Tag Archives: naloxone

09/21/18

Naloxone Works If You Can Afford It

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The CDC has an interactive presentation of data on drug overdose death counts at: “Provisional Drug Overdose Death Counts.” The data visualization is based on current mortality data in the National Vital Statistics System. You can choose between dashboards showing drug overdose deaths from December of 2014 (47,523) to December of 2017 (70,467); or you can examine state-by-state reports on drug over dose deaths between December 2016 and December 2017. You can also see a dashboard showing drug overdose deaths by drug or drug class, which indicated that 47,705 people died from opioid overdoses in a 12-month period ending in December of 2017. If naloxone had been administered to them, 93.5% might have survived and 84.3% of those survivors could have still been alive a year later. Naloxone works.

The above predictions were based on a research study reported in a CNN article. The lead author of the study was Dr. Scott Weiner, an emergency physician at Brigham and Women’s Hospital in Boston. Pessimists might point out the study also found there was a 1 in 10 chance of those individuals not surviving a year (the title to the CCN article itself contained the phrase: “many recipients don’t survive a year”). Thirty-five percent of those deaths were from another opioid overdose. However, Weiner said: “The lesson learned is not that naloxone is failing; it’s working.” Naloxone works, but it doesn’t treat the underlying problem, he added.

The U.S. Surgeon General issued a public health advisory on April 5, 2018, urging more Americans to learn to use and carry naloxone. He encouraged individuals to learn the signs of opioid overdose; to get trained to administer naloxone in the case of a suspected emergency; and to talk to your doctor or pharmacist about obtaining naloxone. Prescribers, pharmacists and treatment providers were urged to learn how to identify patients at high risk of overdose; prescribe or dispense naloxone to individuals who are at elevated risk for opioid overdose and to their friends and family. He also said:

Increasing the availability and targeted distribution of naloxone is a critical component of our efforts to reduce opioid-related overdose deaths and, when combined with the availability of effective treatment, to ending the opioid epidemic.

Caroline Engelmayer reported in the Pittsburgh Post-Gazette how David Lettrich was one of these individuals who carried naloxone; knew how to use it and learned the signs of opioid overdose. Along with another person, Stuart Fisk, who was walking down the street to get coffee, he was able to administer CPR and Narcan—a brand-name version of naloxone—to the unconscious man and he save his life. David Letterich is the founder and director of Bridge to the Mountain, a nonprofit organization serving the homeless and addicted individuals in Pittsburgh. Stuart Fisk is a nurse practitioner with Allegheny Health Network, but their particular interests and skill sets weren’t relevant to what they accomplished. Anyone can carry and be trained to administer naloxone.

The Post-Gazette article pointed out how increased availability of naloxone is essential. Alice Bell, the coordinator of Prevention Point Pittsburgh’s Overdose Prevention Project, said: “In 2017 there is easily twice as much naloxone given out to the community as there was in 2016.”  Increased availability means multiple doses can be distributed to residents. “While a single dose of naloxone revives some people, others sometimes require up to six or seven doses.” David Lettrich said: “The only way naloxone works is if it can be distributed in surplus.”

But there is a problem; the price of naloxone and naloxone-based products has skyrocketed. “In 2009, one vial of naloxone sold by the pharmaceutical company Amphastar cost roughly $20. By 2016, its price had nearly doubled, to $39.60.”

Naloxone used to be a “very cheap” generic drug that cost a dollar or two per dose, Mr. Fisk said. Now, an intranasal device with two doses costs $150, according to Mr. Fisk, and an automated naloxone machine that speaks instructions on how to administer the medicine sells for over $600.

The Bill of Health, a Harvard blog of the Petrie-Flon Center, provided some helpful background information on naloxone. Naloxone was first developed and patented in 1961 as a medication to reverse constipation in opioid patients. The FDA approved its use to reverse opioid overdose in 1971. And naloxone comes in several forms. It can be administered as an intravenous or intramuscular solution and as a nasal spray. It also can be given in tablet form as an abuse deterrent (ReVia). And it comes as an extended-release injectable, also as an abuse deterrent (Vivitrol).

Naloxone has been historically inexpensive and pharmaceutical companies really didn’t care much about it. Only six pharmaceutical companies even made the drug prior to 2014. It wasn’t until the onset of the opioid epidemic, and public health initiatives that allowed public access to this drug, that prices began to soar.

Naloxone’s wholesale generic cost is around $20 for a single dose. The nasal spray product, known as Narcan, costs $133 to $160 for a two-dose kit. A top-of-the-line two-injector kit known as Evizio that talks you through injecting the naloxone starts at $3,758. The Evzio price is a 680 percent increase over its original price in 2014. “These price increases came when the opioid epidemic was at its peak, and they came without any explanation.” There have been actions taken by several states to limit these increases, but little done in the way of federal regulation to enforce them.

The “patented” delivery systems seem to be the justification for the exorbitant cost of Narcan and Evizio. But decongestants and topical steroids use delivery systems similar to Narcan and these methods cost no more than $10 to $20 dollars per unit, not $160. “An atomizer device that can be just as efficacious a means of drug-delivery sells for around $7.00.” Auto-injectors, around since the 1970s to deliver anti-nerve agents, consist of little more than plastic casing, a pressure activated spring and a needle. Remember the outcry over the unjustifiable cost of the EpiPen, a similar delivery system to Evizio costing ($630)?

The exorbitant cost of these drugs crosses an ethical boundary as well. Ethical sales principles ensure that the cost of an item can be justified, and that the buyer is not being exploited. There has been no evidence to date to support the increased cost of either naloxone product. Furthermore, any parent with a child, any spouse, friend or even a neighbor of someone with substance abuse disorder would pay any price to save their loved one’s life. To take advantage of that is simply unethical and detrimental to society.

Naloxone has gone from a $21 million per year industry before 2014 to $274 million per year since 2015. “There is no doubt: pharmaceutical companies are making money off the opioid epidemic. Additionally, those who need this drug the most, often don’t have access to it. They are the under- or uninsured, so waving a co-pay is moot.”

According to the Pittsburgh Post-Gazette, a potential solution to the exorbitant cost of these drugs is to develop an over-the-counter naloxone product. Harm Reduction Therapeutics is currently raising money and preparing for a clinical trial for its own over-the-counter naloxone product. Michael Hufford, the co-founder and CEO of Harm Reduction Therapeutics, “aims to sell naloxone at the lowest possible cost to increase access to the drug.” If you know any venture capitalists, tell them about Harm Reduction Therapeutics.

Dr. Hacker, director of the Allegheny County Health Department supports the idea of an over-the-counter version of naloxone and mentioned it to some federal legislators. The risks associated with the drug are incredibly low. Dr. Hufford wants to make naloxone widely available at minimal cost. He said: “Just like you can go anywhere and buy Band-Aids and Tylenol, we think naloxone should be that available.”

The question is will Harm Reduction Therapeutics be able to successfully navigate the gauntlet of competing lobbyists with the FDA and  federal government from Endo Health Solutions, which manufactures Narcan and Kaleo, which manufactures Evzio. Naloxone works, but only if you can afford it. Let’s see if we can make that true for the next 47,705 people dying from opioid overdoses.

03/16/18

Overdose No-Brainers

© Robert Hyrons | 123rf.com

The governor of Pennsylvania, Tom Wolf, declared the heroin and opioid epidemic as a statewide disaster emergency. Among the enhancements of the declaration, there will be increased access to the Prescription Monitoring Program so that state officials can identify doctors who are overprescribing opioid medication, as well as patients who may be seeing more than one physician to multiply their access to prescription opioids. Several measures to expand, speed up, and improve access to treatment and will be instituted. These measures include: enabling EMS to leave naloxone behind after responding to an overdose and expanding access to medication for Narcotic Treatment Programs. Pharmacists will be permitted to partner with prisons and treatment programs to make naloxone available to individuals leaving those facilities.

The Fix reported there was bipartisan support for the governor’s action. U.S. Senators, Pat Toomey (R) and Bob Casey (D) publically praised the declaration. Senator Toomey said: “The opioid and heroin crisis has rightfully drawn bipartisan attention in Congress and all levels of government. Today’s opioid emergency declaration sends a clear message that more work remains to be done.” Senator Casey added: “This declaration will bring additional resources to bear on this horrific public health emergency that has ripped apart far too many families.”

Increased access to the Prescription Monitoring Program by state officials is not as Orwellian as it may sound. Limitations placed upon the DEA by the “Ensuring Patient Access and Effective Drug Enforcement Act of 2016” hobbled the DEA’s ability to go after drug companies suspected of enabling the widespread distribution of prescription pain medication. “Overall, the drug industry spent $102 million lobbying Congress on the bill and other legislation between 2014 and 2016, according to lobbying reports.” See “Head of a Snake” for more information on this issue.

Drug overdose data from the CDC indicated that in 2016, Pennsylvania had the fourth highest increase in drug overdose deaths with 37.9 per 100,000. West Virginia (52.0 per 100,00), Ohio (39.1 per 100,00), New Hampshire (39.0 per 100,00) and Kentucky (33.5 per 100,000) rounded out the top five states. This was a 44.1% increase from 2015 to 2016 for Pennsylvania, again placing them fourth behind the increases with the District of Columbia (108.6%), Maryland 58.9%) and Florida (46.3%). New Jersey (42.3%) rounded out the top five states with percentage increases of overdose deaths. See the following graphic from the CDC report on rates of drug overdose death by state for 2016.

Another CDC report indicated the death rate for drug overdoses for the twelve-month period ending with the 4th quarter of 2016 was 19.8 per 100,000, an increase over the same time period for the 4th quarter of 2015, 16.3 per 100,000. This was an increase of 21% from 2015. The New York Times said Dr. Andrew Kolodny, the director of opioid policy research at Brandeis University, was not surprised by the data. “We have roughly two groups of Americans that are getting addicted. . . . We have an older group that is overdosing on pain medicine, and we have a younger group that is overdosing on black market opioids.” See the following table from the CDC report.

Naloxone, as it was noted in the opening paragraph, is a crucial tool in the struggle against opioid overdoses. Yet it had a quiet, and rather unassuming life until the rise of the opioid epidemic. Jack Fishman originally synthesized naloxone for a private narcotics lab owned by Mozes Lewenstein in 1961. Harold Blumberg, a colleague of Lewenstein’s, had the idea of developing an opioid antagonist by making a small structural change to oxymorphone, a synthetic opioid. The FDA approved naloxone as an injection, Narcan, to reverse opioid intoxication in 1971. Generic versions of naloxone became available in 1985.

As the opioid crisis began to pick up steam in 2013, the FDA approved Evzio, a portable injection kit with a fixed dose of naloxone. In late 2015, they approved Narcan, now packaged as a nasally administered form of naloxone. A series of governmental initiatives were enacted to increase access to naloxone. From 2012 to 2016, the number of states with at least one law expanding access to naloxone increased from 8 to 46. A growing number of community organizations now provide naloxone kits and education programs to laypersons. But as Gupta et al. reported in The New England Medical Journal, between 2009 and 2015 the annual number of naloxone prescriptions only increased from 2.8 million to 3.2 million. While retail-prescription numbers were unchanged, the proportion attributed to clinics and EMS providers increased from 14% to 29%.

Although the slowed rate of using naloxone could be attributed to the stigma of opioid use and unfamiliarity with how to use naloxone, the rising cost and the limited number of manufacturers producing it, are more insidious reasons. While there are three manufacturers of naloxone approved by the FDA, there is only one supplier for all three formulations. Amphastar, the manufacturer of the 1-mg-per-millileter dose used off-label as a nasal spray, increased its price 95% to $39.60 in September of 2014. “Newer, easier-to-use formulations are even more expensive. Narcan costs $150 for two nasal-spray doses. A two-dose Evzio package was priced at $690 in 2014 but is $4,500 today, a price increase of more than 500% in just over 2 years.” See the following table of previous and current prices for naloxone.

The price increase for naloxone is related to the overall trend of rising prescription drugs prices across-the–board. See “Pharma’s Not Getting the Message” and “Pharma Companies Hunt in Packs” for more information on this. But unfortunately, none of the federal or state initiatives to expand the availability of naloxone address the drug’s high price. “Evzio’s price jumped significantly and without explanation the month before the CDC’s coprescription guidelines were released.” Several U.S. senators have sent letters to naloxone manufacturers asking them to explain their price increases, but this hasn’t resulted in any changes or public outrage, as happened with Mylan, the manufacturer of the EpiPen. Gupta et al. had some recommendations to address naloxone’s price increase.

First, naloxone could be purchased in bulk, which would create stable demand that might motivate additional companies to begin manufacturing the medication — a strategy that’s been used for vaccine manufacturing. Second, governments could invoke federal law 28 U.S.C. section 1498 to contract with a manufacturer to act on behalf of the United States and produce less costly versions of Evzio’s patented auto-injector in exchange for reasonable royalties — an approach that was considered for procuring ciprofloxacin during the anthrax threat in 2001. Third, in response to increases in generic drug prices, some observers have proposed allowing importation of generics from international manufacturers that have received approval from regulators with standards comparable to those of the FDA, a strategy that could be pursued for naloxone.

Gupta et al. also suggested the federal government could motivate additional companies to obtain approval to market generic versions of naloxone by prioritizing timely approval and waiving application fees. This would likely stimulate price competition. Resurrecting a discussion of the FDA switching naloxone to over-the-counter-status would benefit patient access. “The relative ease of receiving FDA authorization for over-the-counter medications would also probably attract additional manufacturers.”

 Naloxone coprescribing and expanded availability represents only one of many potential strategies for reducing the number of prescription-opioid and heroin overdose deaths in the United States. But when governments promote naloxone use, they have a responsibility to ensure the drug’s affordability. Taking action now is essential to ensuring that this lifesaving drug is available to patients and communities.

As illustrated within the actions taken by Governor Tom Wolf of Pennsylvania, naloxone is a key factor in the fight against the opioid epidemic. Given the potential influence of state and federal officials and legislators, concerted efforts to force manufacturers to decrease the cost of naloxone products or to take steps to increase their competition should be a no-brainer strategy. Otherwise—and this itself is another no-brainer—the pharmaceutical companies will continue to siphon as much profit as they can from the opioid epidemic.

05/4/15

The Opioid-Heroin Cycle

© Ouroboros tattoo by Sahua | Stockfresh.com

© Ouroboros tattoo by Sahua | Stockfresh.com

Since the death of Philip Seymour Hoffman on February 2, 2014, there has been a series of calls for the distribution of naloxone or Narcan, which is a prescription medication that reverses an opioid overdose. But it seems that the price of Narcan has doubled over the past year. The Fix and others report that the price of naloxone has recently gone from $51.50 per kit, to nearly $100 per kit. These are the Luer-Jet™ kits sold by Amphastar Pharmaceuticals, the only US company currently selling nasal kits. There is a cheaper injectable form of narcan, but it is supposed to be less user friendly.

Within four days of Hoffman’s death, The New York Times published an article by an emergency physician, noting how greater availability of Naloxone could prevent deaths. He referred to a report in the Annals of Internal Medicine that suggested up to 85 percent of users overdose in the presence of others, providing the opportunity for others to intervene. In Forbes Magazine David Kroll said the CDC reported that naloxone was used in over 10,000 opioid-overdose reversals between 1996 and mid-2010. He also expressed his concerns over potential shortages of naloxone.

Victoria Kim for The Fix reported that Amphastar’s president blamed the price increase of their naloxone product on “steadily increasing” manufacturing costs. But Matt Curtis, the policy director for a New York advocacy group said there had been a fairly steady price for several years. “Then these big government programs come in and now all of a sudden we’re seeing a big price spike. . . . The timing is pretty noticeable.” The Hill reported that Senator Bernie Sanders and Representative Elijah Cummings sent a letter to Amphastar complaining about the price increase and how it is “an obstacle in efforts by police departments to equip officers with the drug.”

Areille Pardes of Vice said that after the CDC said there was an opioid epidemic in 2008, the manufacturer of naloxone, Hospira, increased the price of a dose of naloxone from $3 to a little more than $30. Pardes also reported that the supposed difficulty of a lay-friendly delivery system has also been used to justify the high costs of epipens (around $400) and the naloxone auto-injector, EVIZO (Over $600 for a kit of 2 auto-injectors at Walmart, Sams Club, Target and other retail outlets). However a study found few differences between trained and untrained overdose rescuers in their abilities to use the syringes in a naloxone rescue kit. “Anyone with common sense could figure it out, even without training.”

It does seem that the timing of the price increases for naloxone (a generic drug) and its delivery systems occurred just as the epidemic of overdoses took place. The CDC reported in a March 2015 NCHS Data Brief that from 2000 to 2013 the rate of drug overdoses quadrupled, from .7 deaths per 100,000 to 2.7 deaths per 100,000. Overdoses are now the number one cause of injury-related death in the US. While the overdose deaths involving (prescription) opioid analgesics have leveled off in recent years, those from heroin have almost tripled. See Figure 1 of the NCHS Data Brief. While the heroin overdose rates increased among all age brackets, the highest rate of increase was among 25-44 year olds. Geographically, while there were increases in all regions of the country, the greatest increase took place in the Northeast and the Midwest. See figure 5 of the NCHS Data Brief.

There is some sense that effort to curb problems with overprescribing pain medications has inadvertently led to a boom in the misuse of heroin. Richard Juman reported for The Fix that while some treatment providers suggest that is the case, others note that there is evidence that heroin use was increasing before any state or federal interventions with prescribed opioids were implemented. According to Andrew Kolodny, MD:

The idea that efforts to curb prescription drug misuse have led to a spike in heroin use or overdose has become a common media narrative, but the facts don’t support it. It is the overprescribing of opioids itself that has caused increases in opioid addiction of all kinds, not the efforts to control the prescribing. The transition from prescribed opioids to heroin has been happening since the beginning of the epidemic, and there is no evidence that the interventions brought forth to reduce the overprescribing have been fueling the increase in heroin use or overdoses. Because of the epidemic of opioid addiction, you now have markets for heroin that you didn’t have in the past. So there has been an increase in heroin overdose deaths, but that increase was prior to states’ implementation of Prescription Monitoring Programs or any of the changes from the FDA.

I tend to agree with Dr. Kolodny’s assessment. There is a price factor in the shift for many opioid users switching to heroin. And there has been a global market increase in heroin production that paralleled the rise of prescription opioid use. Increased heroin use in the US is market driven. What does seem to be related to increased heroin availability in the US is the diversification of Mexican drug cartels into growing opium poppies, as their market for marijuana dries up. See “The Economics of Heroin.”

There is something very wrong with the cycle of Pharma marketing for increased use of opioids, leading to overprescribing opioids, leading to increased heroin use and increased overdoses, leading to an increased need for narcan, leading back to increased profits with drug companies, where the cycle began. The ouroboros pictured above is a symbol in Greek mythology of a dragon eating its own tail. It symbolizes something that constantly re-creates itself, which seems to be happening here with the opioid-heroin cycle.