INTRODUCTION

“This downward trend (in life expectancy) could be reversed if we make progress in controlling the COVID-19 pandemic and opioid epidemic.”¹

--Robert H. Shmerling, MD, Senior Faculty Editor, Harvard Health Publishing

 

Data on life expectancy in the United States (U.S.) has been collected since 1900 and, with rare exceptions, has consistently increased.^1,2 Life expectancy in 1900 was 47 years, reached 68 years in 1950, and by 2019, had risen to 79 years.¹ However, in 2020 it fell to 77 and dropped again in 2021 to 76, the sharpest two-year decline in almost 100 years.^1,3

 

Many factors contributed to the decline in life expectancy in the U.S., which was not seen in other parts of the world. These include diseases of the heart and liver, but about two-thirds of the decline can be accounted for by increased rates of COVID-19, drug overdoses, and accidental deaths.^1,4 This reflects a continuation of disturbing trends in increases in what are termed “deaths of despair” (chronic pain, drug and alcohol dependency, and suicides).⁴

 

Harm reduction approaches have been shown to be effective in addressing public health epidemics including preventing death, injury, disease, overdose, and substance misuse.⁵ Harm reduction emphasizes direct engagement with people who use drugs to improve their physical, mental, and social well being, and prevent overdose and infectious disease transmission. It also simplifies accessing substance use disorder treatment and other health care services.⁵

 

Pharmacists have played an important role over the past few years in reducing the harm from COVID through vaccination, testing, and offering anti-viral drugs.⁵ Public health efforts to reduce tobacco consumption contributed significantly to the increase in life expectancy during the 1990s and 2000s, as fewer people died from complications related to smoking and nicotine.² Community pharmacists contributed to this successful effort by providing support to individuals trying to stop smoking.⁶ Can pharmacists also help reduce the harm associated with the record number of drug overdose deaths?

 

This continuing education activity will review some harm reduction strategies that may be useful in coping with the drug overdose epidemic and describes current legal and regulatory issues that may be barriers to more widespread application.

 

PAUSE AND PONDER: How can pharmacists reduce harm from opioids?

 

OPIOID CRISIS

 

Drug overdose deaths have become the number one cause of accidental deaths in the U.S., surpassing even motor vehicle mishaps.⁷ Deaths from drug overdose have risen dramatically, increasing from 16,849 in 1999 to a new record of 104,000 in the 12-month period ending February 2022.⁸ These numbers represented more than a 6-fold increase over this period. The overwhelming majority of drug overdose deaths are associated with an overdose of an opioid. In 2020, approximately three of four overdose deaths involved opioids,⁹ compared with an opioid-related impact of 50% in 1999.¹⁰

 

The modern opioid crisis has occurred in three waves (so far).  The first wave began in 1996 and was largely due to overdose from prescription opioids, fueled by what was perceived to be a widespread problem of undertreatment of chronic pain.¹¹ Health care providers began prescribing more opioid pain relievers and the increased supply and diversion to non-medical use created an opportunity for more overdoses.^11,12

 

This was addressed by clamping down on opioid prescribing. The overall national opioid dispensing rate significantly declined after 2012; by 2020, the dispensing rate had fallen to its lowest level in 15 years.⁶ Despite these efforts, overdose deaths from prescription opioids were higher in 2021 (16,706) than they were in 2012.¹³

 

Opioid overdose deathrates have continued to soar, suggesting that other factors have emerged and measures in addition to reducing supply are necessary to confront the epidemic.

 

The second wave began around 2010 as prescription opioids became harder to obtain and heroin’s price dropped; heroin became more attractive and popular.^12,14 The third and current wave started in 2013 and is associated with an increased supply of illicitly manufactured and trafficked synthetic opioids, especially fentanyl and its analogs.^12,14 (Evidence indicates a fourth wave is materializing characterized by polydrug abuse, typically the use of illegally manufactured opioids in combination with psychostimulants such as cocaine and methamphetamine.^12,15)

 

DECREASING SUPPLY

 

As noted, it was believed that an oversupply of prescription opioids was fueling the overdose crises. (Indeed, opioid prescriptions per capita increased 7.3% from 2007 to 2012 and 259 million prescriptions for opioid analgesics were written in 2012 alone, roughly one prescription for every adult in the U.S.¹⁶) Abatement efforts were geared towards reducing the supply and diversion of opioids. These “supply side” approaches include prescribing limits, prescription drug monitoring programs (PDMPs), and regulation of pain clinics.¹⁷

 

This approach corresponded with the development of an opioid prescribing guideline by the Centers for Disease Control and Prevention (CDC) in 2016, which provided recommendations for primary care clinicians prescribing opioids for chronic pain outside of active cancer treatment, palliative care, and end-of-life care.¹⁶ The guideline’s focus on when to initiate or continue opioids for chronic pain; assessing risk and addressing harms of opioid use; and opioid selection, dosage, duration, follow-up, and discontinuation is detailed in Table 1.

 

Table 1.  Summary of Centers for Disease Control and Prevention Guideline

Clinicians should

• Prescribe the lowest effective dosage when initiating opioid therapy
• Use caution when prescribing opioids at any dosage
• Carefully reassess benefits and risks when increasing dosage to 50 morphine milligram equivalents (MME)/day
• Avoid increasing dosage to 90 MME/day

 

Many states codified these voluntary recommendations through statutes or regulations that imposed enforceable limitations on medical professionals’ ability to prescribe or dispense opioids for pain treatment.¹⁸ The number of states with such restrictions increased from ten in 2016 to 39 by the end of 2019. States differed in their limits. At the end of 2019, the most common duration limit was seven days, with a range of three to 31. Fourteen states imposed limits on the daily dosage of opioids that could be prescribed, ranging from 30 MME to 120 MME.¹⁸

 

Enforced application of the CDC guideline, which was meant to serve as a guide for primary care providers, led to fewer opioid prescriptions along with reduced dosages, opioid tapering, and discontinuation of treatment among patients prescribed long-term opioid therapy.¹⁹ These actions resulted in multiple adverse outcomes including poor pain control and mental health issues for some patients. It forced many patients with pain to seek illicit sources as an alternative source of relief and resulted in an accompanying increase in overdose deaths.¹⁹

 

The most significant illicit substance emerging as the primary driver of the current overdose is fentanyl. Although technically a prescription drug, fentanyl’s primary source in overdose situations derives from illicit manufacture and importation.²⁰

 

Fentanyl is a powerful mu-opioid receptor agonist that is 75–100 times more potent than morphine.²¹ Fentanyl rose to prominence as an alternative to morphine as an analgesic and anesthetic for surgeries more than 50 years ago due to its rapid onset, short duration of action, high potency, and limited cardiovascular risks compared to morphine. The potential for fentanyl misuse was initially believed to be minimal but it has emerged as a dangerous recreational substance.²¹ Although the media commonly describes it as a recent phenomenon, fentanyl has been used as a contaminant in illicit drug supplies since at least 1979.²² Fentanyl and its analogs have become the predominant factor in drug overdose deaths, accounting for almost two-thirds of overdose fatalities in 2021.²²

 

Fentanyl is sold by itself and is also used as an adulterant in other products due to its high potency which permits dealers to traffic smaller quantities that retain the expected opioid effect.^20,22 It is much more profitable for dealers to cut a kilogram of fentanyl compared to a kilogram of heroin. The drug is also made into counterfeit pills that resemble legitimate prescription opioids.²⁰ Since there is no regulatory oversight nor quality control, the pills can contain lethal quantities of fentanyl.²⁰

 

The COVID-19 pandemic made matters worse. Social isolation, loss of economic opportunity, boredom, despair, disruption of normal routines, and political polarization increased distress. Simultaneously, it became more difficult to access treatments, resources, and emergency services that help people suffering from opioid use disorder (OUD).^19,23,24 Lockdowns and distancing efforts made it less likely that an individual who overdosed would be discovered and given rescue naloxone in time to prevent lasting injury or death.²⁴ The decreased access to interventions and treatment led some patients to seek remedies on their own.¹⁹

 

In addition, COVID-19 mobility restrictions made it more challenging to smuggle illegal drugs into the country and border restrictions made it harder to move bulkier drugs.²⁵ As a result, smugglers increased their reliance on fentanyl which, due to its potency, can be transported in small quantities and is easier to traffic by mail.^22,25 This helped increase fentanyl’s availability in areas of the U.S. that had not previously been as impacted by the drug.²⁵ Prior to the pandemic, fentanyl mainly affected urban areas in the eastern regions of the U.S. where it could be easily mixed with the powdered heroin popular there.²⁵ Mortality rates from synthetic opioids more than doubled every two years in 28 states between 1999 and 2016; in Washington, D.C., mortality from opioids more than tripled every year from 2013-2016.²⁶

 

HARM REDUCTION MEASURES

 

It is apparent that reducing supply has had limited success in reversing the upward trend in overdose deaths. Could another strategy be more successful? It is generally believed that harm and demand reduction strategies can contribute to stemming the opioid overdose crisis.^5,17,23 Relevant harm reduction activities that can lessen the risk of adverse outcomes associated with drug misuse include medical treatment of OUD, provision of sterile syringes, overdose prevention sites, fentanyl testing, safe supply, overdose education, expanded availability of naloxone, and Good Samaritan laws.^5,17,23 However, harm reduction approaches are underutilized; the CDC estimates that two-thirds of drug overdose deaths in 2021 had at least one potential opportunity for intervention.⁹

 

Medication Assisted Treatment of Opioid Use Disorder

 

Substance use disorders (SUD) are chronic conditions associated with many biologic, environmental, and social conditions.²⁷ SUD frequently co-occurs with other mental illnesses including depression, anxiety, and post-traumatic stress disorder; half of people with mental illnesses will have an SUD at some point in their lives.²⁷

 

OUD is a persisting and often relapsing condition requiring long-term care that is adjusted to meet individual patients’ needs by allowing changes in treatment designed to address fluctuations in symptomology.^27,28 OUD requires medical and psychosocial therapy similar to the treatment of other chronic disorders.^27,28 Opioid withdrawal, although very unpleasant and uncomfortable, is rarely life-threatening and is characterized by autonomic hyperactivity, and signs and symptoms which include anxiety, insomnia, nausea, vomiting, diarrhea, cramping, back pain, hot and cold flashes, and lacrimation.^27,28 Treatment is generally directed at alleviating these signs and symptoms of withdrawal.^27,28

 

Currently, three medications in the U.S. are Food and Drug Administration (FDA)-approved for use in Medication Assisted Treatment (MAT) of OUD:  methadone, buprenorphine, and naltrexone.²⁹ Medically supervised withdrawal or detoxification can both improve the patient’s health and facilitate participation in a rehabilitation program.³⁰ It can also help patients accept abstinence from opioids after the acute withdrawal phase has subsided.³⁰

 

Traditionally, medically supervised withdrawal was only offered as a hospital-based treatment of varying duration. Today, medically supervised withdrawal is most often provided in outpatient and residential treatment settings and is usually managed by tapering doses of an opioid agonist or partial agonist over a period of between one week to several months. ^27,28 Slower reductions over longer periods of time generally lead to less illicit use during the medically supervised withdrawal. Longer duration of treatment allows restoration of social connections and is associated with better outcomes.^28,31

 

Studies have suggested that MAT reduces overdose mortality by 3- to 4-fold, reduces the incidence of HIV and hepatitis-C transmission by half, doubles adherence to HIV antiviral therapy, and reduces drug-related crime. ^27,28 However, it is usually not sufficient to produce long-term recovery by itself and may also increase the risk of overdose due to a loss of tolerance following abstinence.³⁰

 

Medically supervised withdrawal can also involve the use of nonopioid medications on an off-label basis to help control symptoms. α2-adrenergic agonists such as clonidine (Catapres), tizanidine (Zanaflex), or lofexidine (Lucemyra) can decrease anxiety, piloerection (erection or bristling of hairs due to the involuntary contraction of small muscles at the base of hair follicles, often called goose bumps), and other signs and symptoms of autonomic overactivity.^27,28,30 Adjunct therapy with medications such as anti-anxiety drugs, analgesics, sleep aids, anti-emetics, and anti-diarrheal products can also decrease the predominant withdrawal symptoms and decrease discomfort. ^27,28

 

Long-Acting Opioid Agonists: Methadone and Buprenorphine

 

Prescribing a long-acting oral opioid, such as methadone or buprenorphine, is the most effective approach to treating a patient who is experiencing withdrawal.³⁰ These treatments relieve symptoms. Gradually reducing the dose allows the patient to adjust to the absence of an opioid.

 

Oral methadone has the strongest evidence for effectiveness. Methadone has been used since 1964 when it was introduced as a medical response to the post-War heroin epidemic in New York City and its use has spread to many countries.^27,28,32 Methadone is a full opioid agonist and N-methyl-D-aspartate receptor antagonist producing dose-dependent analgesia and sedation, with a risk of respiratory depression in overdose. It has a long half-life relative to abused forms of opioids, averaging about 24 hours with a variable range of 12-50 hours.³¹ It is typically delivered under direct daily supervision, at least initially, and treatment usually begins with a low dose that is slowly escalated.^27,28

 

Methadone maintenance is used to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with opioids. Treatment occurs for an indefinite period, since methadone maintenance is considered corrective rather than curative for addiction.³²

 

When methadone is discontinued, it can lead to withdrawal which may be protracted due to its long duration of action.^27,28 Consequently, methadone treatment is gradually reduced over several weeks or months. Methadone is primarily metabolized by CYP3A (along with CYP2D6 and CYP1A2) and inhibitors and inducers of these enzymes can affect therapy. ^27,28

 

Although methadone is highly effective as an MAT, it has certain disadvantages related to being a full mu-receptor agonist.³³ First, it has the potential to produce or maintain opioid dependence creating a risk of abrupt withdrawal if a patient misses a scheduled dose. This can be discouraging to patients who are trying to detoxify. In addition, there is no ceiling (or leveling off of effect) to the level of respiratory depression or sedation produced by a full agonist, and this can lead to fatal overdose.³³

 

An alternative to methadone is buprenorphine which has a different pharmacologic profile. It is a partial agonist at mu-opioid receptors, an antagonist of kappa and delta opioid receptors, and an agonist at opioid-like receptor-1 (nociceptin).³⁴ Despite being a partial agonist, it reportedly produces analgesic efficacy comparable to that of full μ-opioid receptor agonists in moderate to severe post-operative pain and pain associated with cancer.³⁴ It shares the beneficial properties of methadone being orally active with a long functional half-life (20 to 73 hours) and produces similar improvement of opioid withdrawal while producing less respiratory depression and sedation.³⁰ Buprenorphine maintenance may also result in a gentler withdrawal phase and the possible option of alternate-day dosing, due to its long duration of action.³⁴ However, as a partial agonist, it can produce a competitive antagonism of a concurrently administered full opioid agonist.  Buprenorphine should be initiated at least 12 to 18 hours after the last dose of opioids in patients who misuse shorter-acting drugs to avoid precipitating abrupt and more intense withdrawal.³⁰

 

Buprenorphine is also available as a combination with the opioid antagonist naloxone, which minimizes intravenous misuse.³¹ Due to the low oral bioavailability of naloxone, it produces little opioid antagonism when the combination is taken orally or sublingually. However, if the preparation is crushed and injected, naloxone will block the reinforcing effects of buprenorphine and may also precipitate opioid withdrawal in a dependent individual.³¹

 

Studies comparing buprenorphine and methadone have reported mixed results, some showing no difference in efficacy between the two therapies, some showing methadone to be superior, and others finding buprenorphine to be superior.³³

 

Opioid Antagonists

 

Opioid antagonists block the reinforcing effects of opioids and help maintain opioid abstinence in highly motivated patients.³⁰ Naltrexone is an orally active long-acting mu- and kappa- opioid receptor antagonist, with effects lasting 24 to 36 hours.^27,28,30 It is also available as an extended-release intramuscular injectable form with effects lasting one month.³⁰ Oral naltrexone is used to treat both OUD and alcohol use disorder.³⁶ However, oral naltrexone is not commonly prescribed for OUD because there is poor compliance and evidence suggests that it may not be more effective than placebo in treating OUD. Since naltrexone can precipitate withdrawal in opioid-dependent individuals, it is recommended that patients wait at least seven days after their last use of short-acting opioids and 10 to 14 days for long-acting opioids, before starting naltrexone.^27,28,30,36 This presents a challenge for patients. An FDA-approved Risk Evaluation and Mitigation Strategy (REMS) that includes a Medication Guide is required for the long acting injectable, but it may otherwise be prescribed and administered by any practitioner licensed to prescribe.³⁶

 

Pharmacists are familiar with the protype opioid antagonist, naloxone, which is also an important harm reduction measure. Naloxone is a short acting antagonist originally used by injection to reverse opioid-induced postoperative respiratory depression and later used to reverse potentially fatal respiratory depression in individuals who overdosed on opioids.³⁶ Earlier rescue drugs such as nalorphine and levallorphan were partial agonists and, unlike naloxone, produced some respiratory depression.³⁷

 

Naloxone’s onset of action in adults is less than two minutes when administered intravenously, and its apparent duration of action is on the order of 20 to 90 minutes; significantly, this is a shorter duration than that of many opioid agonists⁸⁸ so that in some cases, the antagonism may decay before the agonist has been fully eliminated, placing users at risk of delayed respiratory depression.³⁹ In other words, naloxone reverses the effect of the agonist drug but since naloxone wears off quickly, there can still be sufficient drug in the system to re-initiate the toxicity.

 

Pharmacists should note that medication treatments are also being developed and evaluated for other types of drug misuse, such as naltrexone plus buprenorphine for methamphetamine use disorder.²⁷

 

Regulatory Issues

 

In the early 1900s, opiate drugs could be easily obtained from pharmacies. Diacetylmorphine, synthesized in 1874, was not often prescribed before 1900, but favorable reports of its effects stimulated interest from the medical profession.⁴⁰ The German pharmaceutical company Bayer (yes, the aspirin people) started commercial production of the compound in 1898 and marketed it under the name, “Heroin.”⁴⁰

 

Heroin was considered to be a “wonder drug” and the medical profession enthusiastically received it. The interest in heroin was prompted by the high occurrence of tuberculosis and other respiratory diseases and the need to find an effective remedy for cough and to induce sleep. Heroin was also believed to combat morphine addiction, but the inaccuracy of this approach became apparent after a few years.⁴⁰

 

The drug quickly caught the attention of criminal elements and smugglers who recognized that its rewarding properties surpassed those of morphine, the then-dominant abused drug.⁴⁰ Heroin also had the advantage of being able to be delivered by sniffing without the complications associated with intravenous injection.⁴⁰ A new societal problem emerged.

 

The Harrison Act passed in 1914 brought about one of the first federal controls on opioids. The Act regulated “narcotics” (defined as opiates and cocaine) by imposing a special tax upon anyone who produced, imported, manufactured, sold, dispensed, distributed, or compounded these substances.⁴¹ It mandated special order forms and record keeping whenever narcotic drugs were sold and products could only be provided from packages bearing a government stamp.⁴²

 

Physicians interpreted regulatory terms such "legitimate medical purposes," "professional practice," and "prescribed in good faith” to mean that they could provide narcotics to ease the suffering of withdrawal in addicts who were regarded as having a disease.⁴² However, the Treasury Department interpreted the Harrison Act to mean that any prescription for an addict for the purpose of relieving the trauma of addiction was illegal, and the Courts supported this position.⁴²  Consequently, the only source available for an addict to obtain narcotics was through illegal means and physicians who used opioids to treat addicts risked federal and/or state criminal prosecution.^42,43 A law intended to regulate commerce effectively led to criminalization of OUD treatment.

 

In 1972 the US Food and Drug Administration (FDA) approved methadone treatment for OUD and established methadone maintenance as a legitimate medical practice.^43,44 However, concern about methadone diversion and accidental overdose fatalities, combined with political pressure from government agencies and groups committed to drug-free treatments, led to the development of detailed and unprecedented FDA regulations.⁴³ The Narcotic Addict Treatment Act in 1974 created the first federal law governing methadone for OUD while state and local governments placed additional regulatory requirements on methadone.^44,45 Congress granted the Drug Enforcement Agency (DEA) additional oversight of methadone treatment programs. Both the DEA and existing treatment providers have resisted efforts to relax the FDA regulations.⁴³

 

Administration of opioids to treat opioid-use disorders can only be performed by licensed addiction-treatment programs (either office-based or inpatient treatments) or by physicians who have completed specific opioid drug training.³⁰ Medical providers (physicians or advance practice providers such as physician assistants or nurse practitioners) may not use their DEA registration to prescribe methadone for OUD, but they can prescribe methadone tablets as a treatment for chronic pain.⁴⁵

 

Federal law also requires an in-person medical evaluation prior to patient enrollment in an opioid treatment program (OTP).⁴⁵ Initially, patients receiving methadone must return to the clinic a minimum of six days per week for medication administration with appropriate supervision for at least the first 90 days of treatment.⁴⁵ Afterwards, they can qualify for additional take-home doses under certain conditions. After the first 90 days the take home supply may increase to two doses per week. After 180 days, they may receive three take home doses per week. By 270 days, they may qualify for six take home doses per week for the remainder of the first year. In the second year of continuous treatment, a patient may be given a maximum 2-week supply of take-home medication. In the third year, a patient may be given a maximum one-month supply of take-home medication, but must make monthly visits. States have the authority to further restrict administration and dispensing policies.^44.45

 

However, in response to the COVID-19 pandemic, some impediments to methadone treatment were relaxed. In March 2020, the Substance Abuse and Mental Health Services Administration (SAMHSA) issued guidance allowing states to request that patients who are on a stable methadone dose be permitted to receive 28 days of take-home medication, and for patients who are less stable to receive 14 days of take-home medication.²⁴

 

In contrast, buprenorphine can be prescribed by certified physicians, without the requirement for direct supervision of administration since diversion is associated with significantly less risk of fatal overdose than methadone.³¹

 

Patients being treated with MAT also encounter the restrictions of the Ryan Haight Act, named after a minor who overdosed on a controlled substance he obtained over the Internet with a prescription from a physician who did not conduct a proper medical examination. The law requires practitioners issuing a prescription for a controlled substances to first conduct an in-person medical evaluation.⁴⁶

 

During the COVID public health emergency, the DEA waived the requirement that patients receiving buprenorphine must have an in-person consultation with a prescriber and permitted the consultation to occur via telemedicine.²⁴

 

PAUSE AND PONDER: Should pharmacists be involved in facilitating access to OUD medications?

 

The Drug Addiction Treatment Act of 2000 (DATA) was enacted to permit physicians who meet certain qualifications to treat opioid dependence with FDA-approved C-III – C-V opioid medications, including buprenorphine, in treatment settings other than OTPs.⁴⁷ DATA restricted the outpatient treatment of OUD with buprenorphine to clinicians receiving an “X- [or DATA] waiver.”⁴⁸  To receive the waiver, clinicians were required to attend an eight hour training session and submit a Notice of Intent to SAMHSA; other eligible practitioners, including nurse practitioners and physician assistants, were required to obtain an additional 16 hours of training.^48,49 Pharmacists and X Prescriptions were required to have the prescribers’ X-number in addition to their DEA registration number and pharmacists were expected to verify a practitioner's certification, but there were no other requirements for pharmacists beyond those for other Schedule III medications, such as special credentials.

 

In 2023, the Mainstreaming Addiction Treatment Act (MAT Act) eliminated the need for a special waiver to treat patients with OUD.⁵⁰ Any practitioner with current DEA registration that includes Schedule III authority may prescribe buprenorphine for OUD. The MAT Act also removed other federal requirements associated with the waiver. However, pharmacists should be aware that state requirements may differ.⁴⁹

 

Naloxone has also transitioned, becoming a more readily available substance. The FDA approved naloxone in 1971 as a prescription-only medication for intravenous, intramuscular, and subcutaneous administration to reverse postoperative respiratory depression induced by opioid analgesics.^36,51 Overdose rescue was originally limited to emergency departments, but its use expanded to first responders and distribution by community groups to individuals with OUD or their family and acquaintances for emergency use.⁵² Reluctance to administer the drug with a needle led to improvised homemade intranasal naloxone delivery devices.⁵¹ FDA approval of a standardized, pre-assembled intranasal delivery form in 2015 significantly improved and simplified naloxone use.⁵³ Pharmacists in all states were also granted authority to dispense naloxone through collaborative agreements or blanket standing orders.⁵⁴ The FDA approved naloxone for OTC distribution in 2023.⁵⁵

 

Safer Injection

 

Another harm reduction strategy is to make the experience of injecting opioids safer. Several different approaches may enhance the safety of injections.

 

Needle/Paraphernalia Exchange

Syringe services programs (SSPs) are community-based prevention programs which are thought to be a critical component of harm reduction interventions for injectable drug users.^56,57 SSPs provide access to and disposal of sterile syringes and injection equipment and may also include offering referrals to medication-assisted treatment, as well as vaccination, testing, and links to care and treatment for infectious diseases.⁵⁶ The majority of new hepatitis C virus infections are related to injection drug use and 10% of new HIV infections in the U.S. are attributed to injection drug use. Infections occur because needles, syringes, or other equipment used for injections may be contaminated with blood that can carry viruses. HIV can survive in a used syringe for up to 42 days, depending on temperature and other factors.⁵⁸ In addition, people under the influence of substances are more likely to engage in risky sexual behaviors which can increase the risk of transmitting an infection.^56,57

 

SSPs have the added benefit of protecting the public and first responders by facilitating the safe disposal of used needles and syringes. Many SSPs also provide “overdose prevention kits” containing naloxone.^56,58

 

Safe Injection Facilities

Safe injection facilities (SIF; AKA overdose prevention centers, supervised consumption services, supervised injection facilities, drug consumption rooms, or safe havens) provide a sanctioned, safe space where people can inject drugs obtained elsewhere in a controlled setting under the supervision of trained staff with a goal of preventing fatal overdoses.^59,60 Staff at the facility do not directly assist with injections or handle any drugs brought in by clients, but are present to provide sterile injection supplies, answer questions on safe injection practices and vein care, administer first aid if needed, and monitor for overdose. Participants can also receive health care and general medical advice, counseling, and referrals to health and social services, including drug treatment options.^59,60

 

SIFs have operated in Europe since the 1980s.⁵⁹ They generally target high-risk, socially marginalized injectable drug users who would otherwise inject in public spaces or shooting galleries. Reports generally show that SIFs have led to fewer risky injection behaviors and fewer overdose deaths among clients, increased enrollment in drug treatment services, and reduced the incidence of public nuisances associated with open injection.⁵⁹ Although SSPs reduce the risks associated with contaminated needles and syringes, they do not address the harm created by users’ fear of the criminal justice system and stigma.⁵⁹

 

In the U.S., states and some municipalities have the power to authorize SIFs under state law, However, they are still prohibited by the federal Controlled Substances Act.^59,81 A Philadelphia non-profit planned to open consumption sites where individuals could inject controlled substances under supervision, but the Department of Justice (DOJ) sought to prevent it.⁶¹ The DOJ argued that a “consumption room” is intended to be a place where people consume drugs and would therefore be in violation of the CSA which prohibits any person from knowingly and intentionally maintaining a place for the purpose of illegal drug use. The District Court ruled that the CSA does not apply, but the decision was reversed on appeal. The Appellate Court ruled that the safehouse would violate the law because people will visit its facility with the purpose of using drugs. The law requiring CSA oversight of places where there is illegal drug use was originally passed to shut down crack houses. Despite the organization’s “admirable” motives and the need for “innovative solutions” to combat the opioid crisis, the court held that “courts are not arbiters of policy” and “local innovations may not break federal law.”⁶¹ The decision was appealed to the Supreme Court, but they rejected the request to hear the case; some issues are still pending.

 

In November 2021, New York City opened the first supervised injection site in the U.S., six weeks after the Supreme Court decision.⁶² In its first three months, approximately 800 people used the center more than 9500 times and it averted at least 150 overdoses. The site supplies syringes, alcohol wipes, straws for snorting, other paraphernalia, and oxygen and naloxone in case of an overdose.⁶² A few other cities and the state of Rhode Island have also established a pilot program for safe injection sites.⁶²

 

Despite the results in the Philadelphia court case, the DOJ has indicated a willingness to relax its opposition to safe sites, saying that it was evaluating them and discussing “appropriate guardrails.”⁶² Some members of Congress have expressed opposition to permitting sites to operate and a former DEA official has stated that “the goal has to be to stop doing drugs” and encourage treatment.⁶²

 

Safer Supply Prescribing

 

Another possible risk mitigation approach that could impact pharmacists is safer supply prescribing. This expanding movement in Canada allows prescribers at recognized sites to write prescriptions for government-funded, pharmaceutical-grade products, primarily opioids.^63,64 The most commonly offered products at the sites studied were injectable and tablet hydromorphone, and medical grade heroin.⁶³ Some clinics are supplying pharmaceutical-grade fentanyl to offset the unregulated street supply.⁶⁴ One site delivers medication to multiple clients quarantined in a motel.⁶³

 

Pharmacy models included hospital-based pharmacies and partnerships with a service site to either provide the site with medication or provide it directly to clients.⁶³ In some instances, users can select their own pharmacy. There are also machine-dispensed services offering prescribed opioids for up to 15 clients without the barriers of daily observation or check-ins.

 

This practice is currently illegal in the U.S. but has its advocates such as a Yale addiction medicine physician who said “(w)e need to be doing everything possible to try, at a minimum, to make a dent in the unrelenting deaths that in large part have been due to changes in the unregulated drug supply.”⁶⁴

 

Some preliminary studies have suggested that these programs can lower overdose risk. Providing drugs to participants when other treatment strategies haven’t worked can reduce illicit drug use, reduce emergency department visits and hospital admissions, and connect users to care.⁶⁴

 

Critics, including addiction specialists, argue that users should be directed toward treatment for their dependence and that providers should focus on reducing drug use rather than providing drugs. Some people are concerned about the potential for diversion and have likened these programs to the overprescribing of opioids that initially helped fuel the overdose crisis.⁶⁴

 

PAUSE AND PONDER: Would you participate in a safe supply program?

 

Test Kits

Another approach to harm reduction is the use of test strips that can detect contaminants such as fentanyl in street drug samples.⁶⁵ Test strips are prefabricated strips of a carrier material containing dry reagents that are activated by applying a fluid sample. They can detect the presence of substances within a matter of minutes.⁶⁶ Strips are available to detect many different illicit drugs and are similar to commonly used test kits for detecting pregnancy, failure of internal organs (e.g., heart attack, renal failure, or diabetes), infection or contamination with specific pathogens, or the presence of toxic compounds in food or the environment.⁶⁶ The strips rely on a lateral flow chromatographic immunoassay technology for the qualitative detection of fentanyl and many analogs at concentrations above 200 ng/mL.⁶⁷ The strips have no significant cross reactivity to other opiates and the interpretation of test results is simple: positive (one line), negative (two lines), invalid (no lines or no control line).⁶⁷

 

The strips were created in 2011 to detect prescription fentanyl in urine as part of a clinical identification of recent drug use. As fentanyl was found more frequently in analyses from drug overdoses, the harm reduction community began using the tests off-label, especially in syringe services sites, to test samples. This empowered drug users to understand what substances they were consuming, making them safer.⁶⁸ A study of drug users in North Carolina found that receiving a positive test result was associated with changes in drug use behavior and perceptions of overdose safety.⁶⁸ Behavioral changes included using less drug, administering a test shot, injecting more slowly, or snorting the sample instead of injecting it. They introduce an element of caution for the drug user.⁶⁹

 

The use of test strips is restricted in many areas. It is clearly legal to possess some or all drug checking equipment in 22 states, and clearly legal to distribute it to adults in 19 states.⁶⁵ In 14 states where distribution of drug checking equipment is not generally legal, it is legal when the equipment is obtained from a syringe services program.⁶⁵ Tools used to detect fentanyl are classified as drug paraphernalia in more than a dozen states, making it a crime to possess or distribute them.⁷⁰ These state laws emerged in the 1970s at the urging of the DEA claiming that distributing paraphernalia serves to facilitate drug use. Many states continue to maintain a hardline posture.⁷⁰ While laws define drug paraphernalia broadly, they are not always rigorously enforced.⁶⁸ However, violators may face potential penalties ranging from small civil fines to multi-year jail sentences.⁶⁵

 

PAUSE AND PONDER: What reservations might you have about advising a patient to purchase fentanyl test strips?

 

Although these devices have some legal restrictions, demand in the U.S. has grown more than 430% in the past three years.⁷¹ They are becoming available in clubs, bars, restaurants, and pizza shops and are frequently distributed for free. Some advocates equate strips to condoms as a public health measure. The FDA warns that it doesn’t actively regulate fentanyl test strips, which places the burden of determining their reliability on buyers.

 

The strips are available from Amazon and can be obtained from public vending machines in some areas.

 

SUMARY AND CONCLUDING COMMENTS

 

The opioid overdose crisis continues to worsen. Despite many efforts over the past decade to reduce the supply of prescription opioids, overdose deaths continue to climb from drugs obtained via illicit sources.  While efforts to reduce supply continue, there are also attempts to institute harm mitigation programs. However, existing laws and regulations can make accessing these measures difficult.

 

Recent efforts have eased the prescribing and use of MAT. This provides pharmacists with a potential opportunity to become more involved with SUD treatment. MAT is underutilized with evidence suggesting that only 13% of people with drug use disorders receive any treatment, and more than half of those with co-occurring conditions receive treatment for neither. Other measures involving pharmacists include increased naloxone access, and availability of test kits in pharmacies.

 

More controversial models have also gained some acceptance, but strong opposition remains. Pharmacists are or may become involved with programs such as needle/syringe exchange, safe sites, and, as aways, there are opportunities for education and counseling. Pharmacists should also be prepared for the possible, albeit unlikely, introduction of the Canadian model of supplying pharmaceutical grade opioids and other controlled substances to users.

 

Pharmacists have demonstrated value in implementing harm reduction strategies for many disease states and interested pharmacists should be prepared to be involved with the growing number of opportunities to reduce the opioid overdose crisis.

 

Download CE Activity

INTRODUCTION

 

Congress, in order to reduce the black market in illegal drugs, should begin taking incremental steps toward making drugs less of a criminal justice responsibility and more of a public health responsibility.¹

--Former Baltimore Mayor Kurt L. Schmoke

 

Has the time arrived for the incremental steps that Mayor Schmoke envisioned more than 30 years ago? One does not need to look any further than marijuana, which has been a tightly controlled substance in the U.S. for more than 85 years but is rapidly gaining acceptance as a medical product and a permissible intoxicant.^2,3 It is likely that many pharmacists are supportive of this regulatory movement and may even have “experimented” with this Schedule I drug while in school. But what about something like cocaine? “That won’t happen,” you say? Then you should be aware that Oregon passed a law in 2020 that reduced the penalty for the unauthorized possession of less than two grams of cocaine to the payment of a small fine.⁴

 

Other states, municipalities, and countries have also begun taking steps towards loosening or eliminating penalties for prohibited recreational substances, in some cases including other drugs currently listed in Schedule I of the Controlled Substances Act (CSA). Is this the start of a new national trend leading to a relaxation of restrictions on previously controlled substance and perhaps even to someday permit retail sales? Will the future of drug control start to look more like the 1890s than the 1990s?

 

This continuing education activity will review national and international regulation of controlled substances and some changes that governments are enacting or considering to loosen their control. Do these events indicate that society’s view of controlled substances and use disorders—and pharmacy’s role—are evolving?

 

Pause and Ponder: Will biennial controlled substance inventories and the familiar red “C” go the way of manual typewriters and become relics of a bygone era?

 

REGULATION OF CONTROLLED SUBSTANCES

 

Historical Perspective

In the 19^th Century, what we now call controlled substances were readily available in retail locations. In the 1890s, the Sears and Roebuck catalog (that’s the 19^th Century Amazon for our younger readers) offered a syringe and a small amount of cocaine for purchase for $1.50⁵ (equivalent to about $50 today). Individuals could also order the tonic, Wine of Coca, a mixture of coca-leaf extract and Bordeaux wine, which was promoted as “a genuine rich wine ... well known throughout Europe for its strengthening and nourishing qualities” at retail for 95 cents.⁵ In addition to cocaine, consumers could also openly purchase morphine and heroin from catalogs, apothecaries, and physicians. ⁵

 

The popularity of cocaine-infused beverages, tonics, and powders grew in the late 1800s, and were generally held to have therapeutic value for a variety of conditions, including headache and fatigue, constipation, nausea, asthma, and impotence.⁶ Most pharmacy personnel are probably aware that a pharmacist in Atlanta, John Pemberton, took advantage of prohibition being enacted in parts of Georgia and replaced the wine in Wine of Coca with a sugary syrup and added a kola-nut extract containing caffeine in 1886.⁷ He named the concoction Coca-Cola and described it as a temperance drink.⁷

 

Although frequently denied by the company, Coca-Cola contained a small amount of cocaine (and likely the precursor, ecgonine) and became one of the world’s most popular tonic/beverage sold at retail, often at pharmacy soda fountains.^6,8 Early in the 20^th Century, public opinion about cocaine began to turn negative and the company (by then owned by another pharmacist, Asa Candler), tried to remove cocaine from the beverage but it would not become completely cocaine-free until 1929 when newer extraction methods were developed.⁶

 

Recently, the well-known billionaire, Elon Musk, jokingly(?) tweeted “Next I’m buying Coca-Cola to put the cocaine back in.”⁸ Current legislative changes discussed below suggest that this notion is not so far-fetched.

 

During the early part of the 20^th Century, there were no federal agencies that regulated medical and pharmacy practice, and physicians could freely prescribe cocaine and morphine as treatment for pain.⁹ Drug abuse became increasingly common and emerged as a significant social and public health issue, and a less permissive attitude towards drugs began to take hold.⁹

 

The first federal law to ban the non-medical use of a substance was the Smoking Opium Exclusion Act in 1909; it prohibited the possession, importation, and use of opium for smoking, although it could continue to be used medically.¹⁰ A more significant step was the passage of the Harrison Narcotic Tax Act in 1914 which regulated “narcotics” (defined as opiates and cocaine) by imposing a special tax upon anyone who produced, imported, manufactured, sold, dispensed, distributed, or compounded these substances.¹¹ Note that the act was an economic regulation to comply with treaty obligations and did not directly prohibit the use nor sale of opiates and cocaine.¹

 

The Harrison Act required physicians and pharmacists who prescribed or dispensed “narcotics” to be registered and pay a fee of $1 to $24 per year^11,12 (equivalent to $29 to $700 today). The act mandated special order forms and record keeping whenever narcotic drugs were sold. They could only be provided from packages bearing a government stamp.¹²

 

By using the federal government’s taxing power to restrict the use of opiates to professional practices, the Harrison Act effectively created the first class of prescription drugs.¹¹ (The Food Drug and Cosmetic Act in 1938 formally established prescription-only drugs and the 1951 Durham-Humphrey Act [sponsored by two pharmacist-legislators] gave the U.S. Food and Drug Administration (FDA) authority to designate which drugs would require prescriptions.¹³)

 

After 1919, oversight by the Treasury Department expanded to define the scope of professional practice.¹¹ Previously, physicians interpreted terms in the act such as “legitimate medical purposes,” “professional practice,” and “prescribed in good faith” to mean that they could provide narcotics to ease the suffering of withdrawal in addicts who were regarded as having a disease.¹² However, the Treasury Department interpreted the Harrison Act to mean that any prescription for an addict for the purpose of relieving the trauma of addiction was illegal, and the Courts supported this position.¹² Consequently, the only source available for an addict to obtain narcotics was through illegal means.¹²

 

The law also established the first federal narcotics agents, although their enforcement powers were limited. The Federal Bureau of Narcotics (FBN) was established in 1930 and was given the authority to enforce the Harrison Act and other anti-drug laws and later also oversaw the Marijuana Tax Act (see below).¹⁴ President Herbert Hoover appointed Harry J. Anslinger to be Commissioner of Narcotics, a position he would hold under four U.S. presidents for more than three decades. He became the face of the government’s hardline approach to eradicate drug abuse.¹⁴

 

Later, the 18^th Amendment of the Constitution and the Volstead Act banned the manufacture, transportation, or sale of alcohol in 1919.^10,15 (By this time, many states had already banned the sale of alcohol.) Prohibition was overturned by the 21^st Amendment in 1933.

 

By 1930, 30 states had also prohibited the use of marijuana, beginning with California in 1913 and Utah in 1914.¹⁶ (Ironically, California became the first state to approve the medical use of marijuana 83 years later.) In 1937, Congress passed the Marihuana Tax Act which was modeled after the Harrison Act.⁵⁵ The law didn’t specifically criminalize the use or possession of marijuana, but it required practitioners register and pay a tax, and imposed a fine of up to $2000 (about $40,000 today) and five years in prison for non-payment.^10,17 There is a widely held feeling that the push for stricter control of marijuana was fueled by non-health concerns. Those concerns included

• commercial interests
• anti-immigrant and racial bias
• exaggerated fear about violence and crime
• hysteria about the drug’s alleged contribution to moral decay, and
• pressure from the Federal Bureau of Narcotics

All of these factors played major roles in the push for stricter control of marijuana.^17,18 Such feelings persist today and are part of the effort towards deregulation. The Act was ruled unconstitutional in 1969 in a suit brought by Harvard psychology professor and psychedelic guru, Timothy Leary.¹⁹

 

Today, drugs subject to abuse are regulated by the Controlled Substances Act (CSA), signed into law by then-President Richard Nixon in 1970, which, among other things, established the now-familiar five schedules. This will be discussed further below.

 

REGULATION OF RECREATIONAL DRUGS – INTERNATIONAL

 

The United States is a party to three United Nations (U.N.) drug control treaties²⁰:

• the 1961 Single Convention on Narcotic Drugs
• the 1971 Convention on Psychotropic Substances, and
• the 1988 Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.

These are designed to establish effective control over international and domestic trafficking in opiates, coca leaf, cocaine, marijuana, stimulants, depressants, and hallucinogens by limiting the international production and trade of psychotropic substances and their chemical precursors.^9,20 The treaties also establish international mechanisms to monitor treaty adherence.²⁰ More than 95% of U.N. Member States are participants in these international treaties.²⁰ Under the CSA, treaty obligations may require the U.S. Attorney General to control or reschedule a substance if existing limits in the U.S. are less stringent than those required by a treaty.⁹

 

Despite these international agreements, more than two dozen countries have moved toward some form of decriminalization of recreational drugs.²¹ The SIDEBAR differentiates decriminalization and legalization.

 

SIDEBAR: Decriminalization and Legalization

Decriminalization is not the same as legalization.

 

When a drug is legalized, it may be restricted but there is no punishment for possession or use. Typically, regulations may exist regarding where and how the legal drug can be produced, sold, and consumed. Criminal or civil penalties may apply if production, sale, or consumption take place outside of regulations (think alcohol).

 

When a drug is decriminalized, possession and use are still “illegal” but, there are no criminal penalties (e.g., incarceration) for use or possession. Instead, there may be civil penalties (e.g., fines, or mandated treatment or educational programs), and usually, possession limits. In addition, use or possession do not lead to a criminal record that might affect employment, housing, or travel opportunities if a substance is decriminalized. Selling or manufacturing drugs would normally still carry criminal penalties.²²

 

 

Most people will bring up the Dutch city of Amsterdam when discussing lax drug policies. Indeed, people 18 years of age or older can purchase marijuana and other “soft” drugs (magic mushrooms, Salvia, Peyote cactus) legally and openly in coffee shops and other establishments in The Netherlands. .²³ Smoking tobacco products are also tolerated in public places except near schools or playgrounds.

 

Dutch drug policy rests on two principles.²³ (Note that Dutch policy applies nation-wide, but most people think of Amsterdam when this topic arises.) One is the fundamental belief that all human beings may decide about matters relating to their own health and includes acceptance of euthanasia for terminally ill patients. The other is that concealing socially negative phenomena does not cause those practices to disappear and instead makes them far more difficult to influence and control.

 

The Dutch divide drugs into two groups, soft and hard drugs, based on their human health impact. Hard drugs such as cocaine, LSD, morphine, and heroin are forbidden in the Netherlands. Soft drugs are tolerated but strict laws limit quantities, conditions of sale, and use. For example, driving under the influence of a soft drug is treated similarly to driving under the influence of alcohol. Large scale growing, processing, and trading in marijuana is forbidden, but Dutch courts bestow milder penalties than in most other countries.²³

 

Another frequently cited model is Portugal. On July 1, 2001, Portugal became the first country in the world to decriminalize all drugs, including methamphetamine and heroin, removing the distinction between soft and hard drugs.^24,25 Possession is decriminalized for personal use within certain limits, depending on the drug.²⁴ Generally, the limits are based on a hypothetical 10-day supply for an average individual.²⁵ Drug use became an administratively sanctionable misdemeanor under the responsibility of the Ministry of Health, rather than involving law enforcement.²⁵ The intent of the law was to focus police resources on those who profit from the drug trade, rather than their victims, while also providing a public health approach to drug users.²⁴

 

Individuals caught possessing drugs for personal use in Portugal are sent to a commission composed of health experts and a legal expert.²⁶ The commission evaluates the person’s drug use and, if necessary, will refer them to voluntary treatment. (While most treatment is voluntary, in some cases, the commission can choose to issue a fine or mandate some form of therapy.) Additionally, the country expanded access to treatment and harm reduction services like needle exchanges.²⁶

 

However, selling drugs is still illegal. Portuguese law considers it a crime if someone produces, buys, or transports an illicit drug that is above the legal amount for personal use.²⁴ For example, possession of more than 5 grams of hashish could potentially lead to arrest and prosecution for drug trafficking. A conviction for drug trafficking in Portugal can be subject to between one and five years in prison.²⁴

 

Beginning January 31, 2023, drug users 18 years of age and older in British Columbia, Canada who possess up to 2.5 grams of illegal drugs for personal use will not be arrested, charged, nor have their drugs confiscated.²⁷ Drugs include heroin, fentanyl, cocaine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy). While those substances will remain illegal, police will offer users information on available health and social services. The province said it asked for the change in its request to the Canadian government for the drug laws exemption in order "to remove the shame that often prevents people from reaching out for life-saving help."²⁷

 

Canada’s intent is to use the province as a potential model for similar changes elsewhere in the country as part of a multi-faceted health-based strategy to end Canada’s drug overdose crisis, which reached record highs during the COVID-19 pandemic. The program has some exemptions; it will not apply to drug use on primary and secondary school grounds, child-care facilities, airports, or to members of Canada's military. The pilot program is set to run until January 31, 2026.²⁷

 

On the other hand, some countries have very harsh drug laws. In Malaysia, you can be fined, jailed, or deported for having drugs in your possession and those who sell drugs can be punished with death.²⁸ Execution is also the penalty for some drug crimes in China, Vietnam, and The Philippines. In Dubai, you can be imprisoned for possession of many prescription drugs that are legal in other parts of the world and failing a drug test can be grounds for incarceration even if the individual is not in possession of any drugs.²⁸ In Russia, even Americans in possession of vape cartridges containing hashish oil can be subject to arrest and detention, as WNBA star Brittney Griner discovered.²⁹

 

U.S. RECREATIONAL DRUG REGULATION

 

Controlled Substances Act

As noted above, in the early 1900s, drugs could be purchased at retail outlets with few, if any, limitations. Strong restrictions emerged later in the 20^th Century. In the 1960s, attention was being paid to a medical approach to preventing and treating drug abuse along with a powerful emphasis on law enforcement.⁹ By 1969, newly elected President Richard Nixon made reducing drug abuse, especially heroin abuse, one of his top priorities.⁹ Nixon feared that drugs were undermining the integrity of America’s youth and was convinced that abuse and addiction gave rise to crime, the biggest issue in his 1968 campaign.³⁰ Nixon sensed a need to restore control to a broken system and declared a “war on drugs.” Dismissing the current laws as “inadequate and outdated,” he called for a single, modern law to confine drug use to legitimate medical purposes.³⁰

 

One weapon in the war was the enactment of the CSA.⁹ The CSA was part (Title II) of an omnibus bill (a proposed law covering a number of diverse or unrelated topics) called the Comprehensive Drug Abuse Prevention and Control Act of 1970. The new legislation offered a more systematic approach to regulation of abused drugs and provided additional law enforcement resources.⁹

 

Congress, in enacting the CSA, dealt with two competing interests related to drug regulation.³¹ They recognized that while improper use of controlled substances can be detrimental to Americans' health and general welfare, many of these substances have a useful and legitimate medical purpose and are necessary to maintain health and well-being. The Act simultaneously aims to protect the public from the dangers of controlled substances while also ensuring access for legitimate purposes.³¹ To achieve both goals, the statute created two complementary legal schemes. One provision required individuals and entities working with controlled substances to register with the government, report certain information to regulators, and have a responsibility to prevent diversion and misuse of controlled substances.³¹ The act also contained provisions to prevent trafficking in controlled substances by establishing penalties for the production, distribution, and possession of controlled substances outside the legitimate scope of the registration structure.³¹ CSA policies that were intended to curtail illegitimate use of these drugs included prescription refill limitations, security standards, recordkeeping requirements, order forms, production quotas, and the registration of importers and exporters of controlled substances.^11,30 The new law was, however, not exclusively punitive; it eliminated mandatory minimum sentences for drug crimes.³⁰

 

Moreover, Title I of the comprehensive act had more of a public health focus.³⁰ It provided authority and funding to permit the Department of Health, Education, and Welfare to deliver prevention and treatment efforts through community mental health centers and public health service hospitals. It authorized the National Institute of Mental Health to increase substance abuse research and training.³⁰ It also protected subjects’ privacy rights under the care of approved researchers.

 

Over the next few decades, public concern over drug abuse increased and Congress responded by enacting policies that created a harsher system of drug control and served as a basis of the ensuing “War on Drugs.” ³⁰ Congress repeatedly amended the law to address the heightened concern, and it became more punitive and criminally focused and less directed towards rehabilitation and improved treatment.³⁰

 

A new Federal Agency, the Drug Enforcement Administration (DEA), was created in 1973 to enforce the new law. This was done in part to coordinate federal and state enforcement activities and to reduce inter-agency rivalries.^9,30 After the CSA was enacted, there were nearly 500,000 importers, exporters, manufacturers, distributors, and practitioners covered by the law, making the DEA the largest administrative agency in the U.S.¹¹

 

Scheduling

The centerpiece of the CSA, as pharmacists are aware, was the creation of a scheduling system that provided a means for assigning regulated substances into one of five categories based upon the drug’s medical risks, therapeutic use, and potential for abuse and dependence.^9,31 The classification system also establishes the obligations and penalties of the law.³¹ The most restrictive category is Schedule I which is comprised of drugs with high potential for abuse, but no accepted medical use.³² The placement of a drug in a schedule is fluid, and drugs can be moved to a different schedule, either up or down, added to the controlled substances list, or deleted.³⁰ Any individual, not just regulatory officials or health care providers, can request that the DEA add, remove, or change a drug’s scheduling.⁹

 

In determining into which schedule a drug or other substance should be placed, or whether a substance should be re-scheduled or decontrolled, certain factors must be considered. The DEA is required to seek a scientific and medical evaluation of the substance from the Department of Health and Human Services  to apply what is known as the eight-factor test when determining scheduling.³² These factors are

(1) Its actual or relative potential for abuse
(2) Scientific evidence of its pharmacological effect, if known
(3) The state of current scientific knowledge regarding the drug or other substance
(4) Its history and current pattern of abuse
(5) The scope, duration, and significance of abuse
(6) What, if any, risk there is to the public health
(7) Its psychic or physiological dependence liability
(8) Whether the substance is an immediate precursor of a substance already controlled

 

These criteria help to stratify the seriousness of the public health concern among the controlled substances. Will new regulatory strategies remove these distinctions?

 

PAUSE AND PONDER: Do the “C” schedules serve a purpose?

 

DECRIMINALIZATION – STATE AND LOCAL ACTIONS

 

While the general trend at the federal level for the past five decades has been a toughening of the restrictions on abused drugs, especially opioids, one exception is marijuana. States have led the way by actively relaxing restrictions on marijuana, first by legalizing medical use and later permitting limited non-medical use.

 

The medical use of marijuana has been legalized in 37 states plus the District of Columbia (D.C.), Puerto Rico, Guam, the Northern Mariana Islands, and the U.S. Virgin Islands.³³ The medical marijuana movement began in California in 1996, but it wasn’t until 2012 that Colorado and Washington became the first two states to decriminalize the non-medical use of marijuana (for people 21 years of age or older).³³ (California voters had rejected a proposition in 2010.) In the 2022 election, two additional states, Maryland and Missouri, approved the recreational use of marijuana. bringing the total up to 21 (plus D.C.) although similar proposals were rejected in Arkansas, North Dakota, and South Dakota.³³

 

Beyond Marijuana

 

More recently, states and municipalities have gone beyond marijuana and have decriminalized other controlled substances. In May 2019, Denver, Colorado became the first governmental entity in the U.S. to decriminalize a (non-Cannabis) Schedule I drug, the psychedelic ingredient from mushrooms, psilocybin.³⁴ The proposal was placed on the municipal ballot after garnering almost 9500 petition signatures and was supported by 50.5% of voters in the election.³⁴ Denver was also the first major U.S. city to legalize the possession of small amounts of marijuana in 2005.³⁴

 

The new ordinance states that the “enforcement of any laws imposing criminal penalties for the personal use and personal possession of psilocybin mushrooms... shall be the lowest law enforcement priority in the City and County of Denver.” It mandates that “no department... shall use any city funds or resources to assist in the enforcement of laws imposing criminal penalties for the personal use and personal possession of psilocybin mushrooms by adults.”³⁵ Adult is defined as an individual 21 years of age or older.

 

One advocacy group (Decriminalize Denver) noted its support for the ordinance by stating that “Humans have used these mushrooms for thousands of years for healing, rites of passage, spiritual insight, strengthening community, and raising consciousness.” Decriminalize Denver has argued that “One arrest is too many for something with such low and manageable risks for most people, relative to its potential benefits.”³⁴ In contrast, opponents have warned that “Denver is quickly becoming the illicit drug capital of the world” and that the long-term health effects of these drugs are unknown.³⁴

 

Other municipalities have followed the same path as Denver. Oakland and Santa Cruz, California also decriminalized psilocybin in 2019 and 2020, respectively. In both cases, their respective City Councils took the action rather than mounting a referendum.^36,37 The Santa Cruz ordinance is very similar to what was enacted in Denver preventing resources from being used to investigate and arrest people 21 years of age and older solely for the personal use and possession of “entheogenic plants and fungi”³⁷ (a psychoactive, hallucinogenic substance or preparation especially when derived from plants or fungi and used in religious, spiritual, or ritualistic contexts³⁸). Community testimony from people sharing mental health struggles and treatment likely contributed to the Council’s decision. Santa Cruz later extended its policy and banned enforcement actions against individuals using peyote and other mescaline-containing cacti. Oakland also decriminalized mescaline cacti, ayahuasca and ibogaine.³⁹ The City Council in Ann Arbor, Michigan also unanimously approved mushroom decriminalization in 2020.⁴⁰

 

Voters in Washington D.C. also approved similar measures in 2020, termed the Entheogenic Plant and Fungus Policy Act, which would decriminalize natural psychedelics including magic mushrooms, ayahuasca, and mescaline, and makes arrests for their possession or use the lowest priority for DC police. Due to D.C.’s unique status, implementation of the act was delayed for Congressional review and approval. D.C. received approval in 2021 but not before one member of Congress threatened to derail the process.⁴¹

 

In late 2021, Seattle became the largest city (to date) to decriminalize Schedule I psychedelic drugs.^39,42 The City Council unanimously passed a resolution that “the investigation, arrest, and prosecution of anyone engaging in entheogen-related activities should be among The City of Seattle’s lowest enforcement priorities.” Its City Council asked the city’s police department to codify that practice as departmental policy.³⁹ The resolution was limited to natural substances, notably psilocybin and ayahuasca, and later peyote; it excluded synthetic materials such as LSD.^39,42 In support of its approval, the resolution noted both the therapeutic potential of psychedelics and protection of indigenous peoples who use these compounds for cultural and spiritual practices.⁴² More than 100 additional cities are moving to decriminalize psychedelic mushrooms.⁴³

 

States are also supporting decriminalization measures and Oregon is at the forefront of these activities. In the 2020 election, voters in the state passed two companion referenda that significantly changed the state’s drug policy. Measure 109 approved the use of a psychedelic mushroom for medical use by authorizing the Oregon Health Authority to create a program to permit licensed service providers to administer psilocybin-producing mushroom and fungi products to individuals 21 years of age or older.⁴⁴ The new law will allow anyone age 21 or older who passes a screening procedure to access the services for “personal development."⁴⁵ A client does not need to be diagnosed with or have any particular medical condition to receive psilocybin. Clients would complete a preparatory session and then attend a session at a psilocybin service center where they would receive and consume the psilocybin product under the supervision of the service facilitator.⁴⁴

 

Unlike the cities that decriminalized psychedelic drugs for personal use, the Oregon measure took a medical approach with the purpose of improving the physical, mental, and social well-being of people in the state and reducing the prevalence of mental illness conditions among adults who have not been helped by more mainstream therapies.^44,46 The measure restricts psilocybin sales to licensed service providers and does not permit sales directly to users. Individual counties can opt out of the program.⁴⁶

 

In the 2022 election, Colorado became the second state to approve psychedelics.⁴⁷ The proposition legalizes regulated access to natural medicines for people 21 years of age or older, including plants or fungi that impact an individual's mental health and provides civil and criminal immunity for providers and users.⁴⁷

 

Pharmacy staff should note that there is a growing interest in the potential therapeutic applications of psychedelic drugs to help many psychiatric disorders and these may become FDA-approved pharmaceutical products.⁴⁸

 

While several municipalities and states have authorized the decriminalization of mushrooms and other psychedelics and justified their actions due to their healing and spiritual value, there have been other movements to expand decriminalization beyond those with potential medical benefits.

 

In the same election that decriminalized mushrooms, voters in Oregon approved another measure (110) to become the first state to lighten penalties for possession of both large and small amounts of a wide assortment of scheduled substances.⁴

 

Under the new law, the penalty for possession of larger amounts of controlled substances was reduced from a felony offense to a Class A misdemeanor punishable by up to 364 days of imprisonment and a fine of up to $6,250. For possession of smaller amounts of controlled substances, the measure reduced the penalty from a criminal misdemeanor to a new, Class E violation, which is punishable by a $100 fine. In lieu of a fine, a person charged with a violation may instead complete a health assessment at an Addiction Recovery Center.⁴

 

The threshold differentiating large from small amount are defined for different substances. For cocaine, the Class E violation applies to unauthorized possession of less than two grams. For oxycodone, it is unauthorized possession of fewer than 40 pills, tablets, or capsules. Someone in possession of less than 1 gram heroin would be subject to the new Class E penalty.⁴ The new measure also removes penalty enhancements for possession of small amounts of controlled substances where the individual previously had a felony conviction or multiple previous convictions for possession.^4,45

 

The new program is loosely based on Portugal’s model, described above, but was modified in accordance with recommendations from Oregon’s recovery community.²⁶ Oregon’s approach will focus on diversion and harm reduction for people who use drugs while retaining punitive approaches for drug trafficking. A goal of the new program is to improve Oregon’s ranking as one of the worst states at providing treatment for addiction.²⁶ In 2016 and 2017, Oregon ranked first in the country for analgesic drug misuse, second in the U.S. for methamphetamine misuse, and fourth for cocaine and alcohol misuse while ranking 48th in access to treatment.²⁶ In all, almost 10% of the state’s population had a substance use disorder.

 

The state is expanding its addiction recovery centers and anyone will be able to access them whether or not they have received a citation.²⁶ The funding for expanded services will come from a higher than anticipated yield from marijuana taxes, which has exceeded $100 million per year.²⁶

 

Oregon’s program has produced mixed results. In the first year after decriminalization took place, police issued approximately 2000 citations, but, despite the waiver of the fine if a person calls the hotline for a health assessment and counseling, only 92 of those ticketed called the hotline and only 19 of them requested resources for services.⁵⁰ Almost half of people receiving a citation failed to make a court appearance. State health officials reported 473 opioid overdose deaths in the first 8 months of 2021, surpassing the total for all of 2020, and nearly 200 deaths more than the state saw in 2019.⁵⁰ The state also reported that visits to emergency rooms and urgent care centers for opioid overdose have been increasing. The Oregon Health Authority cites an upturn in fentanyl abuse and a pandemic-related downturn in reporting in 2020 as possible reasons for the disappointing results. In addition, Oregon’s inpatient facilities, detox clinics and recovery-focused nonprofits were adversely affected by issues related to COVID-19 including workforce shortages; there is uncertainty whether providers can adequately expand to meet increased needs.⁵¹

 

Pause and Ponder: Is there a role for pharmacists in improving outcomes?

 

However, it has also been suggested that the more lenient rules take away the threat of jail time that some individuals need to encourage them to get into recovery while fewer low-level offenders will be forced into court-ordered behavioral health services.⁵¹ Portugal takes a more robust approach than Oregon, having “dissuasion commissions” that pressure anyone caught using drugs, including marijuana, to seek treatment. Tools include fines, prohibiting drug users from visiting certain venues or from traveling abroad, seizure of personal property, community work, and having to periodically report to health services or other facilities.⁵⁰

 

California, Maine, and New Jersey, among others, have also been considering enacting decriminalization measures.^52,53 A bill pending approval in California would decriminalize most psychedelics. The bill would allow people aged 21 and older to possess psilocybin, DMT, ibogaine, mescaline, LSD, and MDMA for personal use and “social sharing.”⁵² The bill advanced to the final step of Assembly approval when the sponsor removed ketamine from the list of substances due to concerns over date rape. The bill prohibits sharing drugs with anyone under 21 years of age or possessing them on school grounds. It would also allow personal cultivation of mushrooms. Proponents touted the benefits to individuals who would be aided by the use of psychedelics to treat trauma including military veterans. Opponents argued that social sharing could result in more overdoses from contaminated products and give drug dealers a built-in defense.⁵²

 

PROS AND CONS

 

Why have states and municipalities chosen to decriminalize drugs? Although a detailed discussion of the benefits and detriments of lax drug policies is beyond the scope of this activity, it is worth briefly examining some of the arguments that have driven the move towards decriminalization. Table 1 describes the pros and cons frequently used to support the various arguments.

 

 

Table 1. Pros and Cons re: Decriminalization of Recreational Drugs^{1,16,54,55,56,57}

 

Justifications for decriminalization

Justifications for continuing prohibition of recreational drugs

·       A sense that the “War on Drugs” is expensive, harmful to society, and not working ·       The suggestion that a medical model will be more effective ·       Decriminalization will reduce profits for drug traffickers ·       More than half of people in prison have untreated substance use disorders and o   Imprisonment actually leads to increased illicit drug and medication misuse following a period of incarceration with a much higher risk of drug overdose upon release o   Relapse to drug use in someone with an untreated opioid use disorder can be fatal due to loss of opioid tolerance that may have occurred while the person was behind bars o   A criminal conviction or a record of imprisonment can significantly hamper a person’s employment prospects and other opportunities

·       Risk of endorsing or encouraging risky behaviors ·       Decriminalization would drive down the cost of drugs, making them more accessible ·       Few non-violent users are actually imprisoned ·       A black market will still exist for users under the permitted statutory age ·       The current treatment infrastructure is inadequate to accommodate the anticipated increased demand ·       The threat of incarceration is an incentive to seek treatment ·       If restrictions are abandoned, other social costs will increase

 

As a proponent for decriminalization, Mayor Schmoke proposed that the abuse of drugs should be “dealt with as a moral and medical problem than as a criminal problem ... a problem for the surgeon general, not the attorney general.”¹ The number of people incarcerated for drug-law violations in state and federal prisons in the United States increased 12-fold between 1980 and 2018. Yet there is no statistically significant relationship between state drug imprisonment rates and three markers of state drug problems: self-reported drug use, drug overdose deaths, and drug arrests.⁵⁷

 

Pause and Ponder: Should recreational drugs be regulated like alcohol?

 

Many advocates recommend an approach similar to the policy in Portugal and treat illicit drug use the way most states regulate alcohol and marijuana, by making it legal for stores to sell such drugs to adults.⁵⁷ In Portugal, which has led the way towards decriminalization, the use of cocaine among young adults (15-34) is 0.3% compared with 2.1% in the European Union (EU) countries.⁵⁸ Amphetamine and MDMA use are also lower. The overall overdose death rate in Portugal is five times lower than in the EU (which has a lower rate than in the U.S.).⁵⁸ HIV infection rates among IV drug users have also dropped.⁵⁸

 

Where Will This Lead?

Are the localities decriminalizing recreational drug use an anomaly or do they represent the tip of the iceberg for liberalization of personal drug use? The movement could follow the path taken by marijuana.

 

States have pursued a pattern of first decriminalizing and/or allowing medical use of marijuana before finally proposing legalization.^16,59 States used their experiences with the intermediate steps as a means to anticipate the expected effects of total legalization.¹⁶ The liberalized marijuana policies in medical marijuana states exposed the public to more open marijuana use and may have changed attitudes towards the drug, along with a sense that prohibition is too costly.⁵⁹

 

Efforts are ongoing to legalize marijuana at the federal level. Congress is currently considering the Marijuana Opportunity Reinvestment and Expungement (MORE) Act. It would remove marijuana from the list of scheduled substances under the Controlled Substances Act and eliminate criminal penalties for an individual who manufactures, distributes, or possesses marijuana.³ It would also establish a process to expunge convictions and conduct sentencing review hearings for individuals previously convicted of federal cannabis offenses. It would establish and fund a grant program to provide resources to administer services for individuals adversely impacted by the War on Drugs, including job training, legal aid, reentry services, and health education programs and would levy a 5% tax on the sale of cannabis products.³

 

Will legalizing marijuana serve as a model for other C-I drugs to follow? Indeed, a bipartisan bill was recently introduced in the U.S. Senate calling on the DEA to reclassify breakthrough therapies such as psilocybin and 3,4-methylenedioxymethamphetamine (MDMA) as Schedule II drugs.⁶⁰

 

SUMMARY AND CONCLUDING COMMENTS

 

The pendulum of drug control may be swinging closer to the more lenient approach that existed 100 years ago. In a decade, the U.S. moved from no state permitting recreational use of marijuana to almost half of the states doing so, along with decriminalization being debated at the federal level. Will additional recreational drugs follow the same path? Several municipalities and a few states have already made significant strides in that direction. In particular, Oregon and the nation of Portugal have established programs making controlled substances a medical and public health issue rather than a law enforcement issue, although with mixed results. Will the distinction between “hard” and “soft” drugs disappear in the U.S., as more states adopt measures aimed at decriminalizing drugs?

 

If so, there will be many questions about how pharmacy may be affected. Will drugs for which there is some evidence for medical applications like cannabinoids and psychedelics such as psylocibin, find their way to the pharmacy shelf? If Oregon’s medical model for psychedelics is followed by other states, will it enable new opportunities for pharmacists? Will cocaine and heroin once again be available as OTC products in pharmacies?

 

It is important for pharmacy staff to stay abreast of regulatory changes in their own states and nationally. They should become part of the conversation about the direction such regulations should take.

 

 

 

Download CE Activity

INTRODUCTION

“The skyrocketing cost of insulin has become a crisis in the US. Some people are dying because they can't afford the life-saving drug.” Columnist Rachel Gillett.¹

 

Diabetes is a rapidly growing global health problem with enormous health, social, and economic consequences.^1-3 This chronic metabolic disorder is characterized by prolonged hyperglycemia due to inadequate pancreatic production or utilization of the hormone insulin.³ Approximately 6.5% of the global population (almost 300 million people) suffer from diabetes.² In the U.S., the Centers for Disease Control and Prevention (CDC) estimates that 10.5% of the population (34 million people) have diabetes and that the prevalence rises to 26.8% among those aged 65 years or older.⁴ Direct medical costs and lost productivity attributable to diabetes was estimated to be $327 billion in 2017, making it the most expensive chronic disease in the nation.^5,6

 

Complications from diabetes are a serious public health concern. Diabetes is a principal cause of retinopathy, kidney failure, heart attacks and stroke, lower limb amputation, and ketoacidosis which can be fatal.³ Individuals with diabetes are twice as likely to have heart disease or stroke than those without diabetes.⁵ A total of 16 million emergency department (ED) visits were reported with diabetes as a listed diagnosis among adults aged 18 years or older in 2016.⁴

 

Management of diabetes is critical to preventing complications and high health care costs from the disease. However, many patients do not adequately manage their diabetes, in part due to high treatment costs. This continuing education activity will discuss some of the reasons behind the high costs of treating the disease and the impact that high prices have on patients. It will also review regulatory and public health efforts to reign in the rising costs of insulin.

 

INSULIN

 

Diabetes can be managed, and its consequences avoided or delayed with diet, physical activity, tobacco avoidance, and regular screening and treatment for complications.^3,5 Medication, of course, is also a key to management. Prescribers use many different classes of oral medications to manage diabetes,⁷ but the emphasis in this activity will be on insulin. Insulin is the mainstay of therapy for individuals with type 1 diabetes, and many patients with type 2 diabetes also benefit from insulin therapy.⁸ Prior to the discovery of insulin in 1921, diabetes was difficult to manage. The primary treatment consisted of highly restrictive diets, which compromised the immune system and stunted growth, and often led to death by starvation.⁹

 

In 1921, Frederick Banting, a Toronto surgeon without laboratory training, medical student Charles Best, physiologist John Macleod, and biochemist James Collip successfully isolated and purified insulin from a dog’s pancreas and showed that it would normalize blood glucose levels when administered to diabetic animals.¹⁰ Later, insulin was extracted in larger amounts from cattle and was first given to a 14-year-old dying diabetic patient who developed an allergic reaction. After the Canadian researchers purified it further, they gave a second dose to the patient 12 days later; the patient showed dramatic improvement as his blood glucose dropped to near normal levels with no obvious adverse effects.¹⁰ This observation spurred widespread use of insulin in patients with diabetes. Banting and Macleod were jointly awarded the 1923 Nobel Prize in Physiology or Medicine in recognition of their life-saving discovery (The committee did not recognize Best, the lowly med student, for his contribution).¹⁰ Banting, Collip, and Best were also awarded patents on insulin and the method used to make it in 1923. They all sold their patents to the University of Toronto for $1 each.¹⁰ Banting famously said, “Insulin does not belong to me, it belongs to the world,” proclaiming his desire that everyone who needed it should have access to it.¹⁰

 

Researchers at the university tried to manufacture insulin for distribution but realized they could not meet the demands of the North American market.¹¹ The university licensed the technology to Eli Lilly which possessed the expertise to produce large batches of insulin. Under the arrangement, Lilly was allowed to apply for U.S. patents on any improvements to the manufacturing process.¹¹ The university also established licensing agreements to produce insulin with other companies, including Nordisk and Novo which laid the foundation for the future domination of the insulin market by a few companies.¹¹ When the animal-based insulin patents began to expire, researchers developed new technologies. They bioengineered human insulin in 1982 and then analog insulin (insulin which has been genetically modified to improve its pharmacokinetic profile) and created new therapies and continued patent protection.¹¹ Today, approximately 7.4 million Americans use insulin, including roughly 1.4 million people who use it to treat type 1 diabetes.⁹

 

Pharmacists and technicians are aware that patients with type 1 and type 2 diabetes use a combination of short-acting, rapid-acting, intermediate-acting, and long-acting insulins to control their glucose levels. Today, the insulin analogs are widely prescribed and are the standard of care for people with type 1 diabetes and also a component of care for people with type 2 diabetes; the analogs are generally more expensive than other, older types of insulin.⁹

 

Even though diabetes is treatable and has been for more than a century, it remains the 7^th leading cause of death in the U.S., accounting for 87,647 fatalities in 2019.^5,9 Despite the availability of this century-old treatment, many patients undertreat their diabetes, contributing to complications and high mortality from the disease. Results from an international survey of patients with type 1 diabetes found that approximately 25% of patients in the U.S. had rationed insulin in the previous year.¹² Why would patients show such low adherence to a proven, lifesaving medication?

 

One reason is cost. High-list prices, health plan structures, and high out-of-pocket costs make it difficult for many diabetic patients to adhere to their medications, especially insulin. Some patients maintain that they spend an estimated 50% of their monthly income on insulin and diabetes products.¹¹ Studies have found that approximately one of every four survey respondents in the U.S. report underuse of their insulin at least once within the previous year due to high cost.^12,13 This is the highest rate of insulin rationing of any high-income country in the world.¹⁴ An international survey found that only 6.5% of respondents from high income countries excluding the U.S. reported rationing in the previous year, compared with roughly 25% in the U.S.¹⁴ In addition to rationing insulin, 33.5% of individuals from the U.S. reported rationing of blood glucose testing supplies.¹⁴

 

The financial burden is, not unexpectedly, especially acute for economically disadvantaged individuals who have a higher rate of diabetes. Rates of diabetes are higher among people living in impoverished regions of the U.S., such as Appalachia and the Mississippi Delta, and also among those who are eligible for Medicare and Medicaid.⁹ Adults with less than a high school education are also more likely to be diagnosed with diabetes than those with at least a high school diploma.⁹ Similarly, minority communities are also disproportionally affected by this disease, with Native Americans, Hispanics, Black Americans, and Asian Americans representing more than 45% of those diagnosed with the disease, despite these groups making up 39% of the U.S. population.⁹ Cost-related rationing of insulin was the leading cause of hospital admissions for diabetic ketoacidosis among inner-city minority patients.¹⁴ Approximately 24% of adults with diabetes earning below the poverty level use insulin, either alone or in combination with oral medications.¹⁵

 

An online survey performed by the American Diabetes Association in 2018 also found that a quarter of respondents reported that the cost of insulin had affected their purchase or use of insulin during the previous year. The percentage was even higher for dependent child insulin users (34%).¹⁶ More than 20% of users admitted missing doses monthly or even weekly. They also had to choose between buying insulin or other health-related purchases such as physician visits (32%), health insurance (26%), or other medications (36%). Many also had to choose between purchasing insulin or other essential items such as utilities (30%), housing (27%), transportation (32%), as well as non-essential purchases like vacations (41%) and entertainment (43%).¹⁶ Patients have also made employment decisions based on the availability of adequate health insurance to cover the cost of their insulin.¹¹ Patients also claim that they have been forced to make unhealthy food choices that can worsen the disease, purchasing cheaper alternatives due to spending on insulin.¹¹ The excessive costs also caused 23% of individuals to change to a less expensive insulin type or brand, while many skipped filling at least one insulin prescription.¹⁶

 

Moreover, surveys have found that insulin users for whom cost affected their purchase or use of insulin experience adverse health effects at higher rates than those for whom cost was not an issue. When cost was a factor, 72% of individuals experienced episodes of poor blood glucose control during the previous three months (compared with 42% in users who were not affected by the cost), and 80% had their most recent A1C level measured at 7.5 or higher (59% when cost was not a factor).¹⁶ Patients have also claimed that they have intentionally allowed themselves to reach a state of diabetic ketoacidosis so that they would receive insulin in an ED instead of purchasing it.¹¹

 

Not unexpectedly, 73% of individuals dealing with price increases also experience negative emotions (e.g., stress or anxiety), more than twice the rate of those not facing a price increase (31%).¹⁶ There have even been reports of deaths in patients with type 1 diabetes due to a lack of affordable insulin.^14,17 The underutilization of insulin due to concerns over cost not only produces serious avoidable short- and long-term health consequences, but also raises overall costs for the U.S. health care system.^9,15 It is remarkable that this has occurred with a medication whose discoverers refused to profit from it.

 

PAUSE AND PONDER: How would you start a conversation about economic stress with a patient who appears to be underusing insulin?

 

ARE COSTS REALLY THAT HIGH?

 

There is a public perception that the cost of prescription drugs is out of control; indeed, Americans pay an average of three times as much as patients in the U.K. for the world’s top 20 medications.¹⁸ But is insulin, in the words of Representative Tom Reed (R., N.Y.), “the poster child of this broken marketplace”?¹⁸

 

Insulin in the U.S. is more expensive than anywhere else in the world. The average manufacturer price of insulin is more than four times higher in the U.S. than it is in the next most expensive country (Chile) and more than 10 times the average cost in the 32 developed countries surveyed.¹⁹ In 2018, spending on insulin in the U.S. was $28 billion, compared with $484 million in Canada.²⁰ The average American insulin user spends almost five times as much annually than their Canadian counterparts. The average cost per unit of insulin in the United States increased by 10.3% between 2016 and 2019 compared with an increase of only 0.01% in Canada during the same time period.²⁰ By comparison, in 1923, two years after the introduction of insulin therapy, the U.S. had the lowest global price of insulin.²¹ As recently as the 1960s, vials of insulin were available in the U.S. for 84¢, equivalent to $7.36 in today’s dollars.¹⁸

 

The list price of insulin per milliliter in the United States increased, on average, 2.9% annually between 1991-2001, 9.5% per year from 2002 and 2012, 20.7% annually between 2012 and 2016, with a smaller increase from 2016 to 2018.⁶ Analog insulins have seen the largest price increase, rising more than 1000% since the 1990s.^14,17 The average annual per capita cost of insulin now approaches $6,000.⁶ (Note that the average yearly social security benefit in the U.S. is $18,458.)

 

The cost of insulin contributes an estimated $48 billion to the direct costs of treating diabetes (before accounting for any rebates or discounts) which represents 20% of the total spending.⁶ If current trends continue, the cost of insulin could reach $121.2 billion by 2024, or $12,446 annually for each patient receiving insulin.⁶

 

WHY?

The reasons for the enormous increase in the retail price of insulin are complex and varied. It has been argued that one of the common justifications for the high price tag on prescription drugs, research and development costs, is not applicable to insulin.¹⁷ Insulin is not a new drug and even the most commonly used modern analogs are 20 years old or more.¹⁷ In addition, over the past 60 years, the increase in the cost of insulin exceeds the rate of inflation by nearly 43-fold.¹⁸ If research and development costs are not driving the price increase, what is?

 

Notably, there is little competition in the insulin market. Only three companies, Eli Lilly, Novo Nordisk, and Sanofi, manufacture over 90% of the world’s insulin and investigations have found that they generally raise their prices at the same time.^17,21-23 It should be pointed out, however, that the manufacturing of biologics, compared with small molecules, involves a higher level of engineering and facility requirements. Additional steps are needed to ensure compliance with good manufacturing practices, regulatory requirements and to minimize batch-to-batch variability, all of which would affect production costs.²¹ The scale and optimization of production processes are also important to reduce the overall cost of the finished product which hinders smaller pharmaceutical manufacturers from entering the market.²¹

 

Other factors also contribute to rising insulin prices. An important trend over the past decade is a shift in insulin prescribing from less expensive human insulins to more expensive human insulin analogs.¹⁵ More than 90% of privately insured patients with type 2 diabetes in the U.S. who receive insulin are currently prescribed the more expensive analog version.^17,21

 

Price Setting

Another significant factor affecting the price of insulin is the large number of stakeholders (e.g., manufacturers, wholesalers, pharmacy benefit management services [PBMs], pharmacies, health plans, employers, and the Federal government) involved in the insulin supply chain and price setting, all of whom use varying degrees of negotiating power.^9,15 Multiple transactions occur among these stakeholders during distribution and payment and there is no one agreed-upon price for any insulin formulation.¹⁵

 

Although pharmacy staff are generally aware of the pricing dynamics, a brief review will place the insulin costs into context. Prices, rebates, and fees are negotiated among the stakeholders affecting the ultimate price paid by the patient with diabetes at the point of sale. The true cost of insulin can be difficult to pinpoint because of the complex nature and lack of transparency in the financial agreements among the stakeholders.^11,24

 

Manufacturers set a list price for their product, but the list price is usually not what payers pay nor what the manufacturers receive.^15,24 The manufacturers, generally, receive the net price which is the list price minus fees paid to wholesalers, discounts paid to pharmacies, and rebates paid to PBMs or health plans.¹⁵ While manufacturers control the list price of insulin, a substantial portion of the negotiating power has shifted from manufacturers to PBMs.¹⁵

 

PBMs attempt to lower costs by leveraging formulary coverage. PBMs administer the prescription medication benefit for more than 266 million Americans and 70% of all prescription claims are managed by the top three PBMs.¹⁵ PBMs have the power to provide exclusive formulary coverage and use this discretion to give them substantial clout in negotiations with manufacturers.¹⁵ Insulin manufacturers compete fiercely, attempting to gain favorable formulary placement and maximize market share and revenue for their products.^9,15 They use rebates as one bargaining chip.^9,15

 

These interactions give PBMs little incentive to discourage manufacturers from increasing their list prices since rebates, discounts, and fees PBMs negotiate are typically based on a percentage of a drug’s list price.⁹ There is an advantage for manufacturers to raise the list prices to provide bigger incentives (discounts) for the participants in the supply chain.¹¹ In other words, PBMs benefit when there is a larger “spread” between the list price and the real price paid by the health plan, so both the PBMs and manufacturer gain from higher list prices.^9,11,15 Since payers ultimately pay the “real” (discounted) price and not the list price, inflating the benchmark price does not increase the cost to the PBMs.¹¹

 

A Senate investigation found instances in which insulin manufacturers were apparently discouraged from setting lower list prices for their products, which would likely lower out-of-pocket costs for patients, due to concerns that PBMs and health plans would react negatively.⁹ Although it might be expected that rebates would reduce patient costs at the point-of-sale, they may be used instead by the employer or the health plan to reduce insurance premiums.¹¹ Significantly, insulin list prices have tended to rise more rapidly than the net price due to increasing rebates and discounts negotiated between stakeholders. In some cases, rebates and discounts may approach half of the insulin list price.^15,25 This suggests that participants in the distribution system are largely responsible for the increase in insulin costs.²⁵ It has been estimated that proceeds from insulin sales flowing to insulin manufacturers and insurers have decreased over time, while PBMs, pharmacies, and wholesalers have substantially increased their share of the funds.²⁵

 

Many participants in the pricing system benefit from the arrangement, but one essential participant who does not is the patient who needs insulin and is paying the artificially inflated list price. In particular, patients with high deductible insurances, Medicare recipients in the “donut hole,” patients subject to co-insurance, and especially patients without health insurance are in jeopardy.^11,24 Over the past decade there has been a shift away from traditional health plans, which provided broad coverage, to high-deductible health plans, and the deductibles themselves have risen; even plans available under the Affordable Care Act can have high deductibles depending on the “tier.” ¹¹ Thus, it would seem that decisions made from negotiations between stakeholders that affect formulary choice may not be based on the patient’s best financial or medical interest.¹⁵

 

Recently, the Federal Trade Commission (FTC) voted unanimously to conduct an in-depth probe of PBMs since, according to one commission member, “(f)or most Americans, pharmacy middlemen control what medicine you get, how you get it, when you get it, and how much you pay for it. Yet PBM practices are cloaked in secrecy, opacity, and almost impenetrable complexity.”²⁶

 

Patent Issues

Not only do a few companies dominate the market, they also maintain significant patent protection that limits incursion of competitive alternatives into the market. Currently, there are no patents on human insulin and most patents on first generation insulin analogs have also expired.²¹ Manufacturers have made improvements with new formulations providing more reliable control of diabetes and more convenience for users. However, the newer formulations prolong the patent life and provide up to 37 years of market protection.¹⁷ Companies also engage in what is known as “patent evergreening,” where they continually apply for renewed patents for their drugs after making incremental (in some cases, insignificant) changes to their medications.^17,18,23,27

 

For example, the long-acting insulin product insulin glargine (Lantus) was first patented in 1994 and was due to expire in 2015. Sanofi filed 74 patents for newer versions of the drug that can provide protection until 2031.^11,17,18 Sanofi maintains that the newer patents “are related to new and unique inventions” although there is evidence suggesting that the improvements are mostly minimal.¹⁸ Sanofi also points out that while the list price for its insulin has increased, the actual price paid by consumers is lower than it was in 2006, due to the nature of the market.¹⁸ In addition to modifying the insulin product, manufacturers have also filed and received patents for insulin delivery devices which effectively extends the patent life of the delivered insulin.^18,21

 

Patent disputes can influence cost in many ways. The threat of a lawsuit alleging patent infringement would discourage other manufacturers from developing competing products even if the suit is without merit.¹⁷ Even if the suit is litigated and found to be without merit, large litigation costs and marketing delays would occur.²² In 2014, Sanofi filed a suit against Lilly alleging a violation of its patent on insulin glargine. The companies reached a deal under which Lilly agreed to delay the launch of its product until 2016 and pay royalties to Sanofi.²⁸

 

Even more disturbing is the strategy of “pay-for-delay” patent dispute in which a competing manufacturer acknowledges the original patent and agrees to defer marketing its product for a specified period of time.^17,22 In return, the competing manufacturer receives a payment from the patent holder, a legal means for a manufacturer to pay a competitor not to enter the market.²² When Merck filed a new drug application for its rival to insulin glargine, Sanofi filed a suit claiming that Merck violated 10 of its patents, including ones for the drug and its insulin delivery device.²⁸ After the suit was filed, Merck announced it would no longer pursue its interest in the drug, possibly reaching a deal to receive payments from the suing company.²²

 

Biosimilars

Patents are not the only barrier to the introduction of alternatives to brand-name insulin. Insulin is a therapeutic biologic (not a chemically synthesized small molecule/drug) and the FDA treats alternative biologic products as biosimilars and not as generics; this leads to a more cumbersome and expensive regulatory approval process.^17,23 The FDA defines biosimilars as “a biological product that is highly similar to, and has no clinically meaningful differences from, a biological product already approved by the FDA.” ²⁹ Production and approval of biosimilars costs nearly as much as a new drug and requires similar testing and regulatory approval.^22,23 The development of a biosimilar takes five to nine years and costs at least $100 million,³⁰ leaving little financial incentive to develop cheaper options. The first insulin biosimilar, Basaglar, was introduced in the U.S. in December 2016, almost two years after the first biosimilar was approved in Europe, and requires that a prescriber supplies a new prescription.¹⁷ A second biosimilar (Admelog) was approved in 2018.¹⁷

 

In 2021, the FDA approved Semglee (insulin glargine-yfgn) as the first interchangeable insulin biosimilar.²⁹ The “interchangeable” designation means that it can be substituted for Lantus (insulin glargine, approved in 2000) without the intervention of a prescriber, similar to pharmacist-initiated generic drug substitution for small molecules.^27,29

 

PAUSE AND PONDER: What factors would you consider before substituting an interchangeable insulin? Would cost be one?

 

CAN ANYTHING BE DONE TO CONTAIN INSULIN COSTS?

 

The soaring cost of insulin has caught the attention of legislators, healthcare advocates, and the public.

Rising drug prices are a concern to the public at large. More than half of respondents in a March 2022 poll by the Kaiser Family Foundation agreed that limiting how much drug companies can increase the price of prescription drugs each year to the rate of inflation should be a “top priority” for Congress.³¹ A majority of respondents also say placing a limit on out-of-pocket costs for seniors (52%) and, specifically, capping out-of-pocket costs for insulin at $35 a month (53%) should be top priorities for Congress in the coming months.³¹ Several different approaches to reigning in costs involving multiple stakeholders have been proposed.

 

Congressional Actions

The most far-reaching proposal is the Build Back Better Act (BBBA) which was passed by the U.S. House of Representatives on November 19, 2021, but stalled in the Senate. This is a broad and complex 2,135-page bill with many provisions that would commit $2.2 trillion to a long list of health, social, and environmental proposals.³² The BBBA includes several provisions that would lower prescription drug costs for people with Medicare and private insurance and reduce drug spending by the federal government and private payers.^32,33

 

The key proposals dealing with drug costs, if eventually passed, would include³³

• Allowing the Federal Government to negotiate prices for some high-cost drugs covered under Medicare Part B and Part D
• Requiring rebates to limit annual increases in drug prices in Medicare and private insurance for drugs whose prices rise faster than the inflation rate
• Cap out-of-pocket spending for Medicare Part D enrollees by instituting a hard cap of $2,000 in 2024
• Eliminate cost sharing for adult vaccines covered under Medicare Part D
• Limit cost sharing for insulin for individuals with Medicare and private insurance. Currently, Part D and private insurance plans vary in terms of the insulin products they cover and what enrollees pay for insulin products. Under the BBBA, participating plans would cover insulin products at a monthly copayment of $35. Participating plans would not have to cover all insulin products at the $35 monthly copayment but would include one of each dosage form (vial, pen) and insulin type (rapid-acting, short-acting, intermediate-acting, and long-acting).

 

Since the large BBBA endeavor has not progressed in Congress, the House of Representatives passed a scaled back version (Affordable Insulin Now Act) in March of 2022 that specifically addressed insulin costs.³⁴ The bill would cap cost-sharing under the Medicare prescription drug benefit for a month's supply of covered insulin products at $35 and cap private health insurance cost sharing for selected insulin products at $35 or 25% of a plan's negotiated price (after any price concessions). The cap would become effective in 2023. At the time this activity was prepared, the effort was awaiting Senate action. A modified bipartisan Senate bill with a $35 co-pay cap has been introduced.

 

The industry trade group, the Pharmaceutical Research and Manufacturers of America (PhRMA), does not favor the act, calling the proposed law heavy-handed and flawed. PhRMA’s position is that it would make the “broken insurance system worse and throw sand in the gears of medical progress” and “doesn’t address perverse incentives in the system that are leading to higher costs for patients.”³⁵

 

Biosimilars

The previously discussed biosimilars also aim to encourage more affordable insulin substitutes.²³ Before 2010, the U.S. lacked a regulatory pathway for the development of biosimilar medications.^15,36 In 2010, the Biologics Price Competition and Innovation Act (BPCIA) was signed into law as part of the Affordable Care Act. This new law created an FDA approval pathway for biosimilar and interchangeable biologic products while preserving incentives for the development of new medications.^36,37 Typically, biosimilars marketed in the U.S. have launched with initial list prices 15% to 35% lower than comparable list prices of the original reference products.²⁹ The BPCIA provides two separate pathways for a biological product to compete with a reference product: either as a biosimilar or as an interchangeable. Interchangeable products are subject to more stringent requirements.^23,36

 

To be considered a biosimilar, the route of administration, dosage form, and strength must be the same as the reference product.^36,38 The sponsor must show that it is “highly similar” to the reference product and that no clinically meaningful differences between the biosimilar and the reference product exist in terms of safety, purity, and potency of the product.³⁸ Only minor differences in clinically inactive components are permitted in biosimilar products.³⁰

 

The biosimilar must also possess the same mechanism of action as the reference product for the condition it is intended to treat, and the manufacturing conditions and facilities must meet standards to ensure safety, purity, and potency.^36,38 To be interchangeable, the manufacturer must demonstrate two things^36,38:

• That the product produces the same clinical result as the reference product in patients.
• If it is to be used more than once in a given individual, any safety risks or diminished efficacy from switching between the reference substance and the biosimilar is no greater than the risks from using the reference product alone.

 

Pharmacists should take note of an important difference between biosimilars and generics. Generics (small molecules) only need to demonstrate bioequivalence, while biosimilars need to demonstrate therapeutic equivalence.³⁶ The equivalence must be based on data derived from animal studies, clinical studies, and analytics that show a similarity to the reference product.³⁶ As noted above, meeting the biosimilar criteria requires much more time and expense than substantiating generic equivalency. Pharmacists also need to appreciate that even if a product is defined as “interchangeable,” it is not possible to create identical versions of reference biologic medicines due to their complexity.³⁰

 

The BPCIA also has market exclusivity provisions that address manufacturers’ concerns.³⁶ Applicants for biosimilar products cannot submit an application until four years after the date on which the reference product was first licensed. Further, the FDA cannot approve the biosimilar or interchangeable until 12 years after the date on which the reference product was first licensed. In addition, the applicant must provide the manufacturer of the reference product with notice of intent 180 days before marketing the product. The first interchangeable product also has market exclusivity for at least a year.³⁶

 

FDA approval of biosimilars, however, is not the only obstacle to marketing insulin substitutes. As noted above, biosimilars must contend with patent evergreening.^17,27 Biosimilars will also not necessarily grab a large market share.²⁷ Lilly, Novo Nordisk and Sanofi have launched their own “authorized generics,” essentially their own drugs repackaged and marketed at discounted prices.²⁷ Lilly and Sanofi produced the first two (Basaglar and Admelog), which provides little in the way of competition; they are priced only about 15% to 20% less than their respective original forms.^17,39

 

More significantly, the complex price setting maneuvering that affects the cost of insulin could also impede cheaper biosimilar acceptance. Since PBMs can make more money from discounts on brand name products, they have more to gain from prioritizing the dominant brands and little incentive to include biosimilars in formularies.^17,27,39 In addition, since pharmacists can substitute interchangeable products, pharmacists have the discretion whether or not to dispense the less expensive formulation.

 

Over the Counter

Pharmacy personnel should recall that when Congress established federal prescription drug regulations in 1951, the types of insulin available at that time, unlike the more recent analogs, did not require a prescription.⁴⁰ Human insulin injection is available over the counter in 49 U.S. states and the District of Columbia and about 15% percent of U.S. patients who buy insulin purchase it over the counter without a prescription.^40,41 This presents a dilemma for patients and clinicians.^40,41 On one hand, this provides an opportunity for patients to obtain insulin without delay, especially in an urgent situation,⁴¹ at a more affordable price (average price of $54.09, compared with $114.40 for prescription short-acting insulins.¹⁹). On the other hand, it could be dangerous for a patient to adequately assess the appropriate dosage and timing for optimal glucose control without training or guidance from a health care provider especially if they are switching between different versions of insulin.⁴⁰ Physicians may not be aware that insulin can still be purchased OTC and may be puzzled by a patient’s sudden change in blood glucose.⁴¹ The FDA maintains that the older insulins were approved for OTC sale because they are less concentrated and did not require medical supervision for safe use.⁴¹

 

State Activities

States have also taken measures to influence insulin cost and use while waiting for federal actions.

In 2019, Colorado became the first state to limit co-pays for patients who use insulin, capping individual prescription at $100 for a 30-day supply ($200 if patients use two types of insulin), although payers have exploited some loopholes.⁴² The law applies to private insurers but not to patients on Medicare. Since then, seven other states (Illinois, Maine, New Mexico, New York, Utah, Washington, West Virginia) have enacted similar measures and five others (Connecticut, Florida, Kentucky, Tennessee, Virginia) are contemplating similar legislation.⁴² In New Mexico, the cap is set at $25.

 

Pharmacy staff are also reminded that, generally, individual state laws govern generic substitution.⁴² Some states have become concerned that biosimilars are not “identical” to the reference product, consequently pharmacy staff should become familiar with their state’s regulations regarding biosimilar substitution.⁴³ At least one U.S. state (Indiana) does not permit OTC sales of insulin due to the safety concerns noted above.^19,41

 

Individuals

Insulin prices have risen to such an extent that patients have taken matters into their own hands. The disparity in price has motivated many Americans to travel to Canada to purchase their insulin where the price may be as little as 1/10 the cost in the U.S.^1,9,44 Governmental policy controls insulin prices in Canada, including price caps and negotiations with manufacturers and often insulin does not require a prescription.⁴⁴

 

PAUSE AND PONDER: How would you advise a patient who is contemplating purchasing insulin from Canada as a cost-saving measure?

 

In another approach to reducing the cost of insulin, biohackers have been attempting to make insulin by converting proinsulin obtained from yeast to insulin with the hope of providing a method for do-it-yourself production that could be shared online.^18,45 If they are successful, anyone, hypothetically, could construct a lab and manufacture open-source insulin in a garage at a lower cost.¹⁸ However, they could still run afoul of FDA regulations and need to conform to Good Manufacturing Practices.^18,45

 

PAUSE AND PONDER: How would you respond to a patient who asks you about OTC or “homemade” insulin?

 

Patients are also filing lawsuits challenging manufacturer’s “schemes” to unlawfully inflate the benchmark prices of rapid- and long-acting insulins.¹¹

 

SUMMARY AND CONCLUDING REMARKS

Insulin maintains a critical place in the treatment of diabetes more than 100 years after the discovery of its beneficial effects, yet the disease is poorly managed in many patients, in part due to the escalating cost of newer forms of the drug. Insulin prices in the U.S. are far higher than in the rest of the world, fueled by a pricing system riddled with disincentives to keep prices low. Patients with no or low-quality health insurance are particularly impacted. Congress and states are examining possible solutions to the problem, notably by placing caps on out-of-pocket spending on insulin.

 

Pharmacy staff, as the point of contact with patients receiving insulin, are ideally situated to help patients who are struggling with adherence to their medication. Patients would benefit from pharmacists who can advise them about the different forms of insulin and delivery devices.⁴⁶ The Endocrine Society recommends that pharmacists learn about lower cost options offered by manufacturers and share their findings with patients and prescribers.²⁴ Pharmacists should also be ready to discuss the pros and cons of OTC insulin products. Pharmacists have also gained an opportunity (and responsibility) to manage costs with the approval of the first interchangeable insulin product.

 

Another helpful role would be to educate patients about available patient assistance programs especially since many patients may be unfamiliar with them or unsure about whether they qualify and how to apply.⁴⁶ This is a function that pharmacy technicians can fulfill. It is also vital that pharmacy staff remain familiar with Congressional and State efforts to lower out-of-pocket costs of insulin described above and some may choose to serve as patient advocates. Finally, if open-source methods of manufacturing insulin prove to be successful, it could potentially introduce opportunities for compounding pharmacies to make insulin at a lower cost.¹⁸ Insulin may never be as affordable as Frederick Banting hoped, but at least encouraging signs suggest that fewer patients will find it necessary to forego their life-saving treatment because of the expense.

As this activity was being prepared for posting, the Senate passed the long-debated Inflation Reduction Act which dealt with climate, taxes, and health care. The relevant features will allow the government to negotiate costs for certain drugs paid for by Medicare (10 in 2026 and 20 in 2029) and will cap out-of-pocket expenses for insulin at $35 per month for Medicare patients but not for private insurers.

 

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