Tag Archives: opioids

01/22/19

Doubling the Risk of Overdose

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In February of 2018 The New England Medical Journal published an editorial titled “Our Other Prescription Drug Problem.” The authors said that between 1996 and 2013 the number of prescriptions written for benzodiazepines increased by 67% and the quantity of pills dispensed tripled. The number of overdose deaths from benzodiazepines also increased. Three fourths of those deaths involved an opioid; and co-prescribing rates of opioids and benzos have almost doubled since 2001. “Despite this trend, the adverse effects of benzodiazepine overuse, misuse, and addiction continue to go largely unnoticed.”

Both Medscape (“Benzodiazepine Harms Overlooked, Especially in Older Adults”) and Mad in America (“Psychiatrists Warn Policymakers Benzodiazepine Overuse Could Lead to Next Epidemic”) cited the editorial and quoted the above comment. But they seem to have spun the article’s content in different directions. The Medscape article was primarily about benzodiazepine use among older adults, as the title suggests, so readers would likely get the impression ”Our Other Prescription Drug Problem” was as well. The NEMJ article cited and discussed two additional articles on the problems of “benzodiazepine use among the elderly.” But that is not what “Our Other Prescription Drug Problem” was about. In fact, seniors using benzos was not even mentioned there.

Another slight-of-hand was with how the concluding paragraph of the Medscape article sanitized the rhetoric of the authors of “Our Other Prescription Drug Problem,” which referred to opioids and benzodiazepines as “life-threatening drugs.” The final paragraph of the Medscape article is followed by the original paragraph quoted in its entirety from “Our Other Prescription Drug Problem.”

If measures designed to discourage people from using opioids divert them to benzodiazepines instead, “[i]t would be a tragedy,” Lembke and colleagues conclude in their editorial. “We believe that the growing infrastructure to address the opioid epidemic should be harnessed to respond to dangerous trends in benzodiazepine overuse, misuse, and addiction as well.” (Medscape)

It would be a tragedy if measures to target overprescribing and overuse of opioids diverted people from one class of life-threatening drugs to another. We believe that the growing infrastructure to address the opioid epidemic should be harnessed to respond to dangerous trends in benzodiazepine overuse, misuse, and addiction as well. (NEMJ; emphasis added)

The readers of Medscape did not get a clear sense of what Dr. Lembke and her coauthors were saying in “Our Other Prescription Drug Problem.” Lembke et al. said benzos had proven utility if they were used intermittently and for less than 1 month at a time. “But when they are used daily and for extended periods, the benefits of benzodiazepines diminish and the risks associated with their use increase.” They noted how prescribers often don’t realize the potential problems with benzos and that safer alternatives are available.

Many prescribers don’t realize that benzodiazepines can be addictive and when taken daily can worsen anxiety, contribute to persistent insomnia, and cause death. Other risks associated with benzodiazepines include cognitive decline, accidental injuries and falls, and increased rates of hospital admission and emergency department visits. Fortunately, there are safer treatment alternatives for anxiety and insomnia, including selective serotonin-reuptake inhibitors and behavioral interventions.

Lembke et al. did say some patients could benefit from long-term benzodiazepine use, but suggested it was best to avoid daily dosing. They also referred to the newer, highly potent forms of benzodiazepines on the illicit drug market, which are often indistinguishable from prescription benzodiazepines and said they were: “potentially as deadly as the synthetic opioid analogue fentanyl.” They called for efforts to shut down illegal online pharmacies and drug-trafficking networks where individuals purchase illicit benzodiazepines, particularly the “superpotent analogues.”

The Mad in America article by Zenobia Morrill had several quotes from the original editorial and additional discussion of its contents, which addressed how benzodiazepine overuse, misuse and addiction has not received the attention that opioid overuse, misuse and addiction has received. And Morrill did not spin the original editorial. Her article also reproduced the following graph of overdose deaths in the U.S. involving benzodiazepines found in “Our Other Prescription Drug Problem.”

Morrill said Lembke et al. hypothesized the acceleration of benzodiazepine-related overdose deaths may be overlooked because the concurrent use of opioids in 75% of those deaths. Given the dangers of benzodiazepine use alone and in conjunction with opioids, providers should strive to taper benzodiazepines in patients who have been stabilized using opioid-agonist therapy, “taking into account patient’s preferences, the risks and benefits of benzodiazepines, and possible alternatives.”

Hernandez et al. looked at how the risk of overdose changed over time with concurrent opioid and benzodiazepine use in “Concurrent Opioid and Benzodiazepine Use and Risk of Opioid-Related Overdose.” The researchers looked at a random sample of data among Medicare Part D beneficiaries between 2013 and 2014. Their main outcome of interest was opioid-related overdoses—including fatal and nonfatal overdoses. They found that during the first 90 days of concurrent benzodiazepine use, there was a fivefold increase in the risk of opioid-related overdose.

Our study yielded 3 main findings. First, we found that 29% of Medicare Part D beneficiaries who did not have cancer and who used prescription opioids concurrently filled prescriptions for benzodiazepines. Second, we found that the risk of opioid-related overdose is particularly high during the first days with concurrent opioid and benzodiazepine use and then decreases over time. Specifically, during the first 90 days of concurrent benzodiazepine use, the risk of opioid-related overdose is 5 times higher compared with opioid use alone. Third, the numbers of opioid and benzodiazepine prescribers were associated with an increased likelihood of concurrent opioid and benzodiazepine use and an increased risk of overdose and were strong confounders in examining the association between concurrent use and overdose.

Among patients who used both medications longer than 90 days and did not overdose, they still had almost double the risk of overdose between 91 and 180 days of concurrent use. Concurrent use without overdose for more than 180 days did not predict an increased risk of overdose. But those results did not mean patients exposed to concurrent opioid and benzodiazepine use for longer time periods had a lower risk of overdose. “In fact, the longer the duration of concurrent use, the higher the risk of overdose, because the increased risk of overdose predicted during each time window (1-90, 91-180, 181-270, and 271 days of concurrent use) would be cumulative.”

Hernandez et al. said that despite the known increased risk of overdose associated with concurrent opioid and benzodiazepine use, “it is very common in the Medicare population.” They said policy interventions should advocate against concurrent use.  Performance measures should be redefined to prevent or restrict their concurrent use. The risk of overdose is also exacerbated by fragmented medical care.

Overall, these results demonstrate the important role that fragmentation of care plays in the inappropriate use of opioids and in the subsequent risk of overdose, and warrant the extended use of prescription monitoring programs and the implementation of new policy interventions that further control the receipt of opioid prescriptions by multiple prescribers.

The bottom line is the concurrent use of opioids and benzodiazepines at least doubles the risk of an overdose.

07/13/15

Getting High is an Global Problem

Package with a drug against the passports and U.S. dollars

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Looking at information gleaned from the 2014 World Drug Report suggests two drug trends to expect over the next few years. A bumper crop of opium poppies globally (particularly in Afghanistan), points to an increased worldwide problem with heroin. Afghanistan grew about 80% of the world’s opium poppies in 2013. Second, the development of new psychoactive substances (NPS) has accelerated and doesn’t appear to be slowing down anytime soon. By December of 2013, there were 348 known NPS, an increase of 200% since 2009. There are now more NPS than the number of substances under international control (234).

Globally, an estimated 243 million people aged 15-64 used an illicit drug in 2012. The three primary groups of illicit drugs were: cannabis, opioids, and cocaine or amphetamine-type stimulants (ATS). Generally, men are two to three times more likely than women to have used an illicit substance. While there are regional trends to consider, overall global drug use seems to be stable. The extent of problem drug use, determined by the number of regular drug users and those with drug use disorders, was also stable globally, at around 27 million people. The estimated number of global drug users by drug type is in the table below.

Global Drug Use by Drug Type

Cannabis

Amphetamine-like stimulants

Cocaine

Opiates

(heroin, opium)

Opioids (opiates and synthetics)

Amphetamines

Ecstasy

Users in millions

177.6

34.4

19.36

17.20

16.40

33.00

% of global population 15-64

3.80%

0.70%

0.40%

0.40%

0.40%

0.70%

There has been an increase in global opioid and cannabis use since 2009, while the use of opiates, cocaine and ATS has either remained stable or decreased. Reports on the types of drugs individuals seek treatment for can provide information on which drugs have the highest impact on health in the various geographic regions. Cannabis treatment is prevalent in Africa, the Americas and Oceania. It should be noted that between 2003 and 2012 that those seeking treatment for cannabis increased in Western and Central Europe (19% to 25%), Eastern and South Eastern Europe (8% to 15%), Latin America and the Caribbean (24% to 40%) and Oceania (30% to 46%).

Opioids dominate treatment requests in Eastern and Southern Europe and Asia. Cocaine is major treatment factor in the Americas, especially in Latin America and the Caribbean.  ATS use disorders are responsible for a significant proportion of the treatment demand in Asia and Oceania.

Global estimates are that one in six problem drug users got treatment in the past year. However, there are large regional differences. One in 18 problem drug users receive treatment in Africa (mostly for cannabis use), while one in five problem users in Europe, one in four in Oceania and one in three in North America receive treatment.

Drug-related deaths were estimated to be around 183,000 in 2012. Overdose deaths from opioids (heroin and non-medical use of prescription opioids) are the main drug type implicated in those deaths. Most overdoses occur when opioids are mixed with other sedating substances, like alcohol and benzodiazepines. See the global data in the table below from the 2014 World Drug Report.

Table 2

North America continues to be a major market for illicit drug use. It has the largest percentage of opioid users, cocaine users and cannabis users. It was second in percentage of ATS users. Cocaine use has been declining since 2006, partly because of a sustained shortage. Yet there has been a slight increase in prevalence recently. Columbia’s recent decision to stop spraying coca crops could stimulate a greater resurgence in cocaine use.

In the United States, opioid-dependent drug users are increasingly turning to heroin because of its greater availability and lowered cost to regular users. The greater availability of heroin in the United States is likely due to higher levels of heroin production in Mexico and Mexican traffickers expanding into “white heroin” markets. Anecdotal evidence is that Mexican drug cartels are switching from growing marijuana to opium poppies due to the lower demands for marijuana in the United States. See “The Economics of Heroin.”

The rapid growth of NPS has led to a key supply control strategy of restricting the availability of the precursor chemicals necessary to manufacture them. Most drugs, whether they plant-based or synthetic, require chemicals to change them into the final product. While chemical are only one of the components required for the illicit manufacture of plant-based drugs like heroin and cocaine, ‘they constitute the essential components of illicitly manufactured synthetic drugs.”

NPS are found throughout the globe. Of the 103 countries that gave information for the World Drug Report, 94 countries reported the emergence of some kind of NPS in their markets. The increase from August 2012 to December 2013 of newly identified NPS was mostly due to new synthetic cannabinoids (50% of newly identified new psychoactive substances) followed by new phenethylamines (17%), other substances (14%) and new synthetic cathinones (8%). See the following chart from the 2014 World Drug Report.

figure 60Reviewing this report on worldwide drug use reminds me that getting high is an everywhere problem. This year the transition from pharmaceutical painkillers to heroin and the higher cultivation levels of opium poppies suggests a pending increase in heroin addicts and overdose deaths. The rapid explosion of new psychoactive substances onto the drug scene in the past few years feels like a “back to the future” move to the days of patent medicines, when heroin was a cough suppressant and cocaine was a toothache cure. Teething medications contained morphine. Coca-Cola (with cocaine) was a temperance drink and tonic, “a cure for all nervous affections.”

Cannabis is becoming more potent and toxic just as legalization movements gain steam and increase its use and availability. Coca eradication efforts that seemed to have had an effect on the cocaine market are to be suspended—perhaps leading to a resurgence in cocaine use. Getting high is an everywhere problem and it seems like it’s not going away anytime soon.

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.