a rise in rates of opioid abuse, pill diversion, and opioid-related deaths.^1,2 Opioids are associated with adverse effects, including nausea, vomiting, constipation, apathy, and respiratory depression, all of which influence arthroplasty outcomes and affect the patient experience. Although primary care groups account for nearly half of prescriptions written, orthopedic surgeons have the third highest per capita rate of opioid prescribing of all medical specialties.^3,4 This puts orthopedic surgeons, particularly those who perform routine procedures, in an opportune but challenging position to confront this problem through novel pain management strategies.

Approximately 1 million total knee arthroplasties (TKAs) are performed in the US every year, and the US Department of Veterans Affairs (VA) health system performs about 10,000 hip and knee joint replacements.^5,6 There is no standardization of opioid prescribing in the postoperative period following these procedures, and studies have reported a wide variation in prescribing habits even within a single institution for a specific surgery.⁷ Patients who undergo TKA are at particularly high risk of long-term opioid use if they are on continuous opioids at the time of surgery; this is problematic in a VA patient population in which at least 16% of patients are prescribed opioids in a given year.⁸ Furthermore, veterans are twice as likely as nonveterans to die of an accidental overdose.⁹ Despite these risks, opioids remain a cornerstone of postoperative pain management both within and outside of the VA.¹⁰

In 2018, to limit unnecessary prescribing of opioid pain medication, the total joint service at the VA Portland Health Care System (VAPHCS) in Oregon implemented the Minimizing Opioids after Joint Operation (MOJO) postoperative pain protocol. The goal of the protocol was to reduce opioid use following TKA. The objectives were to provide safe, appropriate analgesia while allowing early mobilization and discharge without a concomitant increase in readmissions or emergency department (ED) visits. The purpose of this retrospective chart review was to compare the efficacy of the MOJO protocol with our historical experience and report our preliminary results.

Methods

Institutional review board approval was obtained to retrospectively review the medical records of patients who had undergone TKA surgery during 2018 at VAPHCS. The MOJO protocol was composed of several simultaneous changes. The centerpiece of the new protocol was a drastic decrease in routine prescription of postoperative opioids (Table 1). Other changes included instructing patients to reduce the use of preoperative opioid pain medication 6 weeks before surgery with a goal of no opioid consumption, perform daily sets of preoperative exercises, and attend a preoperative consultation/education session with a nurse coordinator to emphasize early recovery and discharge. In patients with chronic use of opioid pain medication (particularly those for whom the medication had been prescribed for other sources of pain, such as lumbar back pain), the goal was daily opioid use of ≤ 30 morphine equivalent doses (MEDs). During the inpatient stay, we stopped prescribing prophylactic pain medication prior to physical therapy (PT).

We encouraged preoperative optimization of muscle strength by giving instructions for 4 to 8 weeks of daily exercises (Appendix). We introduced perioperative adductor canal blocks (at the discretion of the anesthesia team) and transitioned to surgery without a tourniquet. Patients in both groups received intraoperative antibiotics and IV tranexamic acid (TXA); the MOJO group also received topical TXA.

Further patient care optimization included providing patients with a team-based approach, which consisted of nurse coordinators, physician assistants and nurse practitioners, residents, and the attending surgeon. Our team reviews the planned pain management protocol, perioperative expectations, criteria for discharge, and anticipated surgical outcomes with the patient during their preoperative visits. On postoperative day 1, these members round as a team to encourage patients in their immediate postoperative recovery and rehabilitation. During rounds, the team assesses whether the patient meets the criteria for discharge, adjusting the pain management protocol if necessary.

Results

Forty patients met the inclusion criteria, evenly divided between those undergoing TKA before and after instituting the MOJO protocol (Table 2). A single patient in the MOJO group died and was excluded. A patient who underwent bilateral TKA also was excluded. Both groups reflected the male predominance of the VA patient population. MOJO patients tended to have lower BMIs (34 vs 30, P < .01). All patients indicated for surgery with preoperative opioid use were able to titrate down to their preoperative goal as verified by prescriptions filled at VA pharmacies. Twelve of the patients in the MOJO group received adductor canal blocks.

Results of t tests and χ² tests comparing primary and secondary endpoints are listed in Table 3. Differences between the daily MEDs given in the historical and MOJO groups are shown. There were significant differences between the pre-MOJO and MOJO groups with regard to daily inpatient MEDs (82 mg vs 29 mg, P < .01) and total inpatient MEDs (306 mg vs 32 mg, P < .01). There was less self-reported pain on postoperative day 1 in the MOJO group (5.5 vs 3.9, P < .01), decreased LOS (4.4 days vs 1.2 days, P < .01), a trend toward fewer total ED visits (6 vs 2, P = .24), and fewer discharges to skilled nursing facilities (12 vs 0, P < .01). There were no blood transfusions in either group.

Discussion

Our results demonstrate that a multimodal approach to significantly reduce postoperative opioid use in patients with TKA is possible without increasing readmissions or ED visits for pain control. The patients in the MOJO group had a faster recovery, earlier discharge, and less use of postoperative opioid medication. Our approach to postoperative pain management was divided into 2 main categories: patient optimization and surgical optimization.

Patient Selection

Besides the standard evaluation and optimization of patients’ medical conditions, identifying and optimizing at-risk patients before surgery was a critical component of our protocol. Managing postoperative pain in patients with prior opioid use is an intractable challenge in orthopedic surgery. Patients with a history of chronic pain and preoperative use of opioid medications remain at higher risk of postoperative chronic pain and persistent use of opioid medication despite no obvious surgical complications.⁸ In a sample of > 6,000 veterans who underwent TKA at VA hospitals in 2014, 57% of the patients with daily use of opioids in the 90 days before surgery remained on opioids 1 year after surgery (vs 2 % in patients not on long-term opioids).⁸ This relationship between pre- and postoperative opioid use also was dose dependent.¹²

Furthermore, those with high preoperative use may experience worse outcomes relative to the opioid naive population as measured by arthritis-specific pain indices.¹³ In a well-powered retrospective study of patients who underwent elective orthopedic procedures, preoperative opioid abuse or dependence (determined by the International Classification of Diseases, Ninth Revision diagnosis) increased inpatient mortality, aggregate morbidity, surgical site infection, myocardial infarction, and LOS.¹⁴ Preoperative opioid use also has been associated with increased risk of ED visits, readmission, infection, stiffness, and aseptic revision.¹⁵ In patients with TKA in the VA specifically, preoperative opioid use (> 3 months in the prior year) was associated with increased revision rates that were even higher than those for patients with diabetes mellitus.¹⁶

Patient Education

Based on this evidence, we instruct patients to reduce their preoperative opioid dosing to zero (for patients with joint pain) or < 30 MED (for patients using opioids for other reasons). Although preoperative reduction of opioid use has been shown to improve outcomes after TKA, pain subspecialty recommendations for patients with chronic opioid use recommend considering adjunctive therapies, including transcutaneous electrical nerve stimulation, cognitive behavioral therapy, gabapentin, or ketamine.^17,18 Through patient education our team has been successful in decreasing preoperative opioid use without adding other drugs or modalities.

Patient Optimization

Preoperative patient optimization included 4 to 8 weeks of daily sets of physical activity instructions (prehab) to improve the musculoskeletal function. These instructions are given to patients 4 to 8 weeks before surgery and aim to improve the patient’s balance, mobility, and functional ability (Appendix). Meta-analysis has shown that patients who undergo preoperative PT have a small but statistically significant decrease in postoperative pain at 4 weeks, though this does not persist beyond that period.¹⁹

We did note a lower BMI in patients in the MOJO group. Though this has the potential to be a confounder, a study of BMI in > 4,000 patients who underwent joint replacement surgery has shown that BMI is not associated with differences in postoperative pain.²⁰

Surgeon and Surgical-Related Variables

Patients in the MOJO group had increased use of adductor canal blocks. A 2017 meta-analysis of 12,530 patients comparing analgesic modalities found that peripheral nerve blocks targeting multiple nerves (eg, femoral/sciatic) decreased pain at rest, decreased opioid consumption, and improved range of motion postoperatively.²¹ Also, these were found to be superior to single nerve blocks, periarticular infiltration, and epidural blocks.²¹ However, major nerve and epidural blocks affecting the lower extremity may increase the risk of falls and prolong LOS.^22,23 The preferred peripheral block at VAPHCS is a single shot ultrasound-guided adductor canal block before the induction of general or spinal anesthesia. A randomized controlled trial has demonstrated superiority of this block to the femoral nerve block with regard to postoperative quadriceps strength, conferring the theoretical advantage of decreased fall risk and ability to participate in immediate PT.²⁴ Although we are unable to confirm an association between anesthetic modalities and opioid burden, our clinical impression is that blocks were effective at reducing immediate postoperative pain. However, among MOJO patients there were no differences in patients with and without blocks for either pain (4.2 vs 3.8, P = .69) or opioid consumption (28.8 vs 33.0, P = .72) after surgery, though our study was not powered to detect a difference in this restricted subgroup.

Patients who frequently had reported postoperative thigh pain prompted us to make changes in our surgical technique, performing TKA without use of a tourniquet. Tourniquet use has been associated with an increased risk of thigh pain after TKA by multiple authors.^25,26 Postoperative thigh pain also is pressure dependent.²⁷ In addition, its use may be associated with a slightly increased risk of thromboembolic events and delayed functional recovery.^28,29

Because postoperative hemarthrosis is associated with more pain and reduced joint recovery function, we used topical TXA to reduce postoperative surgical site and joint hematoma. TXA (either oral, IV, or topical) during TKA is used to control postoperative bleeding primarily and decrease the need for transfusion without concomitant increase in thromboembolic events.^30,31 Topical TXA may be more effective than IV, particularly in the immediate postoperative period.³² Although pain typically is not an endpoint in studies of TXA, a prospective study of 48 patients showed evidence that its use may be associated with decreased postoperative pain in the first 24 hours after surgery (though not after).³³ Finally, the use of intra-articular injection has evolved in our clinical practice, but literature is lacking with regard to its efficacy; more studies are needed to determine its effect relative to no injection. We have not seen any benefits to using cryotherapy in our practice; considering the costs for equipment and health care provider time, cryotherapy was not included in our new protocol.

Limitations

This is a nonrandomized retrospective single-institution study. Our study population is composed of mostly males with military experience and is not necessarily a representative sample of the general population eligible for joint arthroplasty. Our primary endpoint (reduction of opioid use postoperatively) also was a cornerstone of our intervention. To account for this, we set a very large effect size in our power analysis and evaluated multiple secondary endpoints to determine whether postoperative pain remained well controlled and complications/readmission minimized with our interventions. Because our intervention was multimodal, our study cannot make conclusions about the effect of a particular component of our treatment strategy. We did not measure or compare functional outcomes between both groups, which offers an opportunity for further research.

These limitations are balanced by several strengths. Our cohort was well controlled with respect to the dose and type of drug used. There is staff dedicated to postoperative telephone follow-up after discharge, and veterans are apt to seek care within the VA health care system, which improves case finding for complications and ED visits. No patients were lost to follow-up. Moreover, our drastic reduction in opioid use is promising enough to warrant reporting, while the broader orthopedic literature explores the relative impact of each variable.

Conclusions

The MOJO protocol has been effective for reducing postoperative opioid use after TKA without compromising effective pain management. The drastic reduction in the postoperative use of opioid pain medications and LOS have contributed to a cultural shift within our department, comprehensive team approach, multimodal pain management, and preoperative patient optimization. Further investigations are required to assess the impact of each intervention on observed outcomes. However, the framework and routines are applicable to other institutions and surgical specialties.

Acknowledgments

The authors recognize Derek Bond, MD, for his help in creating the MOJO acronym.

For decades, opioids have been a mainstay in the management of pain after total joint arthroplasty. In the past 10 years, however, opioid prescribing has come under increased scrutiny due to a rise in rates of opioid abuse, pill diversion, and opioid-related deaths.^1,2 Opioids are associated with adverse effects, including nausea, vomiting, constipation, apathy, and respiratory depression, all of which influence arthroplasty outcomes and affect the patient experience. Although primary care groups account for nearly half of prescriptions written, orthopedic surgeons have the third highest per capita rate of opioid prescribing of all medical specialties.^3,4 This puts orthopedic surgeons, particularly those who perform routine procedures, in an opportune but challenging position to confront this problem through novel pain management strategies.

Approximately 1 million total knee arthroplasties (TKAs) are performed in the US every year, and the US Department of Veterans Affairs (VA) health system performs about 10,000 hip and knee joint replacements.^5,6 There is no standardization of opioid prescribing in the postoperative period following these procedures, and studies have reported a wide variation in prescribing habits even within a single institution for a specific surgery.⁷ Patients who undergo TKA are at particularly high risk of long-term opioid use if they are on continuous opioids at the time of surgery; this is problematic in a VA patient population in which at least 16% of patients are prescribed opioids in a given year.⁸ Furthermore, veterans are twice as likely as nonveterans to die of an accidental overdose.⁹ Despite these risks, opioids remain a cornerstone of postoperative pain management both within and outside of the VA.¹⁰

In 2018, to limit unnecessary prescribing of opioid pain medication, the total joint service at the VA Portland Health Care System (VAPHCS) in Oregon implemented the Minimizing Opioids after Joint Operation (MOJO) postoperative pain protocol. The goal of the protocol was to reduce opioid use following TKA. The objectives were to provide safe, appropriate analgesia while allowing early mobilization and discharge without a concomitant increase in readmissions or emergency department (ED) visits. The purpose of this retrospective chart review was to compare the efficacy of the MOJO protocol with our historical experience and report our preliminary results.

Methods

Institutional review board approval was obtained to retrospectively review the medical records of patients who had undergone TKA surgery during 2018 at VAPHCS. The MOJO protocol was composed of several simultaneous changes. The centerpiece of the new protocol was a drastic decrease in routine prescription of postoperative opioids (Table 1). Other changes included instructing patients to reduce the use of preoperative opioid pain medication 6 weeks before surgery with a goal of no opioid consumption, perform daily sets of preoperative exercises, and attend a preoperative consultation/education session with a nurse coordinator to emphasize early recovery and discharge. In patients with chronic use of opioid pain medication (particularly those for whom the medication had been prescribed for other sources of pain, such as lumbar back pain), the goal was daily opioid use of ≤ 30 morphine equivalent doses (MEDs). During the inpatient stay, we stopped prescribing prophylactic pain medication prior to physical therapy (PT).

We encouraged preoperative optimization of muscle strength by giving instructions for 4 to 8 weeks of daily exercises (Appendix). We introduced perioperative adductor canal blocks (at the discretion of the anesthesia team) and transitioned to surgery without a tourniquet. Patients in both groups received intraoperative antibiotics and IV tranexamic acid (TXA); the MOJO group also received topical TXA.

Further patient care optimization included providing patients with a team-based approach, which consisted of nurse coordinators, physician assistants and nurse practitioners, residents, and the attending surgeon. Our team reviews the planned pain management protocol, perioperative expectations, criteria for discharge, and anticipated surgical outcomes with the patient during their preoperative visits. On postoperative day 1, these members round as a team to encourage patients in their immediate postoperative recovery and rehabilitation. During rounds, the team assesses whether the patient meets the criteria for discharge, adjusting the pain management protocol if necessary.

Results

Forty patients met the inclusion criteria, evenly divided between those undergoing TKA before and after instituting the MOJO protocol (Table 2). A single patient in the MOJO group died and was excluded. A patient who underwent bilateral TKA also was excluded. Both groups reflected the male predominance of the VA patient population. MOJO patients tended to have lower BMIs (34 vs 30, P < .01). All patients indicated for surgery with preoperative opioid use were able to titrate down to their preoperative goal as verified by prescriptions filled at VA pharmacies. Twelve of the patients in the MOJO group received adductor canal blocks.

Results of t tests and χ² tests comparing primary and secondary endpoints are listed in Table 3. Differences between the daily MEDs given in the historical and MOJO groups are shown. There were significant differences between the pre-MOJO and MOJO groups with regard to daily inpatient MEDs (82 mg vs 29 mg, P < .01) and total inpatient MEDs (306 mg vs 32 mg, P < .01). There was less self-reported pain on postoperative day 1 in the MOJO group (5.5 vs 3.9, P < .01), decreased LOS (4.4 days vs 1.2 days, P < .01), a trend toward fewer total ED visits (6 vs 2, P = .24), and fewer discharges to skilled nursing facilities (12 vs 0, P < .01). There were no blood transfusions in either group.

Discussion

Our results demonstrate that a multimodal approach to significantly reduce postoperative opioid use in patients with TKA is possible without increasing readmissions or ED visits for pain control. The patients in the MOJO group had a faster recovery, earlier discharge, and less use of postoperative opioid medication. Our approach to postoperative pain management was divided into 2 main categories: patient optimization and surgical optimization.

Patient Selection

Besides the standard evaluation and optimization of patients’ medical conditions, identifying and optimizing at-risk patients before surgery was a critical component of our protocol. Managing postoperative pain in patients with prior opioid use is an intractable challenge in orthopedic surgery. Patients with a history of chronic pain and preoperative use of opioid medications remain at higher risk of postoperative chronic pain and persistent use of opioid medication despite no obvious surgical complications.⁸ In a sample of > 6,000 veterans who underwent TKA at VA hospitals in 2014, 57% of the patients with daily use of opioids in the 90 days before surgery remained on opioids 1 year after surgery (vs 2 % in patients not on long-term opioids).⁸ This relationship between pre- and postoperative opioid use also was dose dependent.¹²

Furthermore, those with high preoperative use may experience worse outcomes relative to the opioid naive population as measured by arthritis-specific pain indices.¹³ In a well-powered retrospective study of patients who underwent elective orthopedic procedures, preoperative opioid abuse or dependence (determined by the International Classification of Diseases, Ninth Revision diagnosis) increased inpatient mortality, aggregate morbidity, surgical site infection, myocardial infarction, and LOS.¹⁴ Preoperative opioid use also has been associated with increased risk of ED visits, readmission, infection, stiffness, and aseptic revision.¹⁵ In patients with TKA in the VA specifically, preoperative opioid use (> 3 months in the prior year) was associated with increased revision rates that were even higher than those for patients with diabetes mellitus.¹⁶

Patient Education

Based on this evidence, we instruct patients to reduce their preoperative opioid dosing to zero (for patients with joint pain) or < 30 MED (for patients using opioids for other reasons). Although preoperative reduction of opioid use has been shown to improve outcomes after TKA, pain subspecialty recommendations for patients with chronic opioid use recommend considering adjunctive therapies, including transcutaneous electrical nerve stimulation, cognitive behavioral therapy, gabapentin, or ketamine.^17,18 Through patient education our team has been successful in decreasing preoperative opioid use without adding other drugs or modalities.

Patient Optimization

Preoperative patient optimization included 4 to 8 weeks of daily sets of physical activity instructions (prehab) to improve the musculoskeletal function. These instructions are given to patients 4 to 8 weeks before surgery and aim to improve the patient’s balance, mobility, and functional ability (Appendix). Meta-analysis has shown that patients who undergo preoperative PT have a small but statistically significant decrease in postoperative pain at 4 weeks, though this does not persist beyond that period.¹⁹

We did note a lower BMI in patients in the MOJO group. Though this has the potential to be a confounder, a study of BMI in > 4,000 patients who underwent joint replacement surgery has shown that BMI is not associated with differences in postoperative pain.²⁰

Surgeon and Surgical-Related Variables

Patients in the MOJO group had increased use of adductor canal blocks. A 2017 meta-analysis of 12,530 patients comparing analgesic modalities found that peripheral nerve blocks targeting multiple nerves (eg, femoral/sciatic) decreased pain at rest, decreased opioid consumption, and improved range of motion postoperatively.²¹ Also, these were found to be superior to single nerve blocks, periarticular infiltration, and epidural blocks.²¹ However, major nerve and epidural blocks affecting the lower extremity may increase the risk of falls and prolong LOS.^22,23 The preferred peripheral block at VAPHCS is a single shot ultrasound-guided adductor canal block before the induction of general or spinal anesthesia. A randomized controlled trial has demonstrated superiority of this block to the femoral nerve block with regard to postoperative quadriceps strength, conferring the theoretical advantage of decreased fall risk and ability to participate in immediate PT.²⁴ Although we are unable to confirm an association between anesthetic modalities and opioid burden, our clinical impression is that blocks were effective at reducing immediate postoperative pain. However, among MOJO patients there were no differences in patients with and without blocks for either pain (4.2 vs 3.8, P = .69) or opioid consumption (28.8 vs 33.0, P = .72) after surgery, though our study was not powered to detect a difference in this restricted subgroup.

Patients who frequently had reported postoperative thigh pain prompted us to make changes in our surgical technique, performing TKA without use of a tourniquet. Tourniquet use has been associated with an increased risk of thigh pain after TKA by multiple authors.^25,26 Postoperative thigh pain also is pressure dependent.²⁷ In addition, its use may be associated with a slightly increased risk of thromboembolic events and delayed functional recovery.^28,29

Because postoperative hemarthrosis is associated with more pain and reduced joint recovery function, we used topical TXA to reduce postoperative surgical site and joint hematoma. TXA (either oral, IV, or topical) during TKA is used to control postoperative bleeding primarily and decrease the need for transfusion without concomitant increase in thromboembolic events.^30,31 Topical TXA may be more effective than IV, particularly in the immediate postoperative period.³² Although pain typically is not an endpoint in studies of TXA, a prospective study of 48 patients showed evidence that its use may be associated with decreased postoperative pain in the first 24 hours after surgery (though not after).³³ Finally, the use of intra-articular injection has evolved in our clinical practice, but literature is lacking with regard to its efficacy; more studies are needed to determine its effect relative to no injection. We have not seen any benefits to using cryotherapy in our practice; considering the costs for equipment and health care provider time, cryotherapy was not included in our new protocol.

Limitations

This is a nonrandomized retrospective single-institution study. Our study population is composed of mostly males with military experience and is not necessarily a representative sample of the general population eligible for joint arthroplasty. Our primary endpoint (reduction of opioid use postoperatively) also was a cornerstone of our intervention. To account for this, we set a very large effect size in our power analysis and evaluated multiple secondary endpoints to determine whether postoperative pain remained well controlled and complications/readmission minimized with our interventions. Because our intervention was multimodal, our study cannot make conclusions about the effect of a particular component of our treatment strategy. We did not measure or compare functional outcomes between both groups, which offers an opportunity for further research.

These limitations are balanced by several strengths. Our cohort was well controlled with respect to the dose and type of drug used. There is staff dedicated to postoperative telephone follow-up after discharge, and veterans are apt to seek care within the VA health care system, which improves case finding for complications and ED visits. No patients were lost to follow-up. Moreover, our drastic reduction in opioid use is promising enough to warrant reporting, while the broader orthopedic literature explores the relative impact of each variable.

Conclusions

The MOJO protocol has been effective for reducing postoperative opioid use after TKA without compromising effective pain management. The drastic reduction in the postoperative use of opioid pain medications and LOS have contributed to a cultural shift within our department, comprehensive team approach, multimodal pain management, and preoperative patient optimization. Further investigations are required to assess the impact of each intervention on observed outcomes. However, the framework and routines are applicable to other institutions and surgical specialties.

Acknowledgments

The authors recognize Derek Bond, MD, for his help in creating the MOJO acronym.

For decades, opioids have been a mainstay in the management of pain after total joint arthroplasty. In the past 10 years, however, opioid prescribing has come under increased scrutiny due to a rise in rates of opioid abuse, pill diversion, and opioid-related deaths.^1,2 Opioids are associated with adverse effects, including nausea, vomiting, constipation, apathy, and respiratory depression, all of which influence arthroplasty outcomes and affect the patient experience. Although primary care groups account for nearly half of prescriptions written, orthopedic surgeons have the third highest per capita rate of opioid prescribing of all medical specialties.^3,4 This puts orthopedic surgeons, particularly those who perform routine procedures, in an opportune but challenging position to confront this problem through novel pain management strategies.

Approximately 1 million total knee arthroplasties (TKAs) are performed in the US every year, and the US Department of Veterans Affairs (VA) health system performs about 10,000 hip and knee joint replacements.^5,6 There is no standardization of opioid prescribing in the postoperative period following these procedures, and studies have reported a wide variation in prescribing habits even within a single institution for a specific surgery.⁷ Patients who undergo TKA are at particularly high risk of long-term opioid use if they are on continuous opioids at the time of surgery; this is problematic in a VA patient population in which at least 16% of patients are prescribed opioids in a given year.⁸ Furthermore, veterans are twice as likely as nonveterans to die of an accidental overdose.⁹ Despite these risks, opioids remain a cornerstone of postoperative pain management both within and outside of the VA.¹⁰

In 2018, to limit unnecessary prescribing of opioid pain medication, the total joint service at the VA Portland Health Care System (VAPHCS) in Oregon implemented the Minimizing Opioids after Joint Operation (MOJO) postoperative pain protocol. The goal of the protocol was to reduce opioid use following TKA. The objectives were to provide safe, appropriate analgesia while allowing early mobilization and discharge without a concomitant increase in readmissions or emergency department (ED) visits. The purpose of this retrospective chart review was to compare the efficacy of the MOJO protocol with our historical experience and report our preliminary results.

Methods

Institutional review board approval was obtained to retrospectively review the medical records of patients who had undergone TKA surgery during 2018 at VAPHCS. The MOJO protocol was composed of several simultaneous changes. The centerpiece of the new protocol was a drastic decrease in routine prescription of postoperative opioids (Table 1). Other changes included instructing patients to reduce the use of preoperative opioid pain medication 6 weeks before surgery with a goal of no opioid consumption, perform daily sets of preoperative exercises, and attend a preoperative consultation/education session with a nurse coordinator to emphasize early recovery and discharge. In patients with chronic use of opioid pain medication (particularly those for whom the medication had been prescribed for other sources of pain, such as lumbar back pain), the goal was daily opioid use of ≤ 30 morphine equivalent doses (MEDs). During the inpatient stay, we stopped prescribing prophylactic pain medication prior to physical therapy (PT).

We encouraged preoperative optimization of muscle strength by giving instructions for 4 to 8 weeks of daily exercises (Appendix). We introduced perioperative adductor canal blocks (at the discretion of the anesthesia team) and transitioned to surgery without a tourniquet. Patients in both groups received intraoperative antibiotics and IV tranexamic acid (TXA); the MOJO group also received topical TXA.

Further patient care optimization included providing patients with a team-based approach, which consisted of nurse coordinators, physician assistants and nurse practitioners, residents, and the attending surgeon. Our team reviews the planned pain management protocol, perioperative expectations, criteria for discharge, and anticipated surgical outcomes with the patient during their preoperative visits. On postoperative day 1, these members round as a team to encourage patients in their immediate postoperative recovery and rehabilitation. During rounds, the team assesses whether the patient meets the criteria for discharge, adjusting the pain management protocol if necessary.

Results

Forty patients met the inclusion criteria, evenly divided between those undergoing TKA before and after instituting the MOJO protocol (Table 2). A single patient in the MOJO group died and was excluded. A patient who underwent bilateral TKA also was excluded. Both groups reflected the male predominance of the VA patient population. MOJO patients tended to have lower BMIs (34 vs 30, P < .01). All patients indicated for surgery with preoperative opioid use were able to titrate down to their preoperative goal as verified by prescriptions filled at VA pharmacies. Twelve of the patients in the MOJO group received adductor canal blocks.

Results of t tests and χ² tests comparing primary and secondary endpoints are listed in Table 3. Differences between the daily MEDs given in the historical and MOJO groups are shown. There were significant differences between the pre-MOJO and MOJO groups with regard to daily inpatient MEDs (82 mg vs 29 mg, P < .01) and total inpatient MEDs (306 mg vs 32 mg, P < .01). There was less self-reported pain on postoperative day 1 in the MOJO group (5.5 vs 3.9, P < .01), decreased LOS (4.4 days vs 1.2 days, P < .01), a trend toward fewer total ED visits (6 vs 2, P = .24), and fewer discharges to skilled nursing facilities (12 vs 0, P < .01). There were no blood transfusions in either group.

Discussion

Our results demonstrate that a multimodal approach to significantly reduce postoperative opioid use in patients with TKA is possible without increasing readmissions or ED visits for pain control. The patients in the MOJO group had a faster recovery, earlier discharge, and less use of postoperative opioid medication. Our approach to postoperative pain management was divided into 2 main categories: patient optimization and surgical optimization.

Patient Selection

Besides the standard evaluation and optimization of patients’ medical conditions, identifying and optimizing at-risk patients before surgery was a critical component of our protocol. Managing postoperative pain in patients with prior opioid use is an intractable challenge in orthopedic surgery. Patients with a history of chronic pain and preoperative use of opioid medications remain at higher risk of postoperative chronic pain and persistent use of opioid medication despite no obvious surgical complications.⁸ In a sample of > 6,000 veterans who underwent TKA at VA hospitals in 2014, 57% of the patients with daily use of opioids in the 90 days before surgery remained on opioids 1 year after surgery (vs 2 % in patients not on long-term opioids).⁸ This relationship between pre- and postoperative opioid use also was dose dependent.¹²

Furthermore, those with high preoperative use may experience worse outcomes relative to the opioid naive population as measured by arthritis-specific pain indices.¹³ In a well-powered retrospective study of patients who underwent elective orthopedic procedures, preoperative opioid abuse or dependence (determined by the International Classification of Diseases, Ninth Revision diagnosis) increased inpatient mortality, aggregate morbidity, surgical site infection, myocardial infarction, and LOS.¹⁴ Preoperative opioid use also has been associated with increased risk of ED visits, readmission, infection, stiffness, and aseptic revision.¹⁵ In patients with TKA in the VA specifically, preoperative opioid use (> 3 months in the prior year) was associated with increased revision rates that were even higher than those for patients with diabetes mellitus.¹⁶

Patient Education

Based on this evidence, we instruct patients to reduce their preoperative opioid dosing to zero (for patients with joint pain) or < 30 MED (for patients using opioids for other reasons). Although preoperative reduction of opioid use has been shown to improve outcomes after TKA, pain subspecialty recommendations for patients with chronic opioid use recommend considering adjunctive therapies, including transcutaneous electrical nerve stimulation, cognitive behavioral therapy, gabapentin, or ketamine.^17,18 Through patient education our team has been successful in decreasing preoperative opioid use without adding other drugs or modalities.

Patient Optimization

Preoperative patient optimization included 4 to 8 weeks of daily sets of physical activity instructions (prehab) to improve the musculoskeletal function. These instructions are given to patients 4 to 8 weeks before surgery and aim to improve the patient’s balance, mobility, and functional ability (Appendix). Meta-analysis has shown that patients who undergo preoperative PT have a small but statistically significant decrease in postoperative pain at 4 weeks, though this does not persist beyond that period.¹⁹

We did note a lower BMI in patients in the MOJO group. Though this has the potential to be a confounder, a study of BMI in > 4,000 patients who underwent joint replacement surgery has shown that BMI is not associated with differences in postoperative pain.²⁰

Surgeon and Surgical-Related Variables

Patients in the MOJO group had increased use of adductor canal blocks. A 2017 meta-analysis of 12,530 patients comparing analgesic modalities found that peripheral nerve blocks targeting multiple nerves (eg, femoral/sciatic) decreased pain at rest, decreased opioid consumption, and improved range of motion postoperatively.²¹ Also, these were found to be superior to single nerve blocks, periarticular infiltration, and epidural blocks.²¹ However, major nerve and epidural blocks affecting the lower extremity may increase the risk of falls and prolong LOS.^22,23 The preferred peripheral block at VAPHCS is a single shot ultrasound-guided adductor canal block before the induction of general or spinal anesthesia. A randomized controlled trial has demonstrated superiority of this block to the femoral nerve block with regard to postoperative quadriceps strength, conferring the theoretical advantage of decreased fall risk and ability to participate in immediate PT.²⁴ Although we are unable to confirm an association between anesthetic modalities and opioid burden, our clinical impression is that blocks were effective at reducing immediate postoperative pain. However, among MOJO patients there were no differences in patients with and without blocks for either pain (4.2 vs 3.8, P = .69) or opioid consumption (28.8 vs 33.0, P = .72) after surgery, though our study was not powered to detect a difference in this restricted subgroup.

Patients who frequently had reported postoperative thigh pain prompted us to make changes in our surgical technique, performing TKA without use of a tourniquet. Tourniquet use has been associated with an increased risk of thigh pain after TKA by multiple authors.^25,26 Postoperative thigh pain also is pressure dependent.²⁷ In addition, its use may be associated with a slightly increased risk of thromboembolic events and delayed functional recovery.^28,29

Because postoperative hemarthrosis is associated with more pain and reduced joint recovery function, we used topical TXA to reduce postoperative surgical site and joint hematoma. TXA (either oral, IV, or topical) during TKA is used to control postoperative bleeding primarily and decrease the need for transfusion without concomitant increase in thromboembolic events.^30,31 Topical TXA may be more effective than IV, particularly in the immediate postoperative period.³² Although pain typically is not an endpoint in studies of TXA, a prospective study of 48 patients showed evidence that its use may be associated with decreased postoperative pain in the first 24 hours after surgery (though not after).³³ Finally, the use of intra-articular injection has evolved in our clinical practice, but literature is lacking with regard to its efficacy; more studies are needed to determine its effect relative to no injection. We have not seen any benefits to using cryotherapy in our practice; considering the costs for equipment and health care provider time, cryotherapy was not included in our new protocol.

Limitations

This is a nonrandomized retrospective single-institution study. Our study population is composed of mostly males with military experience and is not necessarily a representative sample of the general population eligible for joint arthroplasty. Our primary endpoint (reduction of opioid use postoperatively) also was a cornerstone of our intervention. To account for this, we set a very large effect size in our power analysis and evaluated multiple secondary endpoints to determine whether postoperative pain remained well controlled and complications/readmission minimized with our interventions. Because our intervention was multimodal, our study cannot make conclusions about the effect of a particular component of our treatment strategy. We did not measure or compare functional outcomes between both groups, which offers an opportunity for further research.

These limitations are balanced by several strengths. Our cohort was well controlled with respect to the dose and type of drug used. There is staff dedicated to postoperative telephone follow-up after discharge, and veterans are apt to seek care within the VA health care system, which improves case finding for complications and ED visits. No patients were lost to follow-up. Moreover, our drastic reduction in opioid use is promising enough to warrant reporting, while the broader orthopedic literature explores the relative impact of each variable.

Conclusions

The MOJO protocol has been effective for reducing postoperative opioid use after TKA without compromising effective pain management. The drastic reduction in the postoperative use of opioid pain medications and LOS have contributed to a cultural shift within our department, comprehensive team approach, multimodal pain management, and preoperative patient optimization. Further investigations are required to assess the impact of each intervention on observed outcomes. However, the framework and routines are applicable to other institutions and surgical specialties.

Acknowledgments

The authors recognize Derek Bond, MD, for his help in creating the MOJO acronym.

Areas with active cannabis dispensaries have seen a decrease in opioid-related mortalities, recent research has shown.

“Our findings suggest that higher storefront cannabis dispensary counts are associated with reduced opioid related mortality rates at the county level,” wrote Greta Hsu, PhD, professor of management, University of California, Davis, and Balázs Kovács, PhD, associate professor of organizational behavior, Yale University, New Haven, Conn. “This association holds for both medical and recreational dispensaries, and appears particularly strong for deaths associated with synthetic (nonmethadone) opioids, which include the highly potent synthetic opioid fentanyl and its analogs.”

Results ‘may be even stronger’ than reported

Christopher G. Fichtner, MD, clinical professor of psychiatry and neuroscience at the University of California, Riverside, said in an interview that the evidence for using cannabis as an opioid substitution for pain management has not been balanced, but noted “the bulk of it suggests that there is some harm reduction benefit by having liberalized access to cannabis.”

Courtesy Dr. Christopher Fichtner

One strength of the study by Dr. Hsu and Dr. Kovács was how they were able to examine implementation of legalization of medical or recreational cannabis, rather than simply a change in the law, he said.

“By looking at dispensary count, it’s actually looking at a better measure of on-the-ground implementation than just change in policy,” Dr. Fichtner explained. “You’re looking at what was actually accomplished in terms of making cannabis legally available.”

The choice to evaluate storefront dispensaries only and not include delivery services in their data, “probably makes it a relatively conservative estimate. I think that would be a strength, that their findings may be even stronger than what it is they’re reporting,” Dr. Fichtner said.

“I do think, if anything, the paper is relatively tentative about advancing its conclusions, which I think is a weakness in a lot of these studies,” he added. In 2017, the National Academy of Sciences released a report that found evidence cannabis or cannabinoids can significantly reduce pain symptoms. In that report, “one of their strongest conclusions is that there’s conclusive or substantial evidence that cannabis or cannabinoids are effective management of chronic pain,” Dr. Fichtner said.

He said that digging deeper into what kinds of pain cannabis can treat is one area for future research. “Certainly, it seems that it’s unlikely that cannabis is going to be good for every kind of pain,” he said. “What kinds of pain is it better for than others? Is it some benefit for many kinds of pain, or only a few types of pain?”

The authors reported no relevant financial disclosures. Dr. Fichtner is the author of a book on cannabis policy in the United States, but reported no other financial disclosures.
 

Areas with active cannabis dispensaries have seen a decrease in opioid-related mortalities, recent research has shown.

“Our findings suggest that higher storefront cannabis dispensary counts are associated with reduced opioid related mortality rates at the county level,” wrote Greta Hsu, PhD, professor of management, University of California, Davis, and Balázs Kovács, PhD, associate professor of organizational behavior, Yale University, New Haven, Conn. “This association holds for both medical and recreational dispensaries, and appears particularly strong for deaths associated with synthetic (nonmethadone) opioids, which include the highly potent synthetic opioid fentanyl and its analogs.”

Results ‘may be even stronger’ than reported

Christopher G. Fichtner, MD, clinical professor of psychiatry and neuroscience at the University of California, Riverside, said in an interview that the evidence for using cannabis as an opioid substitution for pain management has not been balanced, but noted “the bulk of it suggests that there is some harm reduction benefit by having liberalized access to cannabis.”

Courtesy Dr. Christopher Fichtner

One strength of the study by Dr. Hsu and Dr. Kovács was how they were able to examine implementation of legalization of medical or recreational cannabis, rather than simply a change in the law, he said.

“By looking at dispensary count, it’s actually looking at a better measure of on-the-ground implementation than just change in policy,” Dr. Fichtner explained. “You’re looking at what was actually accomplished in terms of making cannabis legally available.”

The choice to evaluate storefront dispensaries only and not include delivery services in their data, “probably makes it a relatively conservative estimate. I think that would be a strength, that their findings may be even stronger than what it is they’re reporting,” Dr. Fichtner said.

“I do think, if anything, the paper is relatively tentative about advancing its conclusions, which I think is a weakness in a lot of these studies,” he added. In 2017, the National Academy of Sciences released a report that found evidence cannabis or cannabinoids can significantly reduce pain symptoms. In that report, “one of their strongest conclusions is that there’s conclusive or substantial evidence that cannabis or cannabinoids are effective management of chronic pain,” Dr. Fichtner said.

He said that digging deeper into what kinds of pain cannabis can treat is one area for future research. “Certainly, it seems that it’s unlikely that cannabis is going to be good for every kind of pain,” he said. “What kinds of pain is it better for than others? Is it some benefit for many kinds of pain, or only a few types of pain?”

The authors reported no relevant financial disclosures. Dr. Fichtner is the author of a book on cannabis policy in the United States, but reported no other financial disclosures.
 

Areas with active cannabis dispensaries have seen a decrease in opioid-related mortalities, recent research has shown.

“Our findings suggest that higher storefront cannabis dispensary counts are associated with reduced opioid related mortality rates at the county level,” wrote Greta Hsu, PhD, professor of management, University of California, Davis, and Balázs Kovács, PhD, associate professor of organizational behavior, Yale University, New Haven, Conn. “This association holds for both medical and recreational dispensaries, and appears particularly strong for deaths associated with synthetic (nonmethadone) opioids, which include the highly potent synthetic opioid fentanyl and its analogs.”

Results ‘may be even stronger’ than reported

Christopher G. Fichtner, MD, clinical professor of psychiatry and neuroscience at the University of California, Riverside, said in an interview that the evidence for using cannabis as an opioid substitution for pain management has not been balanced, but noted “the bulk of it suggests that there is some harm reduction benefit by having liberalized access to cannabis.”

Courtesy Dr. Christopher Fichtner

One strength of the study by Dr. Hsu and Dr. Kovács was how they were able to examine implementation of legalization of medical or recreational cannabis, rather than simply a change in the law, he said.

“By looking at dispensary count, it’s actually looking at a better measure of on-the-ground implementation than just change in policy,” Dr. Fichtner explained. “You’re looking at what was actually accomplished in terms of making cannabis legally available.”

The choice to evaluate storefront dispensaries only and not include delivery services in their data, “probably makes it a relatively conservative estimate. I think that would be a strength, that their findings may be even stronger than what it is they’re reporting,” Dr. Fichtner said.

“I do think, if anything, the paper is relatively tentative about advancing its conclusions, which I think is a weakness in a lot of these studies,” he added. In 2017, the National Academy of Sciences released a report that found evidence cannabis or cannabinoids can significantly reduce pain symptoms. In that report, “one of their strongest conclusions is that there’s conclusive or substantial evidence that cannabis or cannabinoids are effective management of chronic pain,” Dr. Fichtner said.

He said that digging deeper into what kinds of pain cannabis can treat is one area for future research. “Certainly, it seems that it’s unlikely that cannabis is going to be good for every kind of pain,” he said. “What kinds of pain is it better for than others? Is it some benefit for many kinds of pain, or only a few types of pain?”

The authors reported no relevant financial disclosures. Dr. Fichtner is the author of a book on cannabis policy in the United States, but reported no other financial disclosures.
 

ILLUSTRATIVE CASE

An 8-year-old girl with congenital heart disease (status: post repair) arrives at your clinic for a routine appointment. Since the age of 12 months, she has experienced significant anxiety during medical visits, especially with blood draws and injections. She enjoys playing video games on her new tablet computer. Her parents want to know what you can do to reduce her anxiety and pain during today’s scheduled blood draw. Should you recommend that she continue playing video games during the venipuncture?

Adequately managing pain while performing venipuncture in children can improve the quality of the experience, reduce children’s fear of going to the doctor, and increase efficiency in medical practice.² Since pharmacologic pain-control methods may have adverse effects, distraction techniques—engaging the child in another activity during a procedure—are commonly used instead to help reduce a child’s pain. These techniques can be active or passive.

Studies have demonstrated that both active and passive distraction techniques reduce children’s pain during medical procedures, including venipuncture. Passive techniques, such as nurse coaching³ and watching cartoons,⁴ have been found to reduce distress and pain. Active distraction techniques, such as playing video games while undergoing a painful procedure (eg, dressing a wound), have been shown to be more effective than passive techniques.^5,6

A Cochrane review and meta-analysis of distraction and hypnosis for needle-related pain and distress in children demonstrated reduced pain, but the quality of evidence was low and the review recommended improved methodological rigor and trial reporting.⁷ Another systematic review and analysis showed strong support for distraction for reducing pain; however, the quality of evidence was low and the researchers cited problems with characteristics of the distraction interventions, child age, and risk of bias in the studies.⁸

There has been a lack of RCTs comparing the effectiveness and superiority of active vs passive distraction techniques. The first high-quality RCT to directly compare 3 of the most common distraction techniques to a control group was recently conducted in a large training and research hospital in Turkey.¹

STUDY SUMMARY

Pain and anxiety levels were lowest in actively distracted children

The RCT included 180 children ages 6 to 10 years randomly assigned to 1 of 3 intervention groups or a control group.¹ Phlebotomy was performed while children watched a cartoon, played a video game, were distracted by parental interaction, or had no distraction (control group).

Investigators independently measured pain and anxiety in the patient and perceived pain and anxiety according to both a family member and a health care worker (medical observer). Researchers used the previously validated Children’s Fear Scale and the Wong-Baker Pain Scale.^9,10 The Children’s Fear Scale was used to assess anxiety in children on a scale of 0 (picture of a calm face) to 4 (picture of the most fearful face). The Wong-Baker Pain Scale was used to assess pain on a scale of 0 (no hurt: happy face) to 10 (hurts worst: saddest face).

Continue to: Results

Results. The pain and anxiety scores were significantly lower in all of the intervention groups compared with the control group (P < .05). The video game (active distraction) group had the lowest levels of both pain and anxiety. The self-reported Children’s Fear Scale scores of children in the video game group were 0.27, compared with 0.76 in the cartoon group, 1.24 in the parental distraction group, and 2.22 in the control group. The anxiety scores recorded by the family member and the medical observer showed similar significant differences.

Allow children to play a video game during procedures such as venipuncture; doing so reduces pain and anxiety.

The Wong-Baker Pain Scale scores showed similar differences in self-reported pain for the video game group (1.42) compared with the cartoon group (3.02), the parental distraction group (2.89), and the control group (5.11). Pain scores reported by the family member and the medical observer (respectively) also reflected benefit from any type of distraction, with active game-playing as the most effective type of distraction (video game: 1.69 and 1.96; cartoon: 3.07 and 3.20; parental distraction: 3.56 and 4.22; and control: 5.29 and 6.13).

In addition, the intraclass correlation coefficient was 0.67 to 0.924 (P < .01), suggesting that the reports from the child, parent, and medical observer about the child’s pain and anxiety were highly correlated.

WHAT'S NEW

All distraction techniques provide benefit, but there’s a clear winner

In this RCT of children undergoing phlebotomy, both active and passive distraction techniques were superior to no distraction in terms of perceived pain and anxiety by the child, a health care provider, or a parent. The active-distraction group played a video game, while the passive-distraction groups watched a cartoon or interacted with a parent. Active distraction was superior to passive distraction.

CAVEATS

Procedure time was short; intervention not blinded

One potential weakness of this study is that it was not a double-blinded trial. Blinding was not possible for much of the study as the patient, parent, and medical observer were fully aware of the intervention or lack thereof. However, the parent and medical observer were blinded to each other’s assessments of the child’s pain and anxiety.

Continue to: Furthermore, the study...

Furthermore, the study was conducted at a single institution in Turkey. There could be cultural differences in reporting of pain and anxiety compared to Western cultures.

Finally, the average duration of the procedure in this study was 3 minutes, with a range of 1 to 5 minutes. It is unclear if the findings can be extrapolated to more time-consuming procedures.

CHALLENGES TO IMPLEMENTATION

Technology is not available to all

The use of tablet computers may seem increasingly ubiquitous, but not all families have access to these devices. Another challenge is that phlebotomy/clinic personnel must learn to work around the device.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

An 8-year-old girl with congenital heart disease (status: post repair) arrives at your clinic for a routine appointment. Since the age of 12 months, she has experienced significant anxiety during medical visits, especially with blood draws and injections. She enjoys playing video games on her new tablet computer. Her parents want to know what you can do to reduce her anxiety and pain during today’s scheduled blood draw. Should you recommend that she continue playing video games during the venipuncture?

Adequately managing pain while performing venipuncture in children can improve the quality of the experience, reduce children’s fear of going to the doctor, and increase efficiency in medical practice.² Since pharmacologic pain-control methods may have adverse effects, distraction techniques—engaging the child in another activity during a procedure—are commonly used instead to help reduce a child’s pain. These techniques can be active or passive.

Studies have demonstrated that both active and passive distraction techniques reduce children’s pain during medical procedures, including venipuncture. Passive techniques, such as nurse coaching³ and watching cartoons,⁴ have been found to reduce distress and pain. Active distraction techniques, such as playing video games while undergoing a painful procedure (eg, dressing a wound), have been shown to be more effective than passive techniques.^5,6

A Cochrane review and meta-analysis of distraction and hypnosis for needle-related pain and distress in children demonstrated reduced pain, but the quality of evidence was low and the review recommended improved methodological rigor and trial reporting.⁷ Another systematic review and analysis showed strong support for distraction for reducing pain; however, the quality of evidence was low and the researchers cited problems with characteristics of the distraction interventions, child age, and risk of bias in the studies.⁸

There has been a lack of RCTs comparing the effectiveness and superiority of active vs passive distraction techniques. The first high-quality RCT to directly compare 3 of the most common distraction techniques to a control group was recently conducted in a large training and research hospital in Turkey.¹

STUDY SUMMARY

Pain and anxiety levels were lowest in actively distracted children

The RCT included 180 children ages 6 to 10 years randomly assigned to 1 of 3 intervention groups or a control group.¹ Phlebotomy was performed while children watched a cartoon, played a video game, were distracted by parental interaction, or had no distraction (control group).

Investigators independently measured pain and anxiety in the patient and perceived pain and anxiety according to both a family member and a health care worker (medical observer). Researchers used the previously validated Children’s Fear Scale and the Wong-Baker Pain Scale.^9,10 The Children’s Fear Scale was used to assess anxiety in children on a scale of 0 (picture of a calm face) to 4 (picture of the most fearful face). The Wong-Baker Pain Scale was used to assess pain on a scale of 0 (no hurt: happy face) to 10 (hurts worst: saddest face).

Continue to: Results

Results. The pain and anxiety scores were significantly lower in all of the intervention groups compared with the control group (P < .05). The video game (active distraction) group had the lowest levels of both pain and anxiety. The self-reported Children’s Fear Scale scores of children in the video game group were 0.27, compared with 0.76 in the cartoon group, 1.24 in the parental distraction group, and 2.22 in the control group. The anxiety scores recorded by the family member and the medical observer showed similar significant differences.

Allow children to play a video game during procedures such as venipuncture; doing so reduces pain and anxiety.

The Wong-Baker Pain Scale scores showed similar differences in self-reported pain for the video game group (1.42) compared with the cartoon group (3.02), the parental distraction group (2.89), and the control group (5.11). Pain scores reported by the family member and the medical observer (respectively) also reflected benefit from any type of distraction, with active game-playing as the most effective type of distraction (video game: 1.69 and 1.96; cartoon: 3.07 and 3.20; parental distraction: 3.56 and 4.22; and control: 5.29 and 6.13).

In addition, the intraclass correlation coefficient was 0.67 to 0.924 (P < .01), suggesting that the reports from the child, parent, and medical observer about the child’s pain and anxiety were highly correlated.

WHAT'S NEW

All distraction techniques provide benefit, but there’s a clear winner

In this RCT of children undergoing phlebotomy, both active and passive distraction techniques were superior to no distraction in terms of perceived pain and anxiety by the child, a health care provider, or a parent. The active-distraction group played a video game, while the passive-distraction groups watched a cartoon or interacted with a parent. Active distraction was superior to passive distraction.

CAVEATS

Procedure time was short; intervention not blinded

One potential weakness of this study is that it was not a double-blinded trial. Blinding was not possible for much of the study as the patient, parent, and medical observer were fully aware of the intervention or lack thereof. However, the parent and medical observer were blinded to each other’s assessments of the child’s pain and anxiety.

Continue to: Furthermore, the study...

Furthermore, the study was conducted at a single institution in Turkey. There could be cultural differences in reporting of pain and anxiety compared to Western cultures.

Finally, the average duration of the procedure in this study was 3 minutes, with a range of 1 to 5 minutes. It is unclear if the findings can be extrapolated to more time-consuming procedures.

CHALLENGES TO IMPLEMENTATION

Technology is not available to all

The use of tablet computers may seem increasingly ubiquitous, but not all families have access to these devices. Another challenge is that phlebotomy/clinic personnel must learn to work around the device.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

An 8-year-old girl with congenital heart disease (status: post repair) arrives at your clinic for a routine appointment. Since the age of 12 months, she has experienced significant anxiety during medical visits, especially with blood draws and injections. She enjoys playing video games on her new tablet computer. Her parents want to know what you can do to reduce her anxiety and pain during today’s scheduled blood draw. Should you recommend that she continue playing video games during the venipuncture?

Adequately managing pain while performing venipuncture in children can improve the quality of the experience, reduce children’s fear of going to the doctor, and increase efficiency in medical practice.² Since pharmacologic pain-control methods may have adverse effects, distraction techniques—engaging the child in another activity during a procedure—are commonly used instead to help reduce a child’s pain. These techniques can be active or passive.

Studies have demonstrated that both active and passive distraction techniques reduce children’s pain during medical procedures, including venipuncture. Passive techniques, such as nurse coaching³ and watching cartoons,⁴ have been found to reduce distress and pain. Active distraction techniques, such as playing video games while undergoing a painful procedure (eg, dressing a wound), have been shown to be more effective than passive techniques.^5,6

A Cochrane review and meta-analysis of distraction and hypnosis for needle-related pain and distress in children demonstrated reduced pain, but the quality of evidence was low and the review recommended improved methodological rigor and trial reporting.⁷ Another systematic review and analysis showed strong support for distraction for reducing pain; however, the quality of evidence was low and the researchers cited problems with characteristics of the distraction interventions, child age, and risk of bias in the studies.⁸

There has been a lack of RCTs comparing the effectiveness and superiority of active vs passive distraction techniques. The first high-quality RCT to directly compare 3 of the most common distraction techniques to a control group was recently conducted in a large training and research hospital in Turkey.¹

STUDY SUMMARY

Pain and anxiety levels were lowest in actively distracted children

The RCT included 180 children ages 6 to 10 years randomly assigned to 1 of 3 intervention groups or a control group.¹ Phlebotomy was performed while children watched a cartoon, played a video game, were distracted by parental interaction, or had no distraction (control group).

Investigators independently measured pain and anxiety in the patient and perceived pain and anxiety according to both a family member and a health care worker (medical observer). Researchers used the previously validated Children’s Fear Scale and the Wong-Baker Pain Scale.^9,10 The Children’s Fear Scale was used to assess anxiety in children on a scale of 0 (picture of a calm face) to 4 (picture of the most fearful face). The Wong-Baker Pain Scale was used to assess pain on a scale of 0 (no hurt: happy face) to 10 (hurts worst: saddest face).

Continue to: Results

Results. The pain and anxiety scores were significantly lower in all of the intervention groups compared with the control group (P < .05). The video game (active distraction) group had the lowest levels of both pain and anxiety. The self-reported Children’s Fear Scale scores of children in the video game group were 0.27, compared with 0.76 in the cartoon group, 1.24 in the parental distraction group, and 2.22 in the control group. The anxiety scores recorded by the family member and the medical observer showed similar significant differences.

Allow children to play a video game during procedures such as venipuncture; doing so reduces pain and anxiety.

The Wong-Baker Pain Scale scores showed similar differences in self-reported pain for the video game group (1.42) compared with the cartoon group (3.02), the parental distraction group (2.89), and the control group (5.11). Pain scores reported by the family member and the medical observer (respectively) also reflected benefit from any type of distraction, with active game-playing as the most effective type of distraction (video game: 1.69 and 1.96; cartoon: 3.07 and 3.20; parental distraction: 3.56 and 4.22; and control: 5.29 and 6.13).

In addition, the intraclass correlation coefficient was 0.67 to 0.924 (P < .01), suggesting that the reports from the child, parent, and medical observer about the child’s pain and anxiety were highly correlated.

WHAT'S NEW

All distraction techniques provide benefit, but there’s a clear winner

In this RCT of children undergoing phlebotomy, both active and passive distraction techniques were superior to no distraction in terms of perceived pain and anxiety by the child, a health care provider, or a parent. The active-distraction group played a video game, while the passive-distraction groups watched a cartoon or interacted with a parent. Active distraction was superior to passive distraction.

CAVEATS

Procedure time was short; intervention not blinded

One potential weakness of this study is that it was not a double-blinded trial. Blinding was not possible for much of the study as the patient, parent, and medical observer were fully aware of the intervention or lack thereof. However, the parent and medical observer were blinded to each other’s assessments of the child’s pain and anxiety.

Continue to: Furthermore, the study...

Furthermore, the study was conducted at a single institution in Turkey. There could be cultural differences in reporting of pain and anxiety compared to Western cultures.

Finally, the average duration of the procedure in this study was 3 minutes, with a range of 1 to 5 minutes. It is unclear if the findings can be extrapolated to more time-consuming procedures.

CHALLENGES TO IMPLEMENTATION

Technology is not available to all

The use of tablet computers may seem increasingly ubiquitous, but not all families have access to these devices. Another challenge is that phlebotomy/clinic personnel must learn to work around the device.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.