Dramatic Rise in Use of Drugs for Opioid-Induced Constipation

Pam Harrison

April 27, 2021

A call for more appropriate use of a new class of drugs for the treatment of opioid-induced constipation (OIC) has been issued by researchers who found that the number of Medicare beneficiaries who use these drugs, as well as associated costs, soared during a 4-year period (2014–2018).

This class of drugs, known as peripheral µ-opioid receptor antagonists (PAMORAs), include methylnaltrexone (Relistor), which was approved by the FDA in 2008; naloxegol (Movantik), approved in 2014; and naldemedine (Symproic), approved in 2017.

Spending on these three drugs increased more than tenfold from 2014 to 2018 ― from $13.6 million to $150.9 million, the researchers report.

During that 4-year period, the number of Medicare beneficiaries taking these drugs increased nearly 20-fold, from 4221 to 72,592 patients.

The team also found that the prescribing of these drugs was not limited to palliative care and pain specialists. Among the 6989 clinicians who prescribed any of the three currently available PAMORAs during the study period, 20.2% were family practitioners, 18% were internal medicine specialists, and 15.4% were nurse practitioners.

"Our findings — significant and increasing expenditure on PAMORAs, and use across specialties — serve as a call for first defining and then implementing the appropriate use of PAMORAs," say the researchers.

The study was published online April 19 in the Journal of Palliative Medicine.

Senior author Arjun Gupta, MD, chief fellow in hematology/oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, suspects that clinical guidelines on the use of these drugs are not being followed. Those guidelines recommend that PAMORAs be used only after traditional laxatives are tried.

He also suspects that aggressive marketing has played a role.

In a tweetorial about their study, Gupta points out that in the middle of the study period (2014–2018), television coverage of the 2016 Super Bowl featured a prominent advertisement for OIC that included a link to a website for naloxegol.



The study documents a sharp rise in the prescribing of these drugs after 2016 and shows that naloxegol was the most used drug of the three drugs that were available in 2018.



The investigators note that their study "does not account for the appropriateness of PAMORA therapy, which we could not evaluate using this database." They point out that PAMORAs are indicated for laxative-refractory OIC.

"In looking at multiple guidelines from oncology or gastrointestinal societies, the use of PAMORAs is only recommended in very select situations, which is just in the treatment of OIC that is already established," Gupta told Medscape Medical News.

For example, 2019 guidelines from the American Gastroenterological Association (AGA) recommend that PAMORAs be used only after an "adequate trial" of traditional laxatives has not resolved symptoms.

The AGA defines an adequate trial as trying two or more laxatives on a scheduled basis rather than on an as-needed basis.

"This means that a PAMORA should only be used in patients who have been on an appropriate regimen of preventive constipation medication, meaning traditional laxatives, which are usually available over the counter and which are dirt cheap," Gupta emphasized.

In contrast, a 10-day supply of PAMORAs costs $700, he points out.

"OIC is perhaps the most common and the most distressing complication of opioid use, so I don't want the message to be that PAMORAs are useless — we have successfully used them in patients who really require them, and patients have really benefited from them," Gupta said.

He also noted that almost every patient who takes an opioid is at very high risk for OIC and that once OIC is established, it is very hard to treat, Gupta stressed.

"There is a memorable dictum — 'The hand that writes the opioid prescription shall write the bowel regimen at the same time, otherwise, the same hand will be responsible for disimpaction,' " Gupta observed.

Commenting on the findings, Timothy Brown, MD, fellow in hematology/oncology, University of Pennsylvania, Philadelphia, Pennsylvania, noted that in his own study, almost 90% of lung cancer patients for whom opioids had been initiated received inadequate or inappropriate OIC prophylaxis. However, he commented, "Much of the data that we collected was before widespread publication of current guidelines in 2019, so it's possible that there was not quite as much attention to OIC at the time."

Brown told Medscape Medical News that in his experience, "most patients are able to tolerate a prophylactic regimen."

Brown agrees with Gupta, noting that because persons who take opioids are at high risk for OIC, "they should receive a prescription for a prophylactic regimen at the same time the opioid is prescribed, and it should be either a cathartic laxative, such as Senna, or an osmotic laxative, such as MiraLAX."

Findings From the Medicare Dataset

For their study, the team used a Medicare dataset that contains outpatient medication expenditures for approximately 75% of all Medicare beneficiaries.

"For each PAMORA, we extracted annual spending, number of beneficiaries who received a PAMORA prescription, number of claims for the PAMORA, and spending per beneficiary and claim," Gupta and colleagues explain. Spending was adjusted for inflation and is reported in 2018 US dollars.

"After FDA approval in 2014, naloxegol overtook methylnaltrexone in the number of users in 2015 and in spending in 2016 and remained the most heavily used drug in 2018," the researchers observe.

Per unit spending was still highest for methylnaltrexone, which peaked at $178 in 2016, after which it declined following the introduction of naloxegol and the oral formulation of methylnaltrexone.

Among the clinicians who prescribed a PAMORA, 8.5% issued a prescription to more than 10 beneficiaries. In this particular subgroup, the most common prescribers were nurse practitioners, at 19.6%, followed by anesthesiologists, at 13.2%, and physician assistants, at 12.2%. Gupta commented that it's not clear whether nurse practitioners were acting alone in prescribing a PANOMA or whether they were part of an oncology practice and did so under the supervision of a physician.

"We just wanted to make the point that it's not just highly specialized practitioners like those in palliative care who generally are dealing with patients on very high doses of opioids and who deal with OIC all the time," he emphasized.

Indeed, an earlier study that analyzed IQVIA data from 2016 to 2017 showed that PAMORA prescribing by hospice and palliative medicine clinicians and oncologists was low.

Gupta and Brown have disclosed no relevant financial relationships.

J Palliat Med. Published online April 19, 2021. Abstract

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