Pill Pushing©

The letter that kicked off the opioid epidemic - (12/1/2018)

By Dr. Ron Gasbarro

One would have to be living in a sack thrown down a hole at midnight not to know there is an ongoing war against opioids. Just as the invasion of Poland by Nazi Germany started World War II and the Iraqi invasion of Kuwait launched Desert Storm, the war on opioids started with a single act. A letter, which at 101 words, was less than half the length of the Gettysburg Address, a speech aimed to reunify a nation divided by its Civil War. A letter that ignited an epidemic that has, thus far, killed over 630,000 Americans – and counting. A letter that has shortened life expectancy for the last 3 years.

Table 1 – United States military casualties of war [DeBruyne, 2018]

Rank

War

Years

Deaths

1

War on Opioids

1999-present

630,000+

2

World War II

1941–45

291,557

3

American Civil War

1861–65

214,938

4

World War I

1917–18

53,402

5

Vietnam War

1955–75

47,424

6

Korean War

1950–53

33,686

7

American Revolutionary War

1775–83

8,000

8

Iraq War

2003–2011

3,836

9

War of 1812

1812–15

2,260

10

War in Afghanistan

2001–present

1,833


This letter appeared in the New England Journal of Medicine on January 10, 1980.
“Recently, we examined our current files to determine the incidence of narcotic addiction in 39,946 hospitalized medical patients [Jick, 1970] who were monitored consecutively. Although there were 11,882 patients who received at least one narcotic preparation, there were only four cases of reasonably well-documented addiction in patients who had no history of addiction. The addiction was considered major in only one instance. The drugs implicated were meperidine in two patients [Miller, 1978], Percodan in one, and hydromorphone in one. We conclude that despite widespread use of narcotic drugs in hospitals, the development of addiction is rare in medical patients with no history of addiction.”
Jane Porter
Hershel Jick, M.D.
Boston Collaborative Drug Surveillance Program Boston University Medical Center, Waltham, MA 02154


Nearly 40 years ago, a respected doctor wrote a letter with some very good news: Out of almost 40,000 patients given powerful pain drugs in a Boston hospital, only 4 addictions were documented. Doctors had been wary of opioids, fearing patients would become hooked. Reassured by the letter, which called this "rare" in those with no history of addiction, physicians pulled out their prescription pads and spread the good news in their own published reports. And that is how a one-paragraph letter with no supporting information helped seed a nationwide epidemic of misuse of drugs like Vicodin® and OxyContin® by convincing doctors that opioids were safer than we now know them to be, according to a 2017 CBS News report. It turns out that they are not safe at all. 

The terrifying numbers
In 2017, 70,237 drug overdose deaths occurred in the US [CDC/NCHS, 2018]. The age-adjusted rate of overdose deaths increased significantly by 9.6% from 2016 (19.8 per 100,000) to 2017 (21.7 per 100,000). Opioids—mainly synthetic opioids (other than methadone)—are currently the main driver of drug overdose deaths. Opioids were involved in 47,600 overdose deaths in 2017 (67.8% of all drug overdose deaths).

Also in 2017, the states with the highest rates of death due to drug overdose were West Virginia (57.8 per 100,000), Ohio (46.3 per 100,000), Pennsylvania (44.3 per 100,000), the District of Columbia (44.0 per 100,000), and Kentucky (37.2 per 100,000) [Scholl, 2018]. States with statistically significant increases in drug overdose death rates from 2016 to 2017 included Alabama, Arizona, California, Connecticut, Delaware, Florida, Georgia, Illinois, Indiana, Kentucky, Louisiana, Maine, Maryland, Michigan, New Jersey, New York, North Carolina, Ohio, Pennsylvania, South Carolina, Tennessee, West Virginia, and Wisconsin [CDC/NCHS, 2018].

The epidemic has shortened human life expectancy
Life expectancy in the US has now declined for 3 years in a row, fueled largely by a record number of drug overdose deaths, reports the National Center for Health Statistics (NCHS) [NCHS, 2018]. Infants born today now can expect to live 78.6 years on average, based on 2017 data, according to NCHS researchers, a decrease from 78.7 years in 2015 and 78.9 years in 2014. There were a total of 2.8 million US deaths in 2017, almost 70,000 more than the previous year, the NCHS stated.

Life expectancy at birth decreased by 0.2 years between 2014 and 2015, which was the first drop seen since 1993. It then decreased another 0.1 years between 2015 and 2016. The opioid epidemic likely plays a large role in the continuing decline with a record 70,000 deaths linked to drug overdoses in 2017 alone. The age-adjusted death rate for drug overdoses in the US increased 72% between 2006 and 2016, to stand at 19.8 by 2016. It then rose by another 9.6% in 2017, and now stands at nearly 22 deaths per 100,000. The rates for 2018 have not yet been reported.

Terminology – Are they opiates or opioids?
Traditionally, “opiates” referred to natural derivatives of opium, whereas “opioids” referred to synthetic drugs with similar properties. Today, the words are used interchangeably. In addition, “narcotic” used to refer to opiates and opioids but now is used to refer to practically any illegal drug. 

What is opiophobia? 
Due to the intense regulation of controlled substances, the US government at both the federal and state level has caused an alarming effect on prescribers’ eagerness to write for powerful medications that would ease the pain of these patients [Moldovan, 2012]. No prescriber wants to lose his/her license overwriting a prescription that another health caregiver could just as easily write. Consequently, patients who need these medications suffer unnecessarily.

This fear of prescribing opioid analgesics is known as “opiophobia.” It is the opposite of overprescribing. Either healthcare providers refuse to prescribe opiates at all, or they prescribe far too little — at doses far too low to alleviate the pain. This phenomenon of opiophobia is widespread in the US, and it results in patients with moderate-to-severe intractable pain being unable to obtain the necessary medication to live a tolerable life.

Case study 
Joe, 33, was hit by a drunk driver, was propelled through his windshield, and was left with severe head and back injuries [Moldovan, 2012]. These injuries resulted in relentless chronic pain. Joe went to almost 20 different healthcare providers, none of whom was willing to give him adequate pain medication. Instead, they gave him antidepressants and anti-inflammatory drugs. As a result, Joe became suicidal. Fortunately, Joe found another healthcare provider who was willing to prescribe the opioid medications required for him to function without the unbearable pain. Subsequently, that same prescriber came under investigation for his use of opiates to treat his patients’ pain. Eventually, the doctor will have to make a choice, and Joe will be the one who suffers.

Reasons why addicts are jumping from pills to heroin 

Heroin is an opioid drug made from morphine, a natural substance taken from the seedpod of the various opium poppy plants grown in Southeast and Southwest Asia, Mexico, and Colombia. Heroin can be a white or brown powder, or a black sticky substance known as black tar heroin. Other common names for heroin include big H, horse, hell dust, and smack. Research suggests that misuse of these drugs may open the door to heroin use. Nearly 80% of Americans using heroin (including those in treatment) reported misusing prescription opioids first [Muhuri, 2013; Jones, 2013]. According to narconon.org, there are four main reasons why addicts switch from pills to heroin.

Heroin is a good substitute for prescription painkillers
The most common prescription painkillers on the market, including hydrocodone (Vicodin®) and oxycodone (OxyContin®, Percocet®), are actually opioid drugs, just like heroin. All of these drugs are derived from opium. Heroin has similar effects to painkillers in terms of the high that users’ experience, making it an ideal substitute for those looking for a way to replace their painkillers.

Heroin is cheaper than pain pills
Once a person is hooked on painkillers, he or she is tied into an enormously expensive habit. At anywhere from $60 to $100 per pill, needed several times a day. A single dose of heroin usually costs around $10, depending on the city where it is purchased. [Chart #x]

Heroin is easier to find
Prescription painkillers are so widely abused throughout the US that overdosing on pain meds now kills more Americans than both heroin and cocaine combined. With so many people suffering from addiction to these powerful medications, state legislatures, law enforcement, and medical regulatory agencies are taking measures to crack down and prevent the drugs from being abused.. One example is the implementation of statewide prescription monitoring programs that keep track of how many painkiller prescriptions that doctors write. This makes it harder for unscrupulous physicians to operate as “pill mills,” selling prescriptions to people who want to get high. The drugs are now far more difficult to obtain, whereas heroin can easily be found both in the city and in the suburbs.

Heroin is easier to use
People who abuse painkillers do not simply swallow the pills. To get high on Vicodin or OxyContin, the pill must be crushed into a powder so that it can be snorted or injected in a dissolved solution. To fight back against painkiller abuse, many of the pharmaceutical drug companies have begun formulating their pills in ways that make them harder to crush. The new version of Oxycontin, for example, cannot easily be ground to a fine powder but instead breaks up into chunks. Even if an addict is successful in dissolving the pill in water, it cannot be injected. Instead, the resulting fluid is a gelatinous glop. Conversely, heroin is delivered as a fine powder that is ready to be mixed for immediate use. 

For these reasons, heroin abuse rates are on the rise following the colossal explosion in the numbers of prescriptions written for opioids over the past decade.

Naloxone
How it works
Many states have increased access to naloxone, a drug that can save lives when administered during an overdose. According to the Centers for Disease Control and Prevention (CDC), naloxone is a non-addictive drug that can reverse the effects of an opioid overdose when it is given in time. The drug works by binding to opioid receptors in your body and reversing or blocking the effects of opioids like heroin, morphine, or hydrocodone, among others. People die of opioid overdoses because the drug binds to receptors on nerve cells that control breathing. Naloxone displaces the opiate from the receptors that are on the nerve cells that control respiration, and the victim is quickly revived. There are a few ways it can be administered.

Evzio auto-injector: This is the first auto-injector approved for non-clinical settings and has a retractable needle that, when a button is pressed, sticks the person who needs naloxone. The auto-injector is to be used on the thigh and can go through the person’s clothes.
Nasal spray: Insert the tip of the spray into one nostril of someone who has overdosed and squirt it.
Injection via syringe: Inject Naloxone into the muscle of the upper thigh or upper arm. Naloxone is time-dependent, meaning it is more effective the earlier it is administered. People will generally die within 1 to 3 hours after an overdose happens, so it is crucial to get the drug to them ASAP [Giglio, 2015]. In some cases, such as when a person overdoses on fentanyl—a highly potent drug that is increasingly being added to street heroin by drug dealers—one dose of naloxone may not be enough. However, the first responder can give the victim additional doses of naloxone until they are revived—if they actually have more than one dose on-hand.

If an OD victim is identified and given Naloxone, call emergency responders right away. Naloxone is only active in the body for 30 to 90 minutes and its effects could wear off before those of the opioids, causing the user to stop breathing again. The obvious benefit is that naloxone can save someone’s life: The drug reversed at least 26,500 opioid overdoses from 1996 to 2014 [Wheeler, 2015]. 

A review of emergency medical services (EMS) data from Massachusetts found that when given naloxone, 93.5% of people survived their overdose. The research looked at more than 12,000 dosages administered between July 1, 2013, and December 31, 2015. A year after their overdose, 84.3% of those who had been given the reversal drug were still alive. However, it also means that once saved from an overdose by EMS, a patient had about a 1 in 10 chance of not surviving a year. About 35% of those who were dead a year later died of an opioid overdose. A good way to describe naloxone is to compare it to a defibrillator when someone’s heart stops – the drug can save a life but it does not treat the underlying condition, that is, addiction to opioids.

How it might not work
Undoubtedly, naloxone has saved many lives. On the other hand, naloxone access may unintentionally increase opioid abuse through two channels: 
Reducing the risk of death, thereby making riskier opioid use more appealing
Saving the lives of active drug users, who survive to continue abusing opioids
By increasing the number of opioid abusers who need to fund their drug purchases, naloxone access laws may also increase theft. 
A recent study has challenged the idea that naloxone is always beneficial [Doleac, 2018]. The study revealed that expanding naloxone access has led to more opioid-related emergency room visits and more opioid-related theft, with no reduction in opioid-related mortality. For example, the most negative effects were seen in the Midwest, with a 14% increase in opioid-related mortality. Other evidence suggests that broadening naloxone access increased the use of fentanyl. 

FDA approves new treatments for opioid addiction for 2017-18
The United States Food and Drug Administration (FDA) recently approved several drugs to help fight opioid addiction. Read how these new drugs can help aid and kick the addiction.

Zubsolv®
This first new drug combines buprenorphine and naloxone, both of which have been used to treat opiate addiction [Heo, 2018]. Zubsolv, made by Swedish drugmaker Orexo, is a tablet that dissolves under the tongue and comes in a menthol flavor. Like other treatments, Zubsolv is to be used as a maintenance treatment with counseling and psychosocial support, for those suffering from opiate addiction. Others like Suboxone®, Subutex®, and Bunavail™ come as film strips to be dissolved under the tongue. They have been introduced over the last decade and are also highly effective in helping patients with their opioid dependence.

However, beware of treatment abuse of these treatments, for they can also lead to addiction. Popularly prescribed Suboxone has produced its own addiction epidemic as well as a few deaths from abusing it. These particular treatments are to be placed under the tongue. However, patients have been known to dissolve the film in water and inject the drug directly into the bloodstream, causing complications and death. This is why Zubsolv is considered a step forward. As a tablet, it cannot be dissolved as easily.

Probuphine®
The FDA has also approved a buprenorphine implant called Probuphine that will provide a constant low-level dose for 6 months to patients who are already on a complete treatment program [Barnwal, 2017]. The drug consists of 4 one-inch rods that are implanted in the skin of the forearm. The reason for the implant is that, as with taking any pill, they are easily forgotten or skipped, making the recovery journey that much more uneven. This way, the patient need not worry about the daily pill.

Lucemyra™
The other opioid withdrawal drug is lofexidine hydrochloride, which is the first non-narcotic and non-addictive medication of its kind approved by the FDA [Gorodetzky, 2017]. In the United Kingdom, it has been used to successfully detoxify more than 200,000 opiate addicts. Lucymyra suppresses the release of adrenaline in the body’s nervous system, thereby reducing some of the withdrawal symptoms. It does not reduce the cravings. This drug is an adrenergic receptor agonist, which means that it stimulates the central nervous system’s receptors to produce a physical reaction – the lessening of the withdrawal symptoms, such as:
Diarrhea
Muscle pain
Stomach cramps
Sweating
Vomiting

Sublocade™
While the majority of options for buprenorphine are sublingual or taken orally, the FDA recently announced its approval of an injectable form of buprenorphine under the brand name Sublocade. Touted as a long-term maintenance drug for opioid dependence, Sublocade offers a few key benefits over oral suboxone: [Aschenbrenner, 2018]
First, Sublocade is slowly and steadily released into the bloodstream over the course of a month, and injections are only needed once per month.
Second, since the injection must be given by medical professionals, it is more likely that patients will keep on schedule and receive their medications at exactly the times recommended. This also makes sure that drug diversion (selling the medication on the streets to others) is not possible, and only the patient meant to receive the medication will receive it.
Sublocade is recommended strictly for the ongoing maintenance of opioid dependence, and not for the early stages of treatment, such as detox. In fact, professionals state that because the initial treatment phases use tapering and dose changes to meet the needs and comfort levels of patients, Sublocade would not be a good fit for anyone who has not already been through the initial treatment phases. However, for those who have completed initial treatment, however, and are looking for a long-term opioid maintenance solution, this option may be a literal life-saver.

Could a vaccine work to stop addiction? 
Researchers have been experimenting with various vaccine formulations that would make it impossible for a recovering addict to get high, should that person relapse and seek their drug of choice. Scientists began working on a vaccine since the 1990s when fentanyl became a national problem. With this latest epidemic of opiate abuse, interest in a polyvalent vaccine – one that will attack several types of drugs – is now renewed [Raleigh, 2018; Hwang, 2018; Raleigh, 2017]. The vaccine would work by teaching the body’s immune system to attack various drug molecules as they enter the bloodstream but before making it into the opioid receptors in the brain. 

For example, Bremer and colleagues sought to test whether a vaccination approach might be a way to combat heroin addiction [Bremer, 2017]. They designed a vaccine that contained part of the heroin molecule, which trained the immune system in monkeys to produce antibodies against heroin. The vaccine was able to neutralize heroin and prevent the heroin high feeling for up to 8 months. Anti-heroin immunity continued to improve over time with the administration of booster shots. The researchers' next aim is to test the vaccine in human trials.

Dr. Jick’s response to his 1980 letter
“I’m essentially mortified that that letter to the editor was used as an excuse to do what these drug companies did,” Jick told the Associated Press in a May 31, 2017 interview. “They used this letter to spread the word that these drugs were not very addictive,” Jick said his letter only referred to people getting opioids in the hospital for a limited time and had no bearing on long-term outpatient use. He also said he testified as a government witness in a lawsuit years ago over the marketing of pain drugs.

In 2017, the New England Journal of Medicine published an editor’s note about the 1980 letter and analysis from Canadian researchers of how often it has been cited — more than 600 times, often inaccurately [Leung, 2017]. Most prescribers used it as evidence that addiction was rare, and most did not say it only concerned hospitalized patients, not outpatient or chronic pain situations such as bad backs and severe arthritis for which opioids came to be used. 

The authors of the 2017 statement stated, “We found that a five-sentence letter published in the Journal in 1980 was heavily and uncritically cited as evidence that addiction was rare with long-term opioid therapy. We believe that this citation pattern contributed to the North American opioid crisis by helping to shape a narrative that allayed prescribers’ concerns about the risk of addiction associated with long-term opioid therapy. In 2007, the manufacturer of OxyContin and three senior executives pleaded guilty to federal criminal charges that they misled regulators, doctors, and patients about the risk of addiction associated with the drug [Meier, 2007].

Yet, the fight against opioid addiction continues to be harder fought with each coming year.

Ron Gasbarro, PharmD, is a registered pharmacist, medical writer, and principal at Rx-Press.com. Read more at www.rx-press.com

References

Aschenbrenner DS. New route for buprenorphine administration. Am J Nurs. 2018;118:23.

Barnwal P, Das S, Mondal S, Ramasamy A, Maiti T, Saha A. Probuphine® (buprenorphine implant): a promising candidate in opioid dependence. Ther Adv Psychopharmacol. 2017;7:119-34. 

Bremer PT, Schlosburg JE, Banks ML, Steele FF, Zhou B, Poklis JL, Janda KD. Development of a clinically viable heroin vaccine. J Am Chem Soc. 2017;139:8601-11.

CDC/NCHS. Multiple cause of death 1999–2017 on CDC Wide-ranging Online Data for Epidemiologic Research (CDC WONDER). Atlanta, GA: CDC, National Center for Health Statistics. 2018. Available at http://wonder.cdc.gov 

Doleac JL, Mukherjee, A. The moral hazard of lifesaving innovations: naloxone access, opioid abuse, and crime. SSRN. 2018. Available at: https://ssrn.com/abstract=3135264 
 
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