Dr. Jeff Fudin graduated from Albany College of Pharmacy & Health Sciences with a BS and PharmD. He is a Diplomate to the Academy of Integrative Pain Management, a Fellow to ACCP, ASHP, & FSMB, a member of several other professional organizations. He is CEO of Remitigate (remitigate.com), an opioid safety software development LLC. Dr. Fudin is a section editor for Pain Medicine & Co_Editor-A-Large for Practical Pain Management. He practices as a clinical pharmacy specialist (WOC) and director of PGY-2 pharmacy pain residency programs at the Stratton Veterans Administration Medical Center in Albany, New York and has academic affiliations with Western New England University and Albany Colleges of Pharmacy.

Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP

 (Epidiolex, Greenwich Pharmaceuticals) in June 2018 for the treatment of seizures associated with Lennox-Gastaut and Dravet syndromes in patients aged 2 years and older.

 This is the first drug approved by the FDA containing a purified marijuana derivative and the first approved medication for patients diagnosed with Dravet syndrome. 

Since its approval in June, cannabidiol (CBD) has been made 

. As pharmacists, we will likely be called upon as experts in CBD therapeutics. 

 plant, but does not cause the intoxication or euphoria associated with marijuana use, as those psychoactive effects are due to tetrahydrocannabinol (THC). CBD acts within the endocannabinoid system, which is involved with pain modulation and inflammation.

 The endocannabinoid system downregulates the stress-related signals that cause chronic inflammation and pain, effecting the psychological response to discomfort. The 2 main ligands acting within this system include cannabinoid-1 (CB

 receptors are present within the central nervous system while CB

The largest challenge with bringing a CBD product to market was creating one that lacked THC to avoid psychoactivity with slow elimination and prolonged duration of action.

 The prolonged duration of action occurs naturally with a pure CBD in part because cannabinoids are highly lipid-soluble. Due to the known mechanism of CBD, antiseizure activity, and upregulation of CB

 receptor activity, Epidiolex was endorsed by both the FDA and the DEA.

The effectiveness of CBD for the treatment of seizures in patients with Lennox-Gastaut syndrome was proven in 2 randomized, double-blind, placebo controlled trials in patients aged 2-55 years.

 The first study compared CBD 20mg/kg/d versus placebo, while the second study compared CBD 10mg/kg/d and 20mg/kg/d versus placebo.

 Inclusion criteria for both trials was minimally 8-drop seizures during the baseline period. The primary endpoint was the percent change from baseline frequency of drop seizures per 28-days over the 14-week treatment trial. Use of CBD in patients with Lennox-Gastaut syndrome was associated with a significant reduction in total seizure frequency versus placebo. The first trial had a mean percent reduction in total seizure frequency per 28-days of 41% in patients on 20mg/kg/d compared to 14% in the placebo group. In the second trial, there was a mean percent reduction in total seizure frequency per 28-days of 36% in the 10mg/kg/d group, 38% in the 20mg/kg/d group and 18% in the placebo group.

The effectiveness of CBD for the treatment of seizures in patients with Dravet syndrome was proven in a single, randomized, double-blind, placebo-controlled trial of patients aged 2-18 years old.

 The study compared CBD 20mg/kg/d with placebo. The trial included a 4-week baseline period, a 2-week titration and 12-week maintenance period. Inclusion criteria for the trial included 4-convulsive seizures while stable on anti-epilepsy drug therapy during the baseline period. The primary endpoint was the percent change from baseline in the frequency per 28-days of convulsive seizures over the 14-week treatment period. The median percentage change in seizure activity during treatment was 39% in the Epidiolex group versus 13% in the placebo group. 

The most common adverse effects in the trials included lethargy, elevated liver enzymes, decreased appetite, diarrhea, poor sleep quality and infections. CBD T

 is 2.5-5 hours at steady state. If the medication is taken with a high fat or high calorie meal, C

 is increased 5-fold and the AUC is increased four-fold.

CBD is metabolized in the liver and has a plasma half-life of 56-61 hours with twice daily dosing and is primarily excreted in the feces.

The FDA granted a priority review designation for the Epidiolex application and fast track designation was granted for Dravet syndrome, due to the lack of alternative treatments. Orphan drug designation was granted for both indications. After significant review, the FDA approved CBD and the DEA assigned it a Schedule V status.

As pharmacists, we should seek out continuing education programs in this ever-expanding medication class. 

This article was co-written with Leah A. Weiss, PharmD Candidate, 2019 Western New England University College of Pharmacy and Health Sciences in Springfield, MA. She recently completed an elective in advanced pharmacy practice at the Stratton Veterans Affairs Medical Center in Albany NY.

FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy [news release]. Silver Spring, MD; June 25, 2018; FDA website. 

https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm611046.htm?rel=0" ?rel=0" 

Fine PG, Rosenfeld MJ. The endocannabinoid system, cannabinoids and pain. 

Friedman D, Devinsky Orrin. Cannabinoids in the treatment of epilepsy. 

Epidiolex [Package Insert]. Carlsbad, CA: Greenwich Biosciences Inc; 2018.

FDA-approved drug epidiolex placed in schedule V of Controlled Substance Act [news release]. Washington DC; DEA website: September 27, 2018. 

https://www.dea.gov/press-releases/2018/09/27/fda-approved-drug-epidiolex-placed-schedule-v-controlled-substance-act?rel=0" ?rel=0" 

Articles

The FDA approved cannabidiol (CBD) last year for the treatment of seizures associated with Lennox-Gastaut and Dravet syndromes in patients aged 2 years and older. As pharmacists, we will likely be called upon as experts in CBD therapeutics. 

Cannabidiol Gets Thumbs Up from Federal Agencies

This article was originally published by 

A migraine is a disabling, neurologic disease characterized by recurrent episodes of severe headache and/or throbbing recurring pain accompanied by other symptoms, including nausea, vomiting, extreme sensitivity to light and sound, and changes in vision.

 Migraine attacks last between 4 hours and 72 hours with symptom expression that varies between individuals and each attack.

More than 30 million American adults have migraines, with 3 times more women affected by them compared to men.

 According to the Medical Expenditures Panel Survey, the total unadjusted cost associated with migraines in the United States is estimated to be as high as $56 billion annually, yet they remain under-recognized and under-treated, as there is no test or biomarker to confirm diagnosis.

There is currently no single cure for migraines.

 Treatment options are aimed at alleviating symptoms, and include simple analgesics (acetaminophen, NSAIDs), combination analgesics (Midrin, Fioricet), opioid analgesics (Stadol, meperidine), triptans, TCA’s and topiramate. However, these options are not ideal as migraine recurrence rate after utilizing these medications is high. From this unmet need, several new options designed for migraine prevention are in the pipeline. On September 27, 2018, the 

 (Galcanezumab-gnlm) 120 mg, a self-administered once monthly subcutaneous (SC) injection, and the third in its class for the preventative treatment of migraine in adults.

Focus on calcitonin gene-related peptide (CGRP) as a potential migraine target began after failure of substance P-blocking drugs. The 37-amino acid sequence was discovered by chance after researchers realized it was produced in the brain by alternative gene splicing of calcitonin.

 After finding prominent CGRP expression in brain pathways of pain management and blood flow regulation, its involvement in migraines was more relevant.

Researchers found CGRP to be a powerful vasodilator of cerebral blood vessels when released from the trigeminovascular system, and the only significant peptide released prior to a migraine attack.

 In a 2002 study, when CGRP was injected into the blood of individuals that experience migraine attacks they developed migraine-like headaches within hours, whereas individuals without a history of migraines developed at most a mild headache.

 This led researchers to believe that individuals who experience migraines are sensitive to the effects of CGRP and inspired the creation of a class of preventative migraine medication.

Galcanezumab-gnlm is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the CGRP receptor and antagonizes CGRP alpha and beta receptor function.

CGRP is an ideal target for migraine pathophysiology as it is distributed throughout the nervous system, and concentration levels are elevated prior and during acute and chronic attacks. Centrally, CGRP is involved in nociceptive transmission through second and third order neurons and pain modulation in the brainstem. Peripherally, CGRP mediates vasodilation through smooth muscle receptors.

The recommended dose for Emgality is 240 mg (2 consecutive SC injections of 120 mg each) once as a loading dose, followed by monthly doses of 120 mg injected subcutaneously. Hypersensitivity reactions (i.e. rash, urticaria and dyspnea) have been reported with Emgality in clinical studies. The most commonly reported adverse reactions (incidence ≥ 2% and at least 2% greater than placebo) were injection site reactions. Annual cost of treatment is $6,900, but patients with commercial insurance are candidates to receive Emgality for up to 12 months free.

Efficacy and safety of Emgality was demonstrated in two Phase 3 clinical trials in patients with episodic migraine (EVOLVE-1 and EVOLVE-2) and one Phase 3 clinical trial in patients with chronic migraine (REGAIN).

 EVOLVE-1 and EVOLVE-2 were 6-month, double blind, placebo-controlled studies that enrolled a total of 1773 adult patients with episodic migraine (defined as 4-14 migraine headache days [MHDs] per month).

Participants were randomized to once-monthly placebo, Emgality 120 mg after an initial loading dose of 240 mg, or Emgality 240 mg. Both studies excluded patients on any other migraine preventative treatment, patients with medication overuse headache, patients with electrocardiogram abnormalities compatible with an acute cardiovascular event and patients with a history of stroke, myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, deep vein thrombosis or pulmonary embolism within 6 months of screening. As there are CGRP receptors within the cardiovascular system, these exclusions ensure that any effect seen was due to the newly proposed mechanism of action.

Primary endpoint was the mean change from baseline in the number of monthly MHDs over months 1 to 6 in the intent-to-treat study population. For EVOLVE-1, galcanezumab 120 mg was given once monthly for 6 months, with participants receiving a loading dose of 240 mg (2 injections of 120 mg each) administered at visit 3 only.

 Baseline migraine headache days for Emgality was 9.2 and placebo was 9.1. Mean change from baseline was -4.7 days (N=210) for Emgality 120 mg compared to -2.8 days (N=425) for placebo (p<0.001). Results showed at least a 50% reduction in MHDs in any given month of 62% (N=210) for Emgality 120 mg was seen compared to 39% (N=425) for placebo (p<0.001), a 75% reduction in MHDs in any given month of 39% (N=210) for Emgality 120 mg compared to 19% (N=425) for placebo (p<0.001) and a 100% reduction in MHDs in any given month of 16% (N=210) for Emgality 120 mg compared to 6% (N=425) for placebo (p<0.001).

For EVOLVE-2, galcanezumab 240 mg was given as a loading dose followed by galcanezumab 120 mg once a month for 5 months by SC injection.

 Baseline migraine headache days for Emgality was 9.1 and placebo was 9.2. Mean change from baseline was -4.3 days (N=226) for Emgality 120 mg compared to -2.3 days (N=450) for placebo (p<0.001). Results showed at least a 50% reduction for MHDs in any given month of 59% for Emgality 120 mg compared to 36% (N=450) for placebo (p<0.001), a 75% reduction in MHDs in any given month of 34% (N=226) for Emgality 120 mg compared to 18% (N=450) for placebo (p<0.001) and a 100% reduction in MHDs in any given month of 12% for Emgality 120 mg compared to 6% (N=450) for placebo (p<0.001). Injection site pain was the most common treatment-emergent adverse event, reported at similar rates in all treatment groups. Both galcanezumab doses had significantly more injection site reactions and injection site pruritus, and the 240 mg group had significantly more injection site erythema compared to placebo.

REGAIN was a 3-month, double blind, placebo-controlled study that enrolled 1113 adult patients with chronic migraine (defined as ≥15 headache days per month with ≥8 migraine days per month). Participants were randomized to receive once-monthly placebo, Emgality 120 mg after an initial loading dose of 240, or Emgality 240 mg. A subset of patients (15%) continued one concomitant migraine preventive medication regardless of study group. Patients exclusion criteria matched that of EVOLVE clinical trials. Primary endpoint was the mean change from baseline in the number of monthly MHDs over the 3-month treatment period. Baseline MHDs for Emgality was 19.4 and placebo was 19.6 and mean change from baseline was -4.8 days (N=273) for Emgality 120 mg compared to -2.7 days (M=538) for placebo (p<0.001). Results showed at least a 50% reduction in MHDs in any given month of 28% (N=273) for Emgality 120 mg compared to 15% (N=538) for placebo (p<0.001). Emgality 120 mg was not significantly better than placebo for the majority of patients with 75% and 100% reduction from baseline.

FDA Approves Preventive Treatment for Migraine

Limitations of these studies are that patients were not tested to determine whether galcanezumab could be effective as an adjunctive treatment, concurrent with other treatment options. Both EVOLVE and REGAIN studies were conducted in North America, primarily United States, which limits generalizability of these results to patients in other geographies. Caution should be used when treating patients with acute cardiovascular events and/or serious cardiovascular risk since patients with co-morbid cardiovascular conditions and cardiovascular risk were not included. There is insufficient human data to establish the safety of galcanezumab during pregnancy since pregnant women were excluded.

To conclude, in phase 3 trials among patients with episodic or chronic migraine, galcanezumab users saw greater reductions in monthly migraine days relative to placebo users and were more likely to achieve a 50% reduction in monthly migraine days. Those with episodic migraines who took galcanezumab were more likely to achieve 75% and 100% reductions in monthly migraine days over placebo recipients.

Good candidates for this medication include individuals who have failed several migraine therapies, as a last-line option to improve quality of life. However, providers should be aware that long-term data is unavailable, as this drug has only been administered for up to 6 months. As such, new adverse events are likely, which may be undesirable and lead to treatment discontinuation. Larger longitudinal, randomized control trials are needed to discover long-term benefits and consequences of drug use.

This article was co-written with Jacqueline Pratt Cleary, PharmD, BCACP, and Nirvana Prashad, PharmD candidate. 

Nirvana T. Prashad is a 2019 Pharm.D candidate at Albany College of Pharmacy and Health Sciences in Albany NY. After pharmacy school, she would like to pursue a pharmaceutical fellowship or work in the community setting. Her interests include teaching and fitness.

Jacqueline Cleary, PharmD, BCACP is an Assistant Professor of Pharmacy Practice at Albany College of Pharmacy and Health Sciences.  Dr. Cleary completed a PGY-1 at Sentera Hospital System and a PGY-2 in Pain and Palliative Care at the Albany Veterans Hospital.  Her teaching and research interests include pain management, pharmacogenomics, naloxone, medication assisted treatment, and palliative care.

		Lipton RB, Bigal ME, Diamond M, et al. Migraine Prevalence, Disease Burden, and the Need for Preventive Therapy. 

		Raval AD, Shah A. National Trends in Direct Health Care Expenditures among US Adults with Migraine: 2004 to 2013. 

		Diamond S, Bigal ME, Silberstein S. Patterns of Diagnosis and Acute and Preventative Treatment for Migraine in the United States: Results from the American Migraine Prevalence and Prevention Study. 

		Karsan N, Goadsby PJ. Calcitonin Gene-Related Peptide and Migraine. 

		Edvinsson L. The CGRP Pathway in Migraine as a Viable Target for Therapies. 

		Lassen LH, Haderslev PA, Jacobsen VB et al. CGRP May Play a Causative Role in Migraine. 

		Raffaelli B, Reuter U. The Biology of Monoclonal Antibodies: Focus on Calcitonin Gene-Related Peptide for Prophylactic Migraine Therapy. 

		Zhu Y, Liu Y, Zhao J et al. The Efficacy and Safety of Calcitonin Gene-Related Peptide Monoclonal Antibody for Episodic Migraine: A Meta-Analysis.

		Monteith D, Collins EC, Vandermeulen C et al. Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the CGRP Binding Monoclonocal Antibody LY2951742 (Galcanezumab) in Healthy Volunteers.

		Oakes TMM, Skljarevski V, Zhang Q et al. Safety of Galcanezumab in Patients with Episodic Migraine: A Randomized Placebo-Controlled Dose-Ranging Phase 2b Study. 

		Stauffer VL, Dodick DW, Zhang Q et al. Evaluation of Galcanezumab for the Prevention of Episodic Migraine: The EVOLVE-1 Randomized Clinical Trial. 

		Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy and Safety of Galcanezumab for the Prevention of Episodic Migraine: Results of the EVOLVE-2 Phase 3 Randomized Controlled Clinical Trial. 

Emgality (Galcanezumab-gnlm) is a self-administered once monthly subcutaneous injection and the third in its class for the preventative treatment of migraine in adults.

Clinical Insights: Galcanezumab for the Preventative Treatment of Migraines

 CGRP is an ideal target for migraine pathophysiology as it is distributed throughout the nervous system, and concentration levels are elevated prior and during acute and chronic attacks. Centrally, CGRP is involved in nociceptive transmission through second and third order neurons and pain modulation in the brainstem. Peripherally, CGRP mediates vasodilation through smooth muscle receptors.

 Participants were randomized to once-monthly placebo, Emgality 120 mg after an initial loading dose of 240 mg, or Emgality 240 mg. Both studies excluded patients on any other migraine preventative treatment, patients with medication overuse headache, patients with electrocardiogram abnormalities compatible with an acute cardiovascular event and patients with a history of stroke, myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, deep vein thrombosis or pulmonary embolism within 6 months of screening. As there are CGRP receptors within the cardiovascular system, these exclusions ensure that any effect seen was due to the newly proposed mechanism of action.

Good candidates for this medication include individuals who have failed several migraine therapies, as a last-line option to improve quality of life. 

Lipton RB, Bigal ME, Diamond M, et al. Migraine Prevalence, Disease Burden, and the Need for Preventive Therapy. 

Raval AD, Shah A. National Trends in Direct Health Care Expenditures among US Adults with Migraine: 2004 to 2013. 

Diamond S, Bigal ME, Silberstein S. Patterns of Diagnosis and Acute and Preventative Treatment for Migraine in the United States: Results from the American Migraine Prevalence and Prevention Study. 

Karsan N, Goadsby PJ. Calcitonin Gene-Related Peptide and Migraine. 

Edvinsson L. The CGRP Pathway in Migraine as a Viable Target for Therapies. 

Lassen LH, Haderslev PA, Jacobsen VB et al. CGRP May Play a Causative Role in Migraine. 

Raffaelli B, Reuter U. The Biology of Monoclonal Antibodies: Focus on Calcitonin Gene-Related Peptide for Prophylactic Migraine Therapy. 

Zhu Y, Liu Y, Zhao J et al. The Efficacy and Safety of Calcitonin Gene-Related Peptide Monoclonal Antibody for Episodic Migraine: A Meta-Analysis.

Monteith D, Collins EC, Vandermeulen C et al. Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the CGRP Binding Monoclonocal Antibody LY2951742 (Galcanezumab) in Healthy Volunteers.

Oakes TMM, Skljarevski V, Zhang Q et al. Safety of Galcanezumab in Patients with Episodic Migraine: A Randomized Placebo-Controlled Dose-Ranging Phase 2b Study. 

Stauffer VL, Dodick DW, Zhang Q et al. Evaluation of Galcanezumab for the Prevention of Episodic Migraine: The EVOLVE-1 Randomized Clinical Trial. 

Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy and Safety of Galcanezumab for the Prevention of Episodic Migraine: Results of the EVOLVE-2 Phase 3 Randomized Controlled Clinical Trial. 

Millions worldwide dread the onset of debilitating migraines. There is a new drug class on the horizon that is thought to put a stop to the root of migraines. 

Galcanezumab: A New Calcitonin Gene-Related Peptide for Treating Migraine

The landscape of pain management over the last 3 decades has cycled from the opiophobia of the late 80s and early 90s through opiophilia and back again.

 Notable pit stops along the way included “pain as the fifth vital sign,” the acceptance of opioid use in chronic noncancer pain, and the advent of “The Opioid Crisis.” 

There has been a definitive decline in the rate of opioid prescribing, yet the CDC reports of opioid related deaths continue to rise.

 As it stands today, illicit opioids, specifically illicit fentanyl/fentanyl analogs, top the charts in opioid related deaths. Between 2015 and 2016, heroin and illicit fentanyl contributed to 35,000 opioid related deaths, and prescription drugs accounted for fewer than 15,000.

 researchers explored the idea that the key to revealing  the veracity of how the opioid epidemic has evolved may lie in the logistics of overdose death reporting, and the pharmacology and pharmacokinetics of prescription and illicit fentanyl.

In the article "Fentanyl: Separating Fact from Fiction

," fentanyl and fentanyl analogs are divided into 3 groups; pharmaceutical fentanyl, pharmaceutical fentanyl derivatives and illicit fentanyl. Pharmaceutical fentanyl is a full mu-opioid receptor agonist with a potency 50-100 times greater than morphine.

 It is a substrate of cytochrome P450 3A4 (CYP3A4), which makes it prone to drug-drug interactions and pharmacogenomic variability due to genetic polymorphisms. Fentanyl is metabolized by CYP3A4 to the inactive molecule, norfentanyl. Depending on the formulation, the kinetics and elimination half-life of pharmaceutical fentanyl vary with half-life ranges from 3.65 hours to 27 hours with consideration to continuous release formulations.

 Otherwise, fentanyl itself has a very short half-life closer to the 3-hour range.

There are 3 fentanyl derivatives approved for use in humans: alfentanil, remifentanil and sufentanil. All 3 are limited in use to the inpatient setting and alfentanil and remifentanil are rarely seen as drugs of abuse. Sufentanil, however, has been detected in combination with other illicit drugs in overdose victims along with a fourth fentanyl derivative, carfentanil, which is approved only for use as a tranquilizing agent in large mammals.

 This drug is 100 times more potent than fentanyl and is being found with increasing frequency in the serum of overdose decedents.

The illicit fentanyl compounds or, nonpharmaceutical fentanyl, are a moving target in terms of street availability and illicit synthesis. This group is comprised of compounds that are illegally altered to create new products which can evade current tests and medical examiners. Illicit fentanyl has been detected as the sole ingredient in drug overdoses, in combination with legally obtained substances (such as legitimate prescriptions, alcohol or over the counter products) and in combination with other licit and illicit substances.

According to the CDC morbidity and mortality weekly report, only 3 states reported detecting carfentanil in overdose deaths during the second half of 2016, but by the end of the first half of 2017, 7 states had reported overdose deaths associated with carfentanil.

 In the same timeframe, the number of counties in which overdose deaths with carfentanil present occurred increased from 54 to 77 with Ohio reporting the highest numbers of carfentanil overdose deaths.

 Between October 2016 and February 2017. the number decreased slightly in proportion with an increase in acrylfentanyl and furanylfentanyl (both forms of nonpharmaceutical fentanyl) deaths.

Further complicating the landscape, the DEA reports that fentanyl and its analogues are often produced in China and then shipped internationally where they are mixed into the heroin supply or combined with other non-opioid drugs and pressed into a tablet form.

This practice partially explains why overdoses with these substances are often misidentified as heroin overdoses or pinned on other prescription opioids present in the body at the time of the overdose.

The reporting of these overdoses often neglects important pharmacological insight into drug metabolism and leads to erroneous documentation.

 When these overdoses are documented as caused by fentanyl or fentanyl analogs, a common misconception follows whereby it is assumed that prescription fentanyl was the cause of these overdoses and further blame is pushed onto prescribers and prescription opioids. As the authors reported, diagnosis codes used for opioid overdose do not differentiate between licit and illicit opioids nor do they capture the nuance of polysubstance overdose.

As a potential bright spot in the effort to shed full light on the true causes of opioid drug overdoses, the state unintentional overdose reporting system (SUDORS) aims to collect information on all substances that contributed to death as well as “all substances for which the decedent tested positive”.

 This database has been receiving reports since August 2017, and as of August 2018, 32 states and District of Columbia are contributing data.

 This is important because the multitude of substances, licit and illicit, that may be present in the body at the time of overdose death could all be considered for their potential contribution. Further, the CDC's Project—Improving the Quality and Timeliness of Data on Drug Overdose Deaths has joined medical examiners, coroners, public health experts and health IT to expedite their processes with the goal of having 90% of drug-related death records made available for public health surveillance and decision-making within 90 days of death.

 It seems that this effort could be further improved with the addition of a pharmacist to the team to fully appreciate the pharmacological and pharmacokinetic complexities of today’s opioid overdose.  

Overall, prescription fentanyl is rarely abused or obtained illegally in comparison to other opioids, such as morphine, oxycodone, and hydrocodone. It is especially important for practicing pharmacists to consider the implications of illicit fentanyl, to separate them from illicit fentanyl analogues that can be up to 1000x more potent than prescription fentanyl, and to educate providers and the community on the differences.

This article was co-written with Amelia L. Persico, PharmD, MBA. Dr. Persico is a graduate of Albany College of Pharmacy & Health Sciences and Union Graduate College. She has practiced as a community pharmacy manager and is currently a PGY1 Pharmacy Resident at the Stratton Veterans Administration Medical Center in Albany, New York.

Information provided is the sole work of the authors, and the stated opinions or assertions do not reflect the opinions of employers, employee affiliates, or any pharmaceutical companies listed. It was not prepared as part of the authors’ duties as federal employees. 

Mark R Jones; et al. A Brief History of the Opioid Epidemic and Strategies for Pain Medicine. 

Bettinger, J; et al. Fentanyl: Separating Fact from Fiction. PPM 6Aug2018;18(5). https://www.practicalpainmanagement.com/treatments/pharmacological/opioids/fentanyl-separating-fact-fiction. Accessed October 2, 2018.

O’Donnell, Julie, R. Matthew Gladden, Christine L. Mattson, Mbabazi Kariisa. Notes from the field: Overdose Deaths with Carfentanil and Other Fentanyl Analogs Detected-10 States, July 2016-June 2017. 

https://www.cdc.gov/mmwr/volumes/67/wr/mm6727a4.htm

Knierim, PE. Tackling Fentanyl: The China Connection. 9 Sep 2018. Department of Justice DEA. https://www.dea.gov/. Accessed October 12, 2018.

CDC. Project- Improving the Quality and Timeliness of Data on Drug Overdose Deaths. CDC website. https://www.cdc.gov/surveillance/projects/improving-data-on-drug-overdose-deaths.html. Accessed October 17, 2018.

Despite a decline in the rate of opioid prescribing, the CDC reports that the number of opioid related deaths continues to rise. The pharmacology and pharmacokinetics of prescription and illicit fentanyl could help to shed light on why the opioid epidemic has taken the path that it has. 

Separating Prescription From Illicit Fentanyl

Opioid allergies are often misdiagnosed because the various reactions associated with opioids are similar to symptoms of true allergies. There are generally three types of reactions to medications: adverse effect (intolerance), pseudo-allergy, and true allergy. These types of adverse events have variable causality. Patients and providers often associate pseudo-allergy reactions to opioid analgesics as true allergies. 

True allergies to opioids occur in <2% of patients.

 An incorrect diagnosis of allergies may lead to delays in treatment and unnecessary drug avoidance. A thorough understanding of opioid reactions is necessary, as safety considerations and therapeutic alternatives vary depending on the severity and presentation of the reaction. Table 1 compares the underlying mechanism for each reaction and the symptoms, which will be further discussed in this commentary.   

Table 1. Select Medication Reactions and Accompanying Symptoms

			Predictable effects from known pharmacologic properties of the drug

			Unpredictable, hypersensitivity reactions that may occur with the first dose of the drug

			Immune mediated hypersensitivity reactions which require prior exposure to drug or repeat dosing

Angioedema/swelling of lips, tongue, face or mouth

			Cutaneous reactions (other than hives, e.g. maculopapular rash)

Adverse effects are predictable, dose-dependent effects from known pharmacologic properties of a drug. Adverse effects make up 80% of all adverse drug reactions.

 Common opioid-related adverse effects include nausea, vomiting, constipation, drowsiness, confusion, androgen deficiency, and urinary retention. Serious complications include addiction and respiratory depression. Tolerance to adverse effects develops within days of use, except for constipation which is expected to continue throughout the course of treatment due to direct opiate receptor binding in the gut.

When an adverse effect is of concern, consider an alternative opioid depending on the adverse effect and the risk. For example, if opioid-induced androgen deficiency is a concern, clinicians may consider using tapentadol if testosterone replacement is contraindicated, due to cardiac risk, history of androgen-dependent tumor, or other.

 If respiratory depression is a concern, clinicians may consider a partial agonist with ceiling effect on respiratory depression such as buprenorphine.

Pseudo-allergies are idiosyncratic hypersensitivity reactions with clinical features that are almost indistinguishable from true allergies, aside from angioedema. The severity is unpredictable and can range from pruritus to anaphylaxis.

 The difference between pseudo-allergies and true allergies is the underlying mechanism. Pseudo-allergies are mediated by endogenous histamine release by cutaneous mast cells whereas true allergies are IgE or T-cell mediated.

 A key distinguishing factor between true and pseudo-allergies is the temporal onset of the reaction. Pseudo-allergies are often elicited by the first dose of a medication without prior sensitization whereas true allergies require prior exposure or repeated dosing.

Opioids can activate mast cell degranulation through direct stimulation and opioid receptor activation, thereby releasing of histamine.

 This mainly causes cutaneous reactions such as flushing, urticaria, and/or pruritus, which are commonly mislabeled as allergic reactions. Not all opioids have the same capacity to release histamine. Morphine, codeine, and meperidine are common culprits.

 Fentanyl, sufentanil, alfentanil, remifentanil, and tramadol, on the other hand, induce little to no histamine release. Pseudo-allergies to opioids are rarely severe, life threatening reactions with cardiovascular collapse and bronchospasms.

When assessing a patient suspected to have an opioid allergy, it is useful to know the onset, location, and severity of the reaction, if the offending opioid is prone to inducing histamine release, and a careful history of any other opioids the patient has tried in the past. Considering the incidence of true opioid allergies, it may be reasonable to assume a patient with hypersensitivity skin reactions likely has a pseudo-allergy instead of an allergy. In the case of severe hypersensitivity reactions such as anaphylaxis, severe bronchospasms, angioedema and/or cardiovascular collapse, it is recommended that the patient be treated as having a true allergy.

 Laboratory testing are unreliable in determining whether a patient has a true allergy or pseudo-allergy.

 Because most opioids have histamine releasing properties, the use of skin tests is dubious. Specific IgE testing are not definitive, as studies have shown positive results to morphine and pholcodine in 5% of blood donors and 10% of patients with other allergies, but no history of opioid allergy.

 Elevated baseline tryptase levels may be indicative of an underlying mast cell disorder which predisposes the patient to severe reactions including anaphylaxis to opioids.

Opioid allergies are often misdiagnosed. Improper allergy diagnosis may lead to delays in treatment and unnecessary drug avoidance. 

Opioid Allergy, Pseudo-allergy, or Adverse Effect?

When it comes to predicting therapeutic or adverse effects (and efficacy), opioid-specific pharmacodynamics play a major role. Pharmacodynamics, as we all well know, is the study of what a drug does to the body, including involvement with receptor binding and conformational changes that ultimately drive therapeutic and non-therapeutic effects (ie, adverse effects). Some of the adverse effects of opioids are listed in 

Table 1. Adverse Effects Associated with Opioid Use

			Decreased testosterone/sexual dysfunction

There are 4 types of opioid receptors that have been identified: mu, delta, kappa, and opioid-receptor like-1 (ORL-1). Some of the receptors may be further divided into subtypes. These receptors are important for expressing pain transmission and modulating pathways, including neurotransmission in the limbic system, midbrain, spinal cord, and thalamus. Opioid receptors are ubiquitously present throughout the body, including but not limited to the gastrointestinal tract (GI), immune cells, pituitary gland, and skin. At these sites, opioid receptors carry out variable analgesic and non-analgesic functions. A summary of pharmacological and physiological effects for each opioid receptor is listed in 

Table. 2. Summarized Effects of Individual Opioid Receptors

Most opioids are mu agonists with varying activity on kappa receptors. 

Opioid receptors are 7 transmembrane spanning proteins that are coupled to inhibitory G-proteins. When activated, they decrease adenyl cyclase production of the secondary messenger cyclic adenosine monophosphate. This causes a decrease in calcium influx from inhibition of voltage-gated calcium channels and results in the activation of potassium channels, which leads to hyperpolarization. The hyperpolarized state causes inhibition of neuronal signaling, which in this case inhibits pain transmission.

Opioids are classified into categories, depending on receptor binding and affinity (

). These classifications are agonist, partial agonist, and antagonist. There are opioids that have dual agonist and antagonist functions.

A look at the different receptor bindings that affect analgesic effect.