INTRODUCTION

More than 72 million individuals of reproductive age (15 to 49 years old) live in the United States (U.S.), and about 43 million of them are at risk of unintended pregnancy.¹ This means they are sexually active and could experience unwanted pregnancy if they and their partners fail to use contraceptives consistently and correctly.

Here is a striking but under-reported fact: about one in two pregnancies in the U.S. is unintended (i.e., mistimed or unwanted at the time of conception).² Compared to intentional pregnancies, people experiencing unintended pregnancy experience more mental health problems, have less stable romantic relationships, and sometimes delay initiation of prenatal care.³ Ideally, those who unintentionally conceive should ideally be in good health and ready to care for a new child, but sometimes that is not the case.

Children born as a result of unintended pregnancies are at an elevated risk of experiencing both mental and physical health challenges and are more likely to struggle in school.³ While the overall rate of unintended pregnancies is on the decline, disparities based on factors such as race/ethnicity, age, income, and education level persist.³

It is crucial to implement interventions that promote the use of contraception methods to prevent unintended pregnancies. While over the counter (OTC) options for pregnancy prevention exist, hormonal methods requiring a prescription (pill, patch, ring, and injection) are more effective than OTC products, withdrawal, or fertility-awareness methods for pregnancy prevention.⁴ Recent laws make it possible for pharmacists to prescribe hormonal contraceptives in some states, increasing access to these more effective therapies.

Note that this activity will employ the terms "woman/women" to align with the biological expectations of ovulation.

 

Understanding the Menstrual Cycle

The length of a woman’s menstrual cycle is a commonly misunderstood concept. While most people consider a natural 28-day cycle “normal,” this is only true for about 13% of women.⁵ The first day of menstrual bleeding is considered cycle day 1 and cycles range from about 21 to 40 days in length.

Hormone levels regulate the menstrual cycle. The pituitary gland produces luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which promote ovulation and release of estrogen and progesterone from the ovaries.⁶ This hormone fluctuation splits the menstrual cycle into three phases; note that the timeframes described below are approximate length based on a 28-day cycle⁶:

• Follicular phase (before egg release)
  • Lasts from cycle day 1 to ovulation
  • FSH levels rise to recruit a small group of follicles for growth and development
  • Between days 5 to 7, one follicle dominates and secretes estradiol to stop menstrual flow
• Ovulatory phase (egg release)
  • Occurs on or around day 14
  • Sustained FSH levels cause an LH surge about 28 to 32 hours before the dominant follicle ruptures, also known as ovulation, releasing the mature oocyte (egg)
• Luteal phase (after egg release)
  • Lasts from ovulation to the last day of the cycle
  • Remaining luteinized (matured) follicles become the corpus luteum, which produces progesterone to prepare the uterus for embryo (fertilized egg) implantation

 

Following the luteal phase, if no egg is fertilized or the egg does not implant, the corpus luteum degenerates after 14 days, estrogen and progesterone levels drop, and a new menstrual cycle begins.⁶ However, if a fertilized embryo is implanted, the cells around the embryo produce human chorionic gonadotropin (HCG). HCG maintains the corpus luteum, which continues to produce progesterone until the fetus can produce its own hormones. Pregnancy tests detect an increase in HCG in the blood or urine, indicating a fertilized embryo is present.⁶

PHARMACY-BASED HORMONAL AND EMERGENCY CONTRACEPTIVES

Contraception refers to the strategies employed to prevent pregnancy after sexual intercourse, which can be categorized into two main approaches⁷:

1. Inhibiting the encounter of viable sperm with a mature ovum, achieved through methods such as barriers or ovulation prevention
2. Preventing the implantation of a fertilized ovum in the endometrium, accomplished through methods that create an unfavorable uterine environment

It is crucial for sexually active individuals to be well-informed about the various contraceptive options available. This knowledge is essential in assisting patients in effectively preventing unintended pregnancies.

This activity will only discuss the birth control methods that pharmacists are directly involved in prescribing.

 

Hormonal Contraceptive Basics

As the name implies, hormonal contraceptives employ hormones—specifically, progestins and estrogens—to prevent pregnancy.⁷ Hormonal contraceptives do not protect patients from sexually transmitted infections, including human immunodeficiency virus, and this is a point that pharmacists need to stress at every visit. Estrogens’ role in birth control is to stabilize the endometrial lining and provide cycle control. However, estrogens also suppress FSH release from the pituitary gland to help block the LH surge and prevent ovulation. Progestins provide most contraceptive effect. They block the LH surge, which inhibits ovulation. Progestins also thicken cervical mucus to⁷

• prevent sperm penetration
• slow tubal motility
• delay sperm transport
• induce endometrial atrophy (thinning), reducing its receptivity to embryo implantation

Achieving the right balance between progestogens and estrogens is vital in hormonal contraceptives. Some hormonal contraceptives contain only a progestin, while others combine an estrogen and a progestin.⁷ Importantly, estrogen alone—or “unopposed estrogen”—does not protect against pregnancy and pose significant safety concerns. Patients with an intact uterus who take unopposed estrogen are at risk of cancer, endometrial hyperplasia, polyps, endometriosis, and adenomyosis.⁸

 

PAUSE AND PONDER: What is the difference between a CHC, a COC, and a POP?

 

Combined hormonal contraceptives (CHCs)—any contraceptive containing both an estrogen and progestin—are not appropriate for women⁷

• older than 35 years who smoke
• with obesity (body mass index 30 or greater)
• with untreated hypertension (greater than 160/100 mm Hg)
• with migraines (especially with aura)
• at risk for deep vein thrombosis

The estrogen component of most CHCs is ethinyl estradiol.⁷ Many different progestins of differing androgenicity and similarity to testosterone exist, but no evidence suggests that a particular progestin is superior to others. Traditionally, experts classified progestins into “generations” based on parent compound and decade of development, but data shows this is not clinically useful.⁷

A woman can start CHCs at any time during her cycle if it is reasonably certain that she is not pregnant.⁹ If a patient starts CHCs within the first five days of menstrual bleeding, no additional protection is needed, but if it has been longer than five days from the start of menses, she should abstain from intercourse or use backup contraception for the next seven days.⁹ Table 1 outlines missed dose guidance for all contraceptive types.

 

Table 1. Missed Dose Guidance for Contraceptives^7,10,11

Missed Dose/Failure	Guidance
COCs: 1 pill late (< 24 hours overdue) or missed (24 to < 48 hours overdue)	·  Take the late/missed pill ASAP ·  Continue taking remaining pills at the same time (even if 2 doses in 1 day) ·  No back-up contraception needed ·  Consider emergency contraception if previous late/missed dose in same cycle or in the last week of the previous cycle
COCs: ≥ 2 consecutive pills missed (≥ 48 hours have passed since last pill)	·  Take the most recently missed pill ASAP ·  Discard any other missed pills ·  Continue therapy as usual ·  Use back-up contraception (e.g., condoms) or remain abstinent until they’ve taken hormonal pills for 7 consecutive days ·  If in last week of hormonal pills, skip placebo interval and start new pack immediately ·  Consider emergency contraception if pills missed in 1st week and unprotected intercourse occurred
POP: more than 3 hours late	·  Take missed pill ASAP, then go back to regularly scheduled time ·  Use back-up contraception until POP taken consistently for at least 48 hours ·  If vomiting occurs soon after taking, use back-up contraceptive for at least 48 hours
Transdermal patch: partially or completely detached	·  Reapply ASAP ·  If no longer sticky or becomes dirty, use a new patch (do not use supplemental wraps or adhesives) ·  If detached ≥ 24 hours, may no longer be protected from pregnancy; stop the current contraceptive cycle and start a new one (use back-up contraception for at least 1 week) ·  If unsure how long it was detached, treat it as if it was ≥ 24 hours
Transdermal patch: forget to change patch	·  At start of a patch cycle (week 1/day 1), apply a patch as soon as possible; this becomes the new “patch change day” and back-up contraception is needed for 1st week ·  In middle of a patch cycle (week 2/day 8 or week 3/day 15) < 48 hours late, apply new patch immediately; no change in “patch change day” and no back-up needed ·  In middle of a patch cycle (week 2/day 8 or week 3/day 15) ≥ 48 hours late, stop current cycle and start a new one with a new patch; this is new “patch change day” and should use back-up for 1 week
EE/E vaginal ring: falls out or removed ≥ 3 hours	·  Weeks 1 or 2: use back-up contraception until ring is in place for 7 consecutive days ·  Week 3: discard ring and either (1) insert new ring immediately to start next 3-week use or (2) insert a new ring ≤ 7 days from removal (only if ring was in for 7 consecutive days before removal) ·  Always use back-up contraception until the ring has been placed for 7 consecutive days ·  If removed < 3 hours, efficacy is not affected; rinse ring with cool/lukewarm water and reinsert ASAP
SAEE vaginal ring: falls out or removed ≥ 2 hours	·  Rinse ring with cool/lukewarm water and reinsert ASAP ·  Use back-up contraception until the ring has been placed for 7 consecutive days ·  If removed < 2 hours, efficacy is not affected

ASAP, as soon as possible; COC, combined oral contraceptive; EE/E, ethinyl estradiol/etonogestrel; POP, progestin-only pill; SAEE, segesterone acetate/ethinyl estradiol.

 

Combined Oral Contraceptives

Combined oral contraceptives (COCs)—meaning oral products containing both an estrogen (e.g., ethinyl estradiol) and a progestin (e.g., norethindrone, levonorgestrel, norgestimate)—come in many forms. COCs are about 91% effective, meaning that 9 of 100 women will become pregnant in a year with typical use.¹² A major distinction in product selection is monophasic versus multiphasic⁷:

• Monophasic COCs contain the same amounts of estrogen and progestin for 21 days, followed by seven days of placebo
• Multiphasic COCs—including bi- and triphasic regimens—contain variable amounts of estrogen and progestin for 21 days, also followed by a 7-day placebo phase

 

Monophasic and multiphasic COCs boast similar safety and efficacy profiles, so product selection relies on hormonal content, patient-preference, and coexisting conditions.⁷ Women should typically initiate a COC containing 35 mcg or less of ethinyl estradiol and less than 0.5 mg of norethindrone (or an equivalent).⁷ Estradiol levels control the incidence of breakthrough bleeding. Few patients require doses of ethinyl estradiol greater than 35 mcg daily to prevent breakthrough bleeding. While some clinicians advocate for starting patients at the lowest possible estradiol dose to minimize risks, data suggests that 10 to 20 mcg of ethinyl estradiol daily is no safer than the 35-mcg dose and lower doses are associated with more breakthrough bleeding.⁷

 

Monophasic COCs are preferred over multiphasic upon initiation, as adverse effects (AEs) are easier to identify and manage. Monophasic COCs also allow for easy cycle extension (continuing the active moiety to bypass a period, an indication for which pharmacists are not authorized to prescribe) by simply skipping the placebo week and starting the next pack of active pills. When attempting this with multiphasic regimens, the variation in drug levels between phases often leads to breakthrough bleeding.⁷

 

Extended- and continuous-cycle COCs contain 84 days of active hormone tablets followed by seven days of inactive tablets, which may be more convenient with fewer AEs.⁷ Extended-cycle COCs are commercially available. Of note, some patients skip the 7-day placebo week of monophasic 28-day COCs to mimic extended-cycle products, but pharmacists are only legally authorized to prescribe hormonal contraceptives as indicated. Continuous-cycle COCs shorten the pill-free interval (e.g., two to four days versus seven days), thus reducing period-related symptoms. Patients using extended- and continuous-cycle regimens have fewer menstrual cycles annually, which is helpful for women with severe premenstrual syndrome (PMS), dysmenorrhea (menstrual cramps), and menstrual migraines.

 

Progestin-Only Pills

Progestin-only pills (POPs)—“minipills”—contain 28 days of active hormone (norethindrone or drospirenone) per cycle.⁷ They are generally less effective than COCs and associated with irregular, unpredictable menstrual bleeding. Patients must take POPs at approximately the same time (within three hours) every day for effective pregnancy prevention. The progestin dose in POPs is about one-third of that in COCs, resulting is less consistent suppression of ovulation. This leaves women at greater risk of breakthrough bleeding and ectopic pregnancy—pregnancy outside the uterus—because women on POPs often continue to ovulate regularly.⁷

 

Despite being less effective, POPs are appropriate for certain women. Postpartum women, for example, can experience hypercoagulability, and should avoid CHCs for at least 30 to 42 days postpartum due to risk of venous thromboembolism. Therefore, those who take contraceptives commonly take POPs.⁷ Women who breastfeed should also avoid CHCs, as the estrogen component can affect lactation, making POPs a better option.

 

POPs can be started at any time during a woman’s cycle if it is reasonably certain she is not pregnant.⁹ If a patient starts POPs within the first five days of menstrual bleeding, she need not use additional protection , but if it has been longer than five days from the start of menses, she should abstain from intercourse or use backup contraception for the next two days.⁹

 

ORAL CONTRACEPTIVE TAKEAWAYS:

• COCs: Initiating a monophasic formulation containing 30 to 35 mcg of ethinyl estradiol and less than 0.5 mg of norethindrone (or an equivalent) offers the best chance of establishing a consistent menstrual pattern without raising AE risk. If patients experience estrogen- or progesterone-related AEs (listed in Table 2), dose adjustment is warranted.
• Extended- or continuous cycle: Patients have fewer menstrual cycles each year, making them ideal for patients with severe PMS, dysmenorrhea, or menstrual migraines.
• POPs: Less effective than COCs, but appropriate for patients within 42 days postpartum and women who breastfeed, as estrogen can affect lactation.

 

Table 2. Hormone-Related Adverse Effects¹³

	Too Much	Not Enough
Estrogen	·  Nausea ·  Breast tenderness ·  Weight gain ·  Headaches ·  Menstruation changes	·  Vasomotor symptoms (night sweats, hot flashes) ·  Early cycle (days 1-9) breakthrough bleeding or spotting ·  Amenorrhea
Progestins	·  Breast tenderness ·  Headache ·  Fatigue ·  Mood changes (depression, irritability) ·  Weight gain ·  Acne/oily skin ·  Hirsutism	·  Dysmenorrhea (painful periods) ·  Menorrhagia (heavy menstrual bleeding) ·  Late cycle (days 10-21) breakthrough bleeding or spotting

 

 

Non-Oral Hormonal Contraceptives

Some patients—particularly those who struggle with daily adherence to oral therapies—may benefit from alternative delivery mechanisms administered less frequently, including transdermal patch, vaginal ring, and injectable contraceptives.

 

The only transdermal CHC patch available in the U.S. contains ethinyl estradiol and norelgestromin (norgestimate’s active metabolite). The transdermal patch has comparable efficacy to COCs.¹² It may be less effective, however, for patients weighing more than 198 lbs (90 kg).¹⁴ Patients apply the patch to the abdomen, buttocks, upper torso, or upper arm at the beginning of the menstrual cycle, avoiding areas where the patch could be rubbed by tight clothing.¹⁴ Patients replace the patch once weekly for 3 weeks, followed by a patch-free week. The patch is formulated to release hormones for nine days, allowing a 48-hour grace period for adherence.¹⁴

 

The CHC patch’s adverse effects are similar to those of COCs, but some patients experience application-site reactions. Patients can prevent these reactions by rotating application sites. Dysmenorrhea and breast discomfort are also possible, as the patch causes higher estrogen exposure compared to COCs.¹⁴

 

Vaginal ring contraceptives offer excellent cycle control, as patients can insert and remove them, and fertility returns rapidly after removal.¹⁵ Two vaginal ring contraceptives are available:

• an ethinyl estradiol/etonogestrel (EE/E) ring that patients replace monthly
• a segesterone acetate/ethinyl estradiol (SAEE) ring that patients replace yearly

 

The EE/E vaginal ring delivers 0.015 mg of ethinyl estradiol and 12 mcg of etonogestrel (desogestrel’s active metabolite) every 24 hours.¹⁶ Estrogen exposure with the EE/E ring is lower than that associated with COCs, so incidence of estrogen-related adverse effects is also decreased. Local reactions, like vaginal irritation and discharge, are more common.¹⁶ The SAEE vaginal system is slightly larger in diameter than the EE/E ring and contains two drug reservoirs delivering 0.15 mg and 13 mcg of segesterone and ethinyl estradiol, respectively, every 24 hours.^15,10 The SAEE ring’s most common adverse effects are headache/migraine, nausea, vomiting, vaginal infections, abdominal pain, dysmenorrhea, vaginal discharge, urinary tract infection, breast discomfort, bleeding irregularities, diarrhea, and genital itching.¹⁰

 

To insert a vaginal contraceptive ring, patients should compress the ring between the thumb and index finger, then push the ring into the vagina.^16,10 There is no danger of inserting too far; the cervix will prevent the ring from traveling up the genital tract. Additionally, precise ring placement is not an issue, as the hormones are absorbed anywhere in the vagina. Patients should leave the ring in place for three weeks, then remove it for one week.

 

If using the EE/E monthly ring, patients should discard the ring (but not flush it down the toilet) after removal and insert a new one on the same day of the week as the previous cycle.¹⁶ Alternatively, the same SAEE ring can be used for up to one year. During the ring-free week, patients should store the SAEE ring only in the provided case away from children, pets, and extreme temperatures.^15,10 They should also wash the ring after removal and again before reinsertion using mild soap and water and pat dry with a clean cloth or paper towel. Patients should never use the same SAEE ring for more than 13 menstrual cycles.^15,10

 

If a vaginal contraceptive ring is removed from the vagina, intentionally or otherwise, no backup contraception is needed if the patient reinserts the ring within three hours for the EE/E ring and two hours for the SAEE ring.^16,10 If the ring remains out of the vagina for longer than these recommended time periods, backup contraception (e.g., male condoms, spermicide) is recommended for seven days after ring reinsertion. Patients should also avoid oil-based lubricants, as these can decrease the effectiveness of vaginal contraceptive rings.

 

Both vaginal ring systems carry risks for toxic shock syndrome (TSS), a rare, potentially life-threatening vital organ failure caused by bacterial infection.^16,10 Items that remain in the vagina for an extended period of time are implicated in TSS because bacteria can be trapped in the vagina and enter the uterus via the cervix or objects in the vagina can also cause tiny cuts through which bacteria can enter the bloodstream. Advise patients to seek medical attention if they experience signs/symptoms of TSS¹⁷:

• nausea or vomiting

• sudden high fever and chills
• watery diarrhea
• rash resembling a bad sunburn or red dots
• dizziness, light-headedness, or fainting
• hypotension
• red eyes (conjunctivitis)
• peeling on the soles of feet or palms of hands

 

Depo-medroxyprogesterone acetate (DMPA) is a longer-lasting injectable contraceptive injected every three months either intramuscularly into the gluteal or deltoid muscle or subcutaneously into the abdomen or thigh.¹⁸ This eliminates daily adherence concerns. DMPA is about 94% effective with typical use.⁹ Note that Connecticut law prohibits pharmacists from administering DMPA injections without a collaborative practice agreement, but patients may self-administer DMPA subcutaneously if desired and indicated.

 

Injection timing is somewhat flexible. Early DMPA injection is safe if women cannot follow routine intervals, and patients can inject up to two weeks late without requiring back-up contraception.¹⁸ Women who are more than two weeks late, however, should use back-up contraception for seven days after receiving the injection. Return to fertility may be delayed six to 12 months after discontinuation, so DMPA is not recommended for women desiring pregnancy in the near future.¹⁸

 

DMPA’s most common adverse effects are weight gain, decreased bone mineral density, and bleeding irregularities (e.g., spotting, prolonged bleeding, amenorrhea).¹⁸ DMPA carries a Boxed Warning indicating patients should not use the drug for more than two years due to bone mineral density loss, which may be irreversible.¹⁸ Patients should only use DMPA for more than two years if all other contraceptive methods are inadequate. Ensure patients are adequately trained to self-inject DMPA before leaving the pharmacy.

 

Emergency Contraceptives

Two oral emergency contraceptives (ECs) are currently available: a single dose of progestin (levonorgestrel 1.5 mg) or an anti-progestin (ulipristal acetate 30 mg).⁷ Levonorgestrel is available over the counter, while ulipristal requires a prescription.^19,20 Neither of these is abortifacient (i.e., they do not end an existing pregnancy), rather they work by blocking or delaying ovulation.

 

Women should take oral EC as soon as possible following unprotected intercourse, levonorgestrel within 72 hours and ulipristal acetate within five days.^19,20 Repeat levonorgestrel use shows no serious adverse effects, but studies have not examined repeat use of ulipristal acetate.⁷ Upon prescribing emergency contraception, pharmacists should evaluate women for long-term contraceptive eligibility to prevent repeat use of EC.

 

EC may alter the next expected menses.^19,20 Patients whose cycles are delayed more than one week should test for pregnancy. Additionally, women who become pregnant after using EC who experience lower abdominal pain should be evaluated for ectopic pregnancy (pregnancy occurring outside the uterus, most often in the fallopian tube).^19,20

 

PAUSE AND PONDER: Where can you find the living document called the United States Medical Eligibility Criteria (U.S. MEC) for Contraceptive Use and how often should you review its contents? (Note that some questions in the post-test will require you to access this document, so you must review it thoroughly.)

 

ELIGIBILITY AND PRESCRIBING

 

CDC Eligibility Criteria

The CDC publishes the United States Medical Eligibility Criteria (U.S. MEC) for Contraceptive Use to guide safe use of contraceptive methods for women with various medical conditions and other characteristics.²¹ The most current version of these guidelines (as of February 2024) can be found at https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/summary.html. Appendix A of this activity includes the entire U.S. MEC and the 2020 update. The CDC has also created a summary chart, included in Appendix B, and pharmacists should note that the summary chart is a convenience that does not replace a responsibility to access the entire document when necessary. Pharmacists actively prescribing hormonal contraceptives should regularly monitor for updates to this living document.

 

The U.S. MEC includes recommendations for contraceptive use based on patient characteristics or medical conditions.²¹ While many off label uses exist for contraceptives, these CDC recommendations apply only to these products’ indicated use to prevent pregnancy.

 

Four categories of medical eligibility criteria for contraceptive use exist within the U.S. MEC:

• Category 1: conditions for which no restrictions exist for use of the contraceptive method
• Category 2: conditions for which the advantages of using the method generally outweigh the theoretical or proven risks; the method can generally be used, but careful follow-up might be required
• Category 3: conditions for which the theoretical or proven risks usually outweigh the advantages of using the method; use is not recommended unless other more appropriate methods are not available or acceptable, so condition severity and the availability, practicality, and acceptability of alternative methods should be considered, and careful follow-up is required
• Category 4: conditions that represent an unacceptable health risk if the contraceptive method is used

 

Be mindful that provision of a contraceptive method to a woman with a condition classified as category 3 requires careful clinical judgement and access to clinical services that may be unavailable to pharmacists. Referral may be needed. Pharmacists should never prescribe a hormonal contraceptive method to a patient with a category 4 health condition related to its use.

 

Pharmacists should also take note of whether continuation criteria exist for the product prescribed.²¹ Continuation criteria is clinically relevant when a medical condition develops or worsens during use of a contraceptive method. When risk categories differ for initiation and continuation, the differences are noted in the Initiation and Continuation columns. When these distinctions are not indicated, the category is the same for initiation and continuation of use.²¹

 

Additionally, these categories only concern safety, but many other factors must be considered when choosing a contraceptive method. Classification as a category 1 means that the method can be used with no regard to safety but does not necessarily mean that method is the best choice for that patient. Consider other factors, including effectiveness, availability, and acceptability.

 

Determining Pregnancy Status

The Centers for Disease Control and Prevention (CDC) recognizes that routine pregnancy testing for women is not necessary before the initiation of contraception in all cases. Based on clinical judgment, healthcare providers can omit a pregnancy test if a woman has no signs or symptoms of pregnancy and meets any of the following criteria²¹:

• Is fewer than seven days after the start of normal menses
• Has not had sexual intercourse since the start of last normal menses
• Has correctly and consistently used a reliable contraception method
• Is fewer than seven days after spontaneous or induced abortion
• Is within four weeks postpartum
• Is fully or nearly-fully breastfeeding (exclusively or at least 85% of feeds), amenorrhoeic, and less than six months postpartum

 

Screening Documents Simplify the Process

A prescribing pharmacist must assist the patient in completing a screening document for hormonal contraceptives or emergency contraceptives, as applicable. These and all documents related to prescribing of hormonal contraceptives by pharmacists in the state of Connecticut are available at the Department of Consumer Protection’s (DCP) website: https://portal.ct.gov/DCP/Drug-Control-Division/Drug-Control/Drug-Control---Pharmacist-Contraceptive-Prescribing. Prescribing pharmacists are responsible for ensuring their pharmacies use the most current version of all screening documents at all times.

 

When an individual requests a hormonal contraceptive, pharmacists must first determine the patient’s age. If the patient is 18 years or older, the pharmacist may continue to prescribe with this guidance, but if the patient is younger than 18 years, the pharmacist may only issue a prescription upon confirming the patient has previously been prescribed a contraceptive by another provider through one of the following means:

• With the patient’s permission, contact the office or clinic where the patient visited a healthcare provider via telephone, facsimile, or shared health record system
• With the patient’s permission, contact the pharmacy that previously dispensed a contraceptive prescription to the patient via telephone, facsimile, or shared health record system
• Other acceptable documentation or evidence that demonstrates the patient has received prescription contraceptives (e.g., visit summary from the clinic that prescribed it, old prescription package/label)

 

The pharmacist must keep an electronic or written record of the action taken to confirm prior prescription for a minimum of 3 years. Whether prescribing a continuation of hormonal contraceptive therapy or initiating a new one, confirm the patient has been seen by a provider within the last 3 years either through written documentation (e.g., a visit summary) or contacting the office or clinic with the patient’s permission. Without this confirmation, pharmacists may not prescribe hormonal contraception.

 

Individuals with obesity (body mass index 30 kg/m² or greater) and patients using drugs that inhibit CYP3A4 (e.g., bosentan, carbamazepine, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, St. John’s wort, topiramate, efavirenz, lumacaftor) may experience decreased efficacy with EC.²¹ Patients ineligible for EC prescribing include those who

• are confirmed pregnant (though no harm to the woman, the course of her pregnancy, or the fetus if EC is inadvertently used is known to exist)
• have undergone bariatric surgery that may affect EC absorption (e.g., Roux-en-Y gastric bypass, biliopancreatic diversion); an emergency intrauterine device may be more appropriate

 

If a patient seeking EC is deemed ineligible for prescribing, the pharmacist should not prescribe the EC, refer the individual to a primary care provider (PCP), and document the reason(s) for refusal on the screening documents. If the patient has no PCP, the pharmacist should provide information regarding local providers.

 

Hormonal Contraceptive Screening and Prescribing

Upon determining patient eligibility, have the patient complete the Connecticut Hormonal Contraceptive Self- Screening Questionnaire found on the DCP website. The questionnaire addresses

• patient demographics (e.g., insurance status, allergies, preferences)
• background information (e.g., last menstrual period, history of contraceptive use)
• medical history (e.g., smoking status, preexisting conditions)
• pregnancy status

 

Review this screening tool with the patient and clarify responses if needed. If a patient is requesting CHCs or they are recommended, measure and record the patient’s seated blood pressure. If the patient does not complete the questionnaire, a pharmacist cannot issue the prescription. Pharmacists should keep the completed questionnaire on file for at least three years. Patients must fill out a new questionnaire at least once every 12 months, but pharmacists can request this more frequently if desired.

 

Pharmacists should then use patient questionnaire responses to follow the Standard Procedures Algorithm for Connecticut Pharmacist Prescribing of Contraceptives found on the DCP website. This algorithm, with its clinical assessment sections summarized in Figure 1, assists in screening for red flags requiring provider referral. Pharmacists should access the complete document on the DCP website before attempting to take the post-test.

 

Figure 1. Simplified Assessment Sections of the Algorithm for Contraceptive Prescribing

*Anticonvulsants, antiretrovirals, antimicrobials, barbiturates, herbs and supplements, including but not limited to: carbamazepine, felbamate, phenobarbital, lamotrigine, oxcarbazepine, ritonavir, primidone, griseofulvin, St. Jonh’s wort, topiramate, phenytoin, lumacaftor/ivacaftor, and rifampin/rifabutin.

 

Pharmacists should pay special attention to steps 6 and 7 of the Standard Procedures Algorithm (and take a moment to access it now). It describes counseling points on starting hormonal contraception, managing expected and unexpected side effects, and appropriate adherence. Not that Step 7 is critical! Women need to be reminded about routine healthcare and sexually transmitted infection prevention. And the pharmacist’s job isn’t done until the paperwork is filed.

 

If hormonal contraceptives are not clinically appropriate based on the treatment algorithm, the pharmacist should refer the patient to a practitioner, not prescribe the hormonal contraceptive, and document the reason(s) for refusal on the screening documents. The State of Connecticut provides a Pharmacist Referral and Visit Summary template that may be used for this purpose. If hormonal contraceptives are clinically appropriate, pharmacists may prescribe a total of no more than 12 months including initial filling of the prescription along with refills. Refills may be transferred to another pharmacy if desired, as a pharmacy that does not have a prescribing pharmacist may dispense a prescription written by a prescribing pharmacist. Pharmacies may not, however, fill prescriptions written by pharmacists authorized to prescribe in other states but not in Connecticut.

 

Emergency Contraceptive Screening and Prescribing

To be eligible for a self-administered EC prescription, an individual must complete the Connecticut Emergency Contraception Self-Screening Questionnaire found on the DCP website indicating that the last day of unprotected intercourse was within the previous five days (120 hours). Pharmacies may create and use an electronic version of this self-screening tool if the collection of patient information and assessment process is at minimum identical to the state-provided questionnaire. The pharmacist must review the screening tool with the patient, clarify responses if needed, and measure and record the patient’s seated blood pressure.

 

Pharmacists should consider the following when choosing between levonorgestrel and ulipristal acetate for EC:

• Levonorgestrel may be less effective than ulipristal acetate for women who weigh more than 165 lbs
• Levonorgestrel may be preferable for patients who need EC due to missed or late administration of existing hormonal contraception
• Starting hormonal contraceptives immediately after taking ulipristal acetate (within 5 days) may make it ineffective
• Insurance may still cover OTC levonorgestrel if a pharmacist prescribes the product
• Ulipristal acetate is more effective than levonorgestrel if more than 72 hours have passed since the last day of unprotected intercourse

 

Prescriptions for EC may not have any refills. Upon prescribing EC, counsel patients on the product’s proper use and potential adverse effects and provide written educational materials. The pharmacist must also notify the patient’s PCP and obstetrician/gynecologist (OB/GYN) with the patient's consent. If the patient does not have a PCP, the pharmacist should counsel the patient regarding the benefits of establishing such a relationship and, upon request, provide information regarding local providers. The pharmacist should also counsel the patient regarding the importance of preventive care, including routine well-woman visits, testing for sexually transmitted infections, and pap smears. Additionally, consider whether patients should also be evaluated for ongoing hormonal contraception, especially if they visit the pharmacy repeatedly for EC.

 

STICKING TO THE LAW

 

PAUSE AND PONDER: Are you ready for pharmacy-based contraceptive prescribing? Where will you maintain your documentation?

 

Documentation and Recordkeeping

Pharmacies must maintain appropriate records of hormonal contraceptive and EC prescribing:

• All completed screening documents must be maintained at the prescribing pharmacy in the same manner as the prescription itself for at least three years.
• All records created as part of the prescribing process must be maintained for at least three years and be readable retrievable and provided to DCP within 48 hours

 

Prohibited Acts

A prescribing pharmacist shall not

• prescribe any hormonal contraceptive or EC in an instance where the screening document for hormonal contraceptive or screening document emergency contraceptives indicates that referral to a practitioner is clinically appropriate
• prescribe any hormonal contraceptive or EC without a completed screening document for hormonal contraceptive or completed screening document for emergency contraceptive, as applicable
• issue a prescription for a total supply period exceeding 12 months based on the directions of use provided on the prescription
• prescribe any hormonal contraceptive or EC outside of the approved use stated in the product’s FDA-approved package insert
• prescribe a medical device, with or without hormonal contraceptives, that is implanted by a practitioner for the purpose of preventing pregnancy, including intrauterine and implantable devices

 

Pharmacy Technician and Intern Involvement

Pharmacy technicians who have completed an approved training course for prescribing of hormonal contraceptives may, at the pharmacist's request, assist the pharmacist in prescribing a hormonal contraceptive by:

• providing the screening document to the patient
• taking and recording the patient's blood pressure
• documenting the patient's medical history

 

A registered pharmacist intern may prepare a prescription for a hormonal contraceptive under the direct supervision of a trained prescribing pharmacist, but a pharmacist authorized to prescribe under this protocol must review, approve, and sign the prescription before the prescription is processed or dispensed.

 

CONCLUSION

Pharmacist prescribing removes significant barriers to patient access and use of hormonal contraceptives and EC to prevent pregnancy especially for those with limited access to healthcare services or busy schedules. More than 90% of Americans live within five miles of a pharmacy, making pharmacists the most accessible healthcare professionals and perfectly positioned to improve contraceptive access.²² Pharmacist involvement can lead to better education and counseling on contraceptive options, promoting informed decision-making and improving therapy uptake and adherence.

APPENDIX A – CDC US Medical Eligibility Criteria for Contraceptive Use, 2016

 

APPENDIX B – CDC US Medical Eligibility Criteria for Contraceptive Use, 2016, SUMMARY CHART

 

 

Download CE Activity

“I believe that misinformation is now our leading cause of death... People are distracted and misled by the medical information Tower of Babel.”¹ Dr. Robert Califf, Commissioner, Food and Drug Administration.

 

INTRODUCTION

The world faced a deadly infection running rampant. Some health experts believed that a vaccine could confer protection against the infection, but this view was met with skepticism and distrust. Misinformation spread within and beyond the scientific community and debates about the inoculation’s safety and efficacy emerged on many fronts. Physicians observed infections in some vaccinated individuals and opponents began speaking publicly about their distrust of the vaccine. The use of an animal source for the vaccine contributed to the belief that miniature cow heads could grow from sites of vaccination. Vaccine hesitancy and fear grew among the public.²

 

While this may sound like recent events, it describes the atmosphere surrounding the development of a vaccine for smallpox in 1796.² Many years later, the increasing popularity of television [like social media today] exaggerated fears of smallpox vaccination by broadcasting both descriptions and visual footage of the rare instances in which the smallpox vaccine produced severe adverse effects.² This messaging skewed perceptions about the vaccine’s risk/benefit profile and further eroded trust in the scientific community. Overall, these misperceptions delayed the worldwide eradication of smallpox by more than 200 years.²

 

This narrative illustrates that misinformation is not a recent phenomenon. Examples can be cited going back thousands of years.³ More significantly, it demonstrates misinformation’s destructive consequences. Recently, misinformation rose to unprecedented prominence with the COVID-19 pandemic, with the Director of the International Fact Checking Network calling COVID-19 “the biggest challenge fact-checkers have ever faced.”⁴

 

Health misinformation can be harmful. U.S. Surgeon General Dr. Vivek Murthy has stated, “Misinformation takes away our freedom to make informed decisions about our health and the health of our loved ones. Simply put, health misinformation has cost us lives.”⁵

 

Health misinformation can influence political, economic, and social well-being. People can become confused and anxious when faced with contradictory information, and this is especially dangerous during a public health crisis.^5,6 It can expose patients to wasteful and harmful products and procedures, delay treatment with a more scientifically based therapy, and divide families and communities.⁶

 

Pharmacists, of course, also have a role during a healthcare crisis and can be either another source of misinformation or a resource to clarify and refute poor advice. This continuing education activity will examine some recent efforts by governmental and non-governmental organizations to limit information that is contrary to mainstream medical advice and the sanctioning (or lack thereof) of healthcare providers for encouraging such therapies. Various approaches by governmental agencies to deal with conflicting information have raised legal issues when trying to restrict the free flow of information.

 

Disclaimer: Please note that the examples referred to in this lesson were chosen based upon their high-profile and impact and should not be interpreted as representing any political commentary, agenda, or endorsement by the author or publisher. It is acknowledged that “misinformation” is hard to characterize, and a consensus can shift as more data are developed. One should also not infer that the examples represent a deliberate intent to deceive by their sponsors.

 

PAUSE AND PONDER: What should be the role for pharmacists and pharmacy technicians in mitigating the impact of misinformation?

 

MISINFORMATION

Misinformation is frequently used as a catch-all term for related concepts such as disinformation, ignorance, rumor, and conspiracy theories, often resulting in different interpretations and imprecise definitions.⁷ Misinformation is often distinguished from disinformation on the basis of intent. In this context, misinformation is used to describe information that is unintentionally erroneous (e.g., mistakenly repeated or due to ignorance) while disinformation is information that is deliberately intended to mislead or deceive (e.g., malicious, fraudulent, or for propaganda).⁷

 

Health misinformation has been defined as information that is false, inaccurate, or misleading according to the best available evidence at the time (emphasis added).⁵ This definition recognizes that the accuracy and recognition of information can change as new data or experiences emerge. Although not health related, one needs to look no further than the writings of Galileo to find an example of information that was once condemned and humiliated. Formerly branded a heretic for claiming that the earth rotated around the sun, Galileo’s ideas later became the fundamental basis for astronomy and space travel.⁸                                   

 

Public health recommendations changed rapidly during the progression of the COVID pandemic and resulted in confusion among the public and distrust of public health agencies. A recent survey found that 60% of adults in the U.S. say they have felt confused as a result of changes to public health officials’ recommendations on how to slow the spread of the coronavirus.⁹ In addition to confusing patients, negative consequences of health misinformation include misallocation of health resources, fraud, increased reliance on unreliable cures, a negative impact on mental health, and an increased hesitancy to seek medical care.

 

CAN MISINFORMATION BE REGULATED?

If misinformation is a dangerous phenomenon, as many have suggested, can anything be done to control its flow? During COVID, officials from the federal government, many states, and healthcare and professional organizations promulgated regulations and policies aimed at limiting or promoting health information as will be described below. Some of these approaches have threatened to impose sanctions against practitioners who have disseminated erroneous or misleading information.

 

However, the suppression of information can face constitutional challenges.¹² Healthcare professionals, like all Americans, have a right to speech that is free of government restrictions even if the content is false.¹³

 

Justice Thurgood Marshall wrote in a Supreme Court decision in 1972, “…the First Amendment means that government has no power to restrict expression because of its message, its ideas, its subject matter, or its content.”¹⁴ The rights enumerated in the First Amendment protect individual against government infringement on their expression, but do not protect them from other individuals, businesses, or private organizations.¹⁵ Healthcare professionals can be disciplined by professional licensing boards and health departments for certain actions, but these organizations are governmental bodies (termed state actors in constitutional law) and they, along with public hospitals and universities, are prohibited from infringing on free speech.¹⁵

 

A content-based restriction “discriminates against speech based on the substance of what it communicates” and receives the greatest protection from any government-imposed restrictions.¹⁶ Content-based restrictions are presumptively unconstitutional and can only be applied if the state shows that the prohibition is the least restrictive means of achieving a compelling state interest such as the protection of public health and safety.¹⁶ (Compelling means essential or necessary rather than a matter of choice, preference, or discretion.¹⁶) The Supreme Court recognizes that certain narrow categories of expression, such as obscenity, child pornography, true threats, and incitement to imminent lawless action, can be barred because of their harmful content.¹⁶ Learners who are interested in learning more about how the courts scrutinize speech can find excellent information here: https://crsreports.congress.gov/product/pdf/R/R47986

 

Commercial speech, on the other hand, does not receive as much protection as content speech. Commercial speech applies when there is some form of transaction and includes commercial advertising and solicitations.^12,16 Historically, commercial speech did not receive any First Amendment protection, but an important 1976 Supreme Court decision involving pharmacies extended protection to commercial speech.¹⁶ The case, Virginia State Board of Pharmacy v. Virginia Citizens Consumer Council, challenged a state law that made it illegal for pharmacies to advertise drug prices. The Court reasoned that the First Amendment not only granted the speaker the right to speak, it also granted the listener the right to receive information. Commercial speech receives some protection because it serves the important societal interests of providing information to consumers and promoting the economic interests of the speaker.¹² In the case cited, consumers had a right to receive lawful information about drug prices.¹⁶ This narrow exception to free speech could apply in cases where a healthcare practitioner monetizes health misinformation.¹²

 

Commercial speech can be restricted if it is false, misleading, or proposes an illegal transaction since consumers must be able to make informed decisions.¹² Unlike political speech, where it may be difficult to ascertain what is truthful, courts recognize that commercial advertising is more objective and more readily subject to determination of its truthfulness.¹⁶

 

Courts have also traditionally recognized a third form of speech, professional speech, which is “uttered in the course of professional practice” as distinct from “speech . . . uttered by a professional.”¹⁷ This form of speech could also be restricted. Some courts have ruled that healthcare practitioners are entitled to less stringent First Amendment protection when providing professional advice to individual patients than when speaking to a larger audience about public issues.¹³

 

However, a 2018 Supreme Court decision overturned the prior recognition of professional speech as a separate category that would receive lesser First Amendment protection.¹² The Court’s decision stated that “speech is not unprotected merely because it is uttered by 'professionals.’” Consequently, speech expressed by professionals receives complete protection unless it falls under the commercial exception.

 

There are also practical concerns that sanctioning health professionals for questioning accepted medical standards when they feel they are inaccurate or misguided may stifle advances in practice.¹³ This is especially troublesome during a public health crisis when guidance from public health officials evolves as circumstances and knowledge unfold. The many examples of shifting public health recommendations during the COVID pandemic underscore this concern.¹⁸ Generally, healthcare providers have greater latitude when speaking on medical matters to the general public, such as on social media, than they do when providing medical advice to a specific patient.¹⁹

 

While constitutional protection is available to healthcare providers when sharing their view on medical matters, other legal situations can impact speech.¹⁹ An employment contract can restrict how much leeway a healthcare provider has, and tort law (malpractice claims) may provide penalties for improper medical advice, especially in the context of informed consent.^15,19

 

DISCIPLINING HEALTHCARE PROVIDERS FOR MISINFORMATION

Professional licensing boards provide oversight to ensure that rules governing the profession are followed.¹³ The structure and authority of medical and pharmacy boards vary from state to state.¹³ Each state has Practice Acts that prohibit licensed healthcare practitioners from engaging in “unprofessional conduct,” although the definition of unprofessional conduct may vary from state to state. Unprofessional conduct is the most common reason for disciplinary action against healthcare personnel.¹³ States have applied standards of professional conduct when trying to sanction healthcare personnel for misinformation (see below).

 

It should be apparent that when attempting to sanction a healthcare provider for misinformation, state regulatory agencies must walk a fine line. During COVID, a number of healthcare organizations endorsed revocation of the licenses and certifications of physicians who disseminated harmful health misinformation such as rejection of widely accepted preventive measures and endorsement of unproven treatments. The organizations included the Federation of State Medical Boards (FSMB) and professional certification boards such as the American Boards of Family Medicine (ABFM), Internal Medicine (ABIM), and Pediatrics (ABP).¹³

 

The FSMB took note of the “dramatic increase in the dissemination of COVID-19 vaccine misinformation and disinformation by physicians and other healthcare professionals on social media platforms, online and in the media” and issued a warning to physicians that that they risk suspension or revocation of their medical licenses by state medical boards if they generate and spread COVID-19 vaccine misinformation or disinformation.²⁰

 

The FSMB commented, “Due to their specialized knowledge and training, licensed physicians possess a high degree of public trust and therefore have a powerful platform in society, whether they recognize it or not. They also have an ethical and professional responsibility to practice medicine in the best interests of their patients and must share information that is factual, scientifically grounded and consensus-driven for the betterment of public health.” Although the statement focused on vaccination, it could apply to all health information and spreading inaccurate information undermines that responsibility and “threatens to further erode public trust in the medical profession and puts all patients at risk.”²⁰ Of course, the same comments would apply to pharmacists and other health professionals.

 

State medical boards have traditionally brought disciplinary actions against physicians for making false or misleading statements in situations such as serving as an expert witness in malpractice cases.²¹ Some state laws explicitly authorize disciplinary action against physicians who make false, deceptive, or misleading statements to the public. In most cases, these statutes apply to statements made in connection with advertising, especially when solicitating patients. (See distinction between content-based and commercial speech above.) However, some are worded broadly enough to cover other forms of misrepresentation.^13,21 For example, Minnesota authorizes disciplinary action against physicians who engage in “conduct likely to deceive or defraud the public.”²¹

 

It is not clear how often healthcare professionals are sanctioned for spreading misinformation, but it appears to be infrequent.²² The president of the FSMB has pointed out that medical license renewals are designed to be simple for applicants and it is usually an automatic procedural step. He added that medical boards do not have the capacity to review the large number of renewals that occur each year.²²

 

The license suspension process is long and slow with procedural barriers. Investigations will ordinarily begin only in response to a complaint, rather than being initiated by the board itself.²³ Licensing boards are primarily concerned with medical malpractice, patient abuse, and illegal activity, so misinformation takes a relatively low priority.²³ Moreover, both non-renewals and suspensions require due process.²² In addition, it can be difficult to evaluate whether a comment is outside the range of scientific and medical consensus and boards are reluctant to take action on a “fringe” opinion.²³ Investigations can take months or years to complete and many proceedings are conducted in private.²⁴ In many states the legal framework for discipline, which was developed in the 20^th century, may narrowly apply to actions or speech related directly to patients under the physician’s care and not to broader circumstances like social media.²⁵ Moreover, boards face daunting legal and policy obstacles if they try to take action (see below).^25,26 Political opposition from legislators in some states can also impede a board’s actions (see below).²⁵

 

The arguments for disciplinary proceedings by licensing boards usually emphasize the potential harm to public health.¹³ However, this may be insufficient to achieve constitutionality in most cases where it would be necessary to apply the “least restrictive means” test mentioned above.¹³ A state can instead mitigate the harm by disseminating factually accurate messages, especially in instances where the commercial speech exception would not apply.¹³

 

PAUSE AND PONDER: Is a state licensing board the best party to try to dissuade healthcare practitioners from issuing information of questionable validity?

 

Professional credentialing boards (private organizations providing certification) can also take steps to minimize misinformation. For example, consider a pharmacist who works in a large health system and has a specialized position running a hypertension clinic; she has been credentialed to prescribe medication and adjust dosing. The terms of her credentialing may restrict the type and quality of the information she can provide to patients and the credentialing board can retract her credentials if she begins to tell patients that ACE inhibitors are terrible antihypertensives. A joint statement from the ABFM, ABIM, and ABP declared that providing misinformation about the COVID-19 vaccine contradicts physicians' ethical and professional responsibilities and warned physicians that such conduct may prompt a Board to take action that could put their certification at risk.²⁸ (Credentialing boards as non-state actors have more latitude to impose penalties.)

 

STATE ACTIONS AND PUSHBACK

Concerns over misinformation during the pandemic prompted various health related organizations to take steps. Boards in at least a dozen states have issued sanctions against physicians for spreading dubious information.²⁴

 

While private professional organizations can impose loss of credentialing, state licensing boards can levy more serious sanctions such as loss of licensure or fines. Recent Board actions have generated a number of legal skirmishes. In addition to state regulatory bodies like licensing boards, state legislatures have acted directly to address misinformation. Different states have taken different – even opposite – approaches to this issue.

 

California

In 2022, the California legislature passed a bill stating that “the dissemination of misinformation or disinformation related to COVID-19 by physicians and surgeons constitutes unprofessional conduct.”²⁸ The types of false or misleading information that could lead to disciplinary action include communication about the nature and risks of the COVID-19 virus; its prevention and treatment; and the development, safety, and effectiveness of COVID-19 vaccines. False statements regarding prevention and treatment “would presumably include the promotion of treatments and therapies that have no proven effectiveness against the virus.” The bill’s proponents expressed the view that “providing patients with accurate, science-based information on the pandemic and COVID-19 vaccinations is imperative to protecting public health.” They also said that the bill was necessary because “licensed physicians ... possess a high degree of public trust and therefore must be held accountable for the information they spread.”²⁸ By passing this legislation, the law continues, “California will show its unwavering support for a scientifically informed populous to protect ourselves from COVID-19.”²⁸

 

PAUSE AND PONDER: Should laws such as those discussed above include other healthcare professionals, such as pharmacists, instead of focusing only on physicians?

 

Under the statute, the misinformation or disinformation must be conveyed “[by] the licensee to a patient under the licensee's care in the form of treatment or advice.”²⁸ It excludes speech outside of a direct physician-relationship such as social media postings.²⁹ California Governor Newsom also indicated that he is “confident that discussing emerging ideas or treatments including the subsequent risks and benefits does not constitute misinformation or disinformation under this bill's criteria."²⁹

 

The bill’s original intent was an effort to grant California’s Medical Board the power to discipline providers who were found to have conveyed misinformation about COVID vaccines and treatments. The proposed bill included statements they might make on social media or in other public forums such as public protests. It was narrowed, however, to apply only to conversations between a provider and a patient in clinical settings when the practitioner made statements that were "contradicted by contemporary scientific consensus contrary to the standard of care."³⁰ Opponents said the statute was overly broad and that information considered scientific consensus about the rapidly-mutating virus could change daily.³⁰ They also argued that providers had the right to express their opinions in clinical settings.³⁰

 

Two different lawsuits were filed seeking an injunction against enforcing the law and the judges hearing the cases reached different conclusions.³¹ In one case, the judge declined to grant the injunction.³¹

 

In the other, filed in a different California judicial district, a group of physicians licensed in California were joined by organizations representing the interests of doctors and patients. They sued the State alleging that the above statute was in breach of their First and Fourteenth Amendments rights (i.e., free speech and equal protection rights).³² The physicians had provided advice and treatments contrary to public health recommendations (universal masking or vaccines) and intended to continue to do so, claiming it was consistent with the standard of care.^32,33 They also claimed that the law’s definition of misinformation as false information that is “contradicted by contemporary scientific consensus” would suppress the ability of physicians to advise patients about the pros and cons of alternative COVID-19 treatment and practices.^32,33

 

The court in this case granted a temporary injunction, ruling that the law’s definitions of misinformation and the uncertainty about its enforcement were “unconstitutionally vague”³² The Court noted that a phrase defining the unlawful conduct, as contradicting “contemporary scientific consensus,” lacked any established meaning within the medical community and was not clarified further in the statute.³² They went on to say that it “fails to provide sufficiently objective standards to focus the statute’s reach.” The judge found this particularly problematic in the context of the pandemic since scientific understanding of the virus had repeatedly changed, negating a true consensus.³²

 

He went on to say that the law leaves many questions unanswered, such as who determines whether a consensus exists? Moreover, the judge ruled that the term “scientific consensus” is so ill-defined that the physicians would be “unable to determine if their intended conduct contradicts the scientific consensus, and accordingly ‘what is prohibited by the law.’”

 

The conflicting decisions necessitated a resolution (since the law could not be simultaneously upheld and enjoined). The first case was appealed, but the state repealed the law before the court could rule.³⁴ Following the court’s decision granting the injunction, the state rescinded the law about a year after it was signed.^30,31

 

Missouri

Missouri also enacted statutes dealing with the dissemination of COVID-related health information, but their approach was quite different from California. A law passed in 2022 prohibits the state boards overseeing medicine and pharmacy from disciplining a registered practitioner for “lawfully” prescribing or dispensing ivermectin or hydroxychloroquine for human use.³⁵ In other words, the prescribing or promotion of these drugs could not be used as a basis for establishing unprofessional conduct and sanctioning a healthcare practitioner.

 

A second part of the law prohibits pharmacists from contacting the prescribing a physician or the patient to dispute the efficacy of ivermectin or hydroxychloroquine unless the physician or patient inquires of the pharmacist about the drug’s efficacy.³⁵ In other words, a pharmacist would be prohibited from expressing legitimate concern about questionable treatments.³⁶ (The Missouri Pharmacy Association issued a clarification that pharmacies are not required to dispense nor stock the drugs, nor does it prevent a pharmacist from counseling a patient who should not take these drugs due to certain health conditions or interactions.³⁶)

 

A sponsor of the bill indicated that these actions were necessary because “certain pharmacists wanted to begin acting like physicians and denying the filling of the prescriptions. This re-establishes the professional equilibrium between doctors and pharmacists.”³⁷ No doubt most pharmacists are grateful that the equilibrium has been reestablished.

 

A pharmacist also challenged this law on First Amendment grounds. The pharmacist’s suit alleged that “all pharmacists in Missouri, now face the impossible—and constitutionally impermissible—conundrum of deciding whether to endanger their livelihood when choosing whether to speak in a manner that is both vital to their professional duties to patients and protected by the First Amendment.”³⁸ The pharmacist believed that it is a matter of legitimate professional ethics to contact a patient or prescriber to dispute a medication’s efficacy.

 

The court granted an injunction against implementation of the new law stating that the relevant section quoted above “infringes the free speech rights of Plaintiff and other Missouri-licensed pharmacists by threatening to impose liability based on the viewpoint of their speech.”³⁸ The court pointed out that the regulation “does not prohibit pharmacists from initiating contact to tout, endorse, or acclaim the drugs, thus it is taking sides in a politically charged debate about the drugs efficacy."³⁸ In other words, it was a content-based restriction of speech (see above) and therefore was an impermissible infringement of the First Amendment.

 

The Board replied that the statute was constitutional because it regulated conduct and not speech.³⁸ Unpersuaded by this argument, the court noted that the statute does not prohibit initiating contact with patients or prescribers which would be a permissible regulation of conduct. Instead, it prohibits contact only if the pharmacist wishes to "dispute the efficacy of ivermectin tablets or hydroxychloroquine sulfate tablets for human use.” The court also said that this interpretation is “consistent with the legislature's apparent purpose in enacting (the law): to insulate ivermectin or hydroxychloroquine from criticism.”³⁸

 

Elsewhere Around the U.S.

In other states, attempts by medical boards to restrict dissemination of health information that deviates from mainstream medicine have faced backlash from state legislatures. Dozens of state legislatures (e.g., North Dakota) have introduced or passed measures that would prevent a regulatory agency from punishing medical providers who promote COVID-19 misinformation or unproven treatments.^15,39

 

A particularly contentious dispute arose in Tennessee between the state licensing board and the state legislature. The Board of Medical Examiners unanimously declared that physicians spreading false information about COVID would put their license in jeopardy and the board posted the new policy on its website.⁴⁰ Soon afterwards, state legislators charged that the board had overstepped its authority and demanded that the statement be deleted from the state’s website. The state threatened to disband the board.^39,40

 

Many of the same Tennessee legislators had previously threatened to defund the Health Department when it promoted COVID vaccines to teens and introduced a bill that would have prevented the board from disciplining physicians for administering any treatment for COVID-19, even if it is not recommended by the Department of Health nor the FDA.³⁹ Another proposed bill would have prevented pharmacists from interfering with prescriptions to treat COVID.

 

Despite the threats, the Tennessee board voted to retain the misinformation policy with a tweaking of the definition of misinformation.⁴¹

 

A similar situation arose in Washington state. Four physicians threatened with disciplinary action by the state Medical Commission for misinformation challenged the commission's policy statement. They claimed that the commission did not follow their standard procedures in implementing the policy and that the position statement infringed their constitutional right to free speech.⁴² The physicians faced charges over their alleged care for COVID patients with unproven treatments and "false and misleading" statements regarding the pandemic and vaccination. The physicians maintained that the distinction between them and “other medical professional[s] who were not investigated and charged under the Statement is that plaintiffs dissented politically, scientifically and medically from health officials on various matters related to COVID.”⁴³ The physicians were charged with negligent care; one physician allegedly “failed to discuss alternative treatments” (monoclonal antibodies) with an elderly, unvaccinated patient with a COVID-19 infection who later died.⁴³

 

FDA Lawsuit

On a broader scale, the controversy over misinformation has even touched the FDA. In 2024, a lawsuit was brought against the FDA’s messaging with potentially very significant consequences. Three physicians in Texas who prescribed ivermectin to thousands of their patients for COVID initiated the suit.⁴⁴ They objected to the FDA’s public advisory and social media posts (“You are not a horse,” a post that is no longer available) warning patients not to use the drug. (See image here: https://www.pharmamanufacturing.com/compliance/regulatory-guidance/news/11291402/you-are-not-a-cow-fda-warns-public).⁴⁵ The physicians claimed that the messages exceeded the FDA’s authority and encroached on the practice of medicine.⁴⁴ The physicians alleged that the posts interfered with their “ability to exercise professional medical judgment in practicing medicine” and harmed their reputations.

 

The FDA claimed sovereign immunity (a legal doctrine that the government cannot be sued without its consent) in its defense.⁴⁶

 

The District Court (first level) judge hearing the case dismissed it, ruling that sovereign immunity protects the FDA.⁴⁶ The court also noted that Congress charged the FDA “with protecting public health and ensuring that regulated medical products are safe and effective” and that “FDA has the authority, generally, to make public statements in-line with these purposes.”⁴⁶

 

The physicians appealed, and the appellate judge reversed the decision, finding, often in very colorful language, that the FDA did exceed its legal authority.⁴⁶ The judge stated that no legal basis allows the FDA to issue recommendations or give medical advice. He wrote that the “FDA is not a physician. It has authority to inform, announce, and apprise—but not to endorse, denounce, or advise.”⁴⁶

 

The FDA argued that it has the authority to communicate information to the public and that the posts are purely informational and not imperative. The court, however, disagreed, finding that the posts contained syntax that directed patients to take action such as “Stop it with the #ivermectin.”⁴⁶ The court also chided the FDA for failing to mention that there is also a human version of ivermectin which was being used off-label to treat the coronavirus.⁴⁶

 

The FDA responded to the decision by agreeing to retire the consumer update entitled "Why You Should Not Use Ivermectin to Treat or Prevent COVID-19" and to delete various related social media posts.⁴⁷ The FDA issued a statement stating that "the agency has chosen to resolve this lawsuit rather than continuing to litigate over statements that are between two and nearly four years old" and that it “stands by its authority to communicate with the public regarding the products it regulates."⁴⁷ Furthermore, the agency indicated that it “has not changed its position that currently available clinical trial data do not demonstrate that ivermectin is effective against COVID-19” and reiterated that it “has not authorized or approved ivermectin for use in preventing or treating COVID-19."⁴⁷

 

While this might appear to be a minor dispute involving the agency and aggrieved prescribers, there are fears that it could have far-reaching implications. There is a concern that the FDA, and possibly other consumer-related regulatory agencies, may need to reevaluate all their communications to the public to ensure that they comply with the decision.⁴⁸ This would obviously limit the agency’s role as a public health educator. It could also disrupt the FDA’s ability to limit a manufacturer’s promotion of off label drug use.⁴⁸ In addition, the physicians’ claim that they suffered harm as a result of the FDA’s actions could lead to more claims against regulatory agencies for damages.⁴⁸ On the other hand, there is a consideration that the ruling could be challenged since it may be at odds with the constitutional principle of government speech in which the government can itself be a speaker and is not required to be neutral when expressing an opinion.⁴⁸

 

PAUSE AND PONDER: What should the FDA’s role be in discouraging misinformation?

 

SUMMARY AND FINAL COMMENTS

Misinformation about health matters became more troublesome during the COVID pandemic, raising concerns that this has had negative consequences for society and public health. Many professional and governmental organizations have expressed apprehension about the influence of health misinformation and have sought to limit its spread by sanctioning healthcare professionals. This has been met with legal challenges by the affected healthcare providers centering around First Amendment protection of speech. At the same time, legislators in many states have tried to suppress these efforts and limit the ability of licensing boards to discipline healthcare providers for their promotion of remedies outside of mainstream medicine. Some legislative efforts have also tried to restrict the ability of healthcare providers, including pharmacists, to express concerns about unproven treatments. Recently, messaging by the FDA has also been challenged with potentially far-reaching consequences. It is important for pharmacists to be aware of the positions taken by governmental agencies and legislators in their state and to respond accordingly.

 

 

 

 

 

 

 

 

 

 

Download CE Activity

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.

 

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