Jeffrey Fudin, PharmD, FCCP, FASHP, FFSMB

Abuse-deterrent formulations (ADFs) of opioid medications were first marketed in 2010 when a reformulated version of OxyContin (extended-release oxycodone) was

released at the mandate of the FDA in an effort to address the nationwide opioid epidemic.

This product was created with both chemical and physical barriers to its manipulation.

 The intention was to reformulate traditional opioid medications in ways that would make it more difficult to chemically and physically alter the delivery of their active pharmaceutical ingredient in an effort to reduce the potential for abuse. These efforts were particularly directed at extended-release and long-acting formulations, which are especially attractive to abusers of opioid medications because of the high-milligram content in a single-dose unit.

Prescription opioid abuse is not limited to taking intact tablets by mouth. Rather, those who abuse prescription opioids chew, crush, dissolve, and otherwise manipulate the tablets to take them intranasally, intravenously, orally, via inhalation, and by other routes of administration. By altering the route of administration and delivery systems, users are able to achieve different pharmacokinetics with preference toward increasing peak concentration and decreasing time to peak. Manipulation causes a “dose-dumping” effect in which higher serum levels are achieved more rapidly, resulting in enhanced psychoactive effects.

 Because of this, abuse via intranasal and intravenous routes is associated with more severe individual and societal risks.

Abuse-deterrent formulations have been created with alternate bases or harder outer shells, or coformulated with opioid antagonists to make manipulation and abuse more difficult.

 No amount of reformulation can completely deter all forms of manipulation, eliminate the potential for drug diversion, or deter users from taking more medication than prescribed. But the creation of ADFs was intended only as 1 component of a multifaceted approach to reducing opioid abuse and misuse.

Since the introduction of ADFs, the products have only gradually seen enough use in the market to preliminarily demonstrate decreased diversion and rates of intentional abuse.

 However, there is a dearth of knowledge regarding patients with chronic pain and their experiences with and opinions about ADFs. Further, those patients and their caregivers have historically reported concerns regarding the stigma associated with chronic opioid therapy. There is potential for further apprehension

and stigma associated with opioids in general and with the prescription of ADFs in particular—specifically, being labeled or thought of as an abuser. Health care providers, in turn, may be concerned about patients having a false sense of security when they issue a prescription for an ADF instead of a traditional opioid formulation.

The American Chronic Pain Association (ACPA), with support from Collegium Pharmaceutical, conducted an anonymous needs assessment/survey of ACPA members to gather information on patient experience with ADFs and their knowledge and perceptions about the medications. Until this point, patients’ knowledge and opinions regarding ADFs had not been explored. Of the 1154 respondents to the survey, 936 completed it in full. As participants were recruited through the ACPA and more than 98% of them were people living with chronic pain, it is likely that they had a higher baseline knowledge regarding opioids and safe medication practices than the general population. Therefore, conclusions about the generalizability of survey results should be filtered through this lens.

The survey addressed patients’ knowledge on topics ranging from the existence of ADFs to safety and tampering. Further questions assessed patients’ behaviors and beliefs associated with ADFs. Respondents were stratified based on whether they were currently prescribed an ADF, and additional questions were posed to those patients with the goal of assessing their actual use. More than half of the survey respondents had never heard of an ADF. Therefore, 1 of the most significant findings of this study is a large knowledge gap regarding ADFs in the community of people living with pain.

Notably, the vast majority of respondents from both groups believed that it is not safe to take more ADFs than prescribed or to share an ADF with others. Most respondents who are currently prescribed an ADF reported that they do not crush, cut, or dissolve their tablets in water, whereas respondents not currently prescribed an ADF were more likely to report that they did not know whether tablets could be crushed, cut, or dissolved. Importantly, most respondents who are prescribed an ADF answered that they did not feel their prescriber was concerned about possible abuse when they prescribed the ADF. Those who take an ADF were divided as to

whether it is as effective as other opioids they have been prescribed.

This survey and an educational video have begun to fill a void in the literature regarding patients with chronic pain and their beliefs, experiences, and knowledge about ADF opioid medications. Certainly, some respondents voiced negative attitudes about incurring additional costs for ADFs when they do not personally think they are at risk for abuse or manipulation of the dose form. Others worried about the stigma, wondering if their physicians felt they were abusers. These views were not universal, however, and some respondents understood the potential need for ADFs in the context of continuing concerns related to the opioid epidemic. Thus, a potential takeaway for those who prescribe or dispense ADFs is that these patients are not uniformly concerned with stigma or as negatively inclined toward ADFs as some clinicians have thought. Rather, any apprehension or misgivings on the part of patients could be attributable to a lack of knowledge. This can be managed through individualized education and sensitivity to the patients’ pre-existing attitudes.

Clinicians can also be advised that both groups of patients were largely aware that they should not take more ADFs than prescribed nor should they share their ADFs with others. This advice could serve to assuage some concern for the potential false sense of security that some providers fear when prescribing ADFs.

The authors conclude that, concerning ADFs, patients who suffer from chronic pain have neither a commonly held negative view nor a commonly held positive view, and that this population respects and understands opioid safety, overall. These findings support the notion that ADFs can be a valuable part of a comprehensive approach to managing the opioid epidemic. As practitioners on the frontlines of both patient and provider education, pharmacists are poised to impart this important information regarding ADFs to their medical colleagues and patients alike.

, is a PGY-2 pain and palliative care pharmacy resident at the Albany Stratton VA Medical Center in Albany, New York.

, is chief executive officer and founder of Remitigate, LLC and the owner and managing editor of paindr.com. He is also an adjunct associate professor at Western New England University College of Pharmacy and Health Sciences in Springfield, Massachusetts, an adjunct associate professor of pharmacy practice and pain management at Albany College of Pharmacy and Health Sciences in Albany, New York, and the director of the PGY-2 pain residency at Albany Stratton VA Medical Center.

 is the founder and chief executive officer of the American Chronic Pain Association in Rocklin, California.

, is a research assistant and evaluations specialist at the Native American Rehabilitation Association of the Northwest, Inc, in Portland, Oregon.

Adler JA, Mallick-Searle T. An overview of abuse-deterrent opioids and recommendations for practical patient care. 

. 2018;11:323-332. doi: 10.2147/JMDH.S166915.

FDA. Abuse-deterrent opioid analgesics. FDA website. www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm600788.htm. Updated June 11, 2019. Accessed February 20, 2020.

Green JL, Bucher Bartelson B, Le Lait MC, et al. Medical outcomes associated with prescription opioid abuse via oral and non-oral routes of administration [published online March 28, 2017]. 

. 2017;175:140-145. doi: 10.1016/j.drugalcdep.2017.01.039.

Pergolizzi JV Jr, Raffa RB, Taylor R Jr, Vacalis S. Abusedeterrent opioids: an update on current approaches and considerations [published online January 10, 2018]. 

. 2018;34(4):711-723. doi: 10.1080/03007995.2017.1419171.

Dart RC, Iwanicki JL, Dasgupta N, Cicero TJ, Schnoll SH. Do abuse deterrent opioid formulations work? 

. 2017;13(6):365-378. doi: 10.5055/jom.2017.0415.

Articles

Pharmacists can extend education to prescribers and provide important guidance on abuse-deterrent opioid formulations.

Offer Patients Counseling on ADFs

Warfarin has been the gold standard for oral anticoagulation therapy for more than 50 years.

 Drawbacks to warfarin therapy, however, include a narrow therapeutic window with a low median lethal dose, many potential drug—drug/diet/disease interactions, and necessary frequent blood draws and individualized dosing to monitor the international normalized ratio (INR). The INR is calculated from prothrombin time, which is used to assess the time that a clot takes to form. An elevated INR can lead to an increased risk of hemorrhage, whereas a decreased INR can indicate ineffectiveness of the blood thinner and can lead to stroke and thromboembolism.

 The introduction of direct oral anticoagulants (DOACs) has reduced the need for routine INR monitoring as a result of a more predictable pharmacokinetic profile and a wider therapeutic window with fixed dosing.

 Although the need for monitoring has decreased, the potential for interactions still exists with the new oral anticoagulants.

Warfarin is the most commonly prescribed oral anticoagulant. However, it is known to interact with many foods, herbal supplements, and OTC and prescription medications. It is particularly important to monitor warfarin carefully because of a narrow therapeutic window and variability in individual response. Concomitant administration of drugs that decrease or increase the INR and warfarin can lead to an elevated risk of hemorrhage or thrombotic event, respectively. A major consideration of warfarin drug interactions is metabolism by cytochrome P 450 (CYP) enzymes. Warfarin is primarily metabolized by CYP2C9 with minor metabolism by CYP2C8, 1A2, 3A4, 2C18, and 2C19. When warfarin is administered with inhibitors of CYP3A4, such as statins, except pravastatin and rosuvastatin, which are not metabolized by CYP450 enzymes, the INR is increased.

 Other medications that cause clinically relevant increases in the INR because of CYP enzyme inhibition include amiodarone (1A2, 3A4, and 2C9), diltiazem (3A4), fenofibrate (3A4), propafenone (3A4), and propranolol (1A2).

 Another consideration is the protein-binding nature of warfarin. Warfarin is 99% plasma protein bound to albumin. Therefore, other medications that are highly protein bound, such as amlodipine and ibuprofen, can cause displacement of warfarin from protein-binding sites, leading to increased anticoagulant activity and INR.

 Consumption of excess foods high in vitamin K, such as leafy green vegetables, can decrease the INR.

 Study results have shown that herbal supplements also induce or inhibit certain enzymes associated with warfarin metabolism. For example, St John’s wort induces CYP1A2, 3A4, and 2C9, resulting in a decreased INR.

 Additionally, clinicians must also consider pharmacodynamic interactions when prescribing warfarin concomitantly with other medications that increase bleeding risk. These include nonsteroidal anti-inflammatory drugs (NSAIDs), because of their inherent ability to cause bleeding as a result of cyclooxygenase 1 inhibition, and serotonin norepinephrine reuptake inhibitors (SNRIs), because of the role of serotonin in platelet aggregation.

 Frequent monitoring of the INR is crucial in maintaining safe and therapeutic levels of anticoagulation in patients on warfarin and interacting medications.

DOACs are highly effective anticoagulants in the treatment of deep vein thrombosis and pulmonary embolism, as well as in stroke prevention associated with atrial fibrillation, and require less monitoring than warfarin. The DOACs comprise 2 groups: direct factor Xa inhibitors, including apixaban (Eliquis), exoxaban (Savaysa), and rivaroxaban (Xarelto); and direct thrombin (factor IIa) inhibitor, dabigatran (Pradaxa). Similar to warfarin, DOACs have a potential for drug interactions with medications that may increase bleeding risk and with strong P-glycoprotein (P-gp) and CYP3A4 inducers and inhibitors. As DOACs are substrates of P-gp, an efflux transporter, coadministration with a P-gp inducer or inhibitor can significantly affect the absorption of the DOAC.

 All DOACs have drug—drug interactions with other anticoagulants, antiplatelets, chronic NSAIDs, estrogen derivatives, and SNRIs. Estrogen derivatives, in particular, may prevent DOACs’ efficacy, resulting in an increased risk of thromboembolism.

Apixaban is primarily metabolized by CYP3A4 and is a substrate of P-gp. Administering apixaban with inhibitors of CYP3A4 and P-gp, such as carbamazepine, itraconazole, ketoconazole, rifampin, ritonavir, and St John’s Wort, may increase the overall exposure of apixaban and therefore increase the risk of unwanted bleeding.

 This drug—drug interaction has specific clinical recommendations. If a patient is receiving 5- or 10-mg twice-daily dosing of apixaban that is to be administered with a CYP3A4 and P-gp inhibitor, clinicians should reduce the apixaban dose by half, to 2.5 or 5.0 mg twice daily, respectively.

 On the other hand, inducers of CYP3A4 and P-gp would decrease exposure of apixaban, subsequently increasing the risk of stroke and other thrombotic events. Concomitant use with strong inducers should be avoided.

 Apixaban is not associated with inducing or inhibiting CYP3A4 or P-gp, as the metabolic clearance of medications administered with apixaban is not affected.

 Because of an increased risk of bleeding, physicians should closely monitor the benefit versus risk of apixaban administered with antiplatelet agents, aspirin, chronic NSAIDs, fibrinolytics, and heparin.

Rivaroxaban is primarily metabolized by CYP3A4 and is a substrate of P-gp. Concomitant use of rivaroxaban with known combined CYP3A and P-gp inhibitors should be avoided. Rivaroxaban may also increase the risk of bleeding with concomitant use with medications that inhibit hemostasis, including anticoagulants, aspirin, fibrinolytics, NSAIDs, P2Y12 platelet inhibitors, selective serotonin reuptake inhibitors, and SNRIs.

 In vitro data suggest that rivaroxaban does not induce or inhibit CYP3A or inhibit P-gp and will therefore not affect the administered substrates or pharmacokinetics of CYP3A or P-gp.

Edoxaban is predominantly unchanged in plasma with minimal metabolism via CYP3A4 but is a substrate of P-gp.

 Concomitant use with known P-gp inhibitors, such as amiodarone, cyclosporin, erythromycin, ketoconazole, quinidine, and verapamil, may increase the area under the curve and peak plasma concentration of edoxaban. Coadministration with other anticoagulants, antiplatelets, and long-term NSAIDs is associated with an increased risk of bleeding and is not recommended.

Dabigatran is not an inducer, inhibitor, or substrate of CYP450 enzymes but is a substrate of P-gp. Therefore, clinicians should avoid or dose-adjust concomitant administration of dabigatran with inducers or inhibitors of P-gp enzymes based on the creatinine clearance (CrCl) and induction or inhibition. Patients with a CrCl <30 mL/min should avoid concurrent use of any P-gp inhibitor, such as amiodarone, quinidine, and verapamil with dabigatran.

 Clinicians should also monitor dabigatran with coadministration with other anticoagulants, antiplatelets, and NSAIDs for increased risk of bleeding. HMG- CoA reductase inhibitors, such as atorvastatin, lovastatin, and simvastatin, may enhance the anticoagulant effect of dabigatran and require additional monitoring. 

Anticoagulants, including DOACs and vitamin K antagonists, are subject to interactions when administered with foods, herbal supplements, and other OTC and prescribed medications. Patients on warfarin therapy should monitor their INR frequently, especially when adding medications that may interact with warfarin. Although DOACs may require less monitoring and be safer than warfarin, clinicians must still consider potential drug—drug interactions because of CYP metabolism and/or P-gp interactions. Additional information regarding CYP and inducers, inhibitors, and transporter substrates is available at the FDA website.

 Pharmacists must carefully assess potential interactions in patients on anticoagulation therapy to prevent placing them at an increased risk of hemorrhagic or thrombotic event.

 are PharmD candidates at Albany College of Pharmacy and Health Sciences (ACPHS) in New York and are completing the VA Learning Opportunities Residency program at the Albany Stratton VA Medical Center (ASVMC) in New York.

 is the associate chief of pharmacy services, the PGY-1 pharmacy residency director, and the PGY-2 pain and palliative care pharmacy residency coordinator at ASVMC. She coordinates and precepts in the VA Learning Opportunities Residency intern program and is an adjunct advanced pharmacy practice experience preceptor for ACPHS and Western New England University College of Pharmacy and Health Sciences (WNEUCPHS) in Springfield, Massachusetts.

Jeffrey Fudin, PharmD, FCCP, FASHP, FFSMB,

 is CEO and founder of Remitigate LLC and the owner and managing editor of paindr.com. He is also an adjunct associate professor at WNEUCPHS, an adjunct associate professor of pharmacy practice and pain management at ACPHS, and the director of the PGY-2 pain residency at ASVMC.

Conway SE, Hwang AY, Ponte CD, Gums JG. Laboratory and clinical monitoring of direct acting oral anticoagulants: what clinicians need to know. 

 2017;37(2):236-248. doi: 10.1002/phar.1884. 

American Association for Clinical Chemistry. Prothrombin time and international normalized ratio (PT/INR). Lab Tests Online website. 

labtestsonline.org/tests/prothrombin-time-and-international-normalized-ratio-ptinr

 Bauer KA. Pros and cons of new oral anticoagulants. 

2013;2013:464-470. doi: 10.1182/asheducation-2013.1.464.

Di Minno A, Frigerio B, Spadarella G, et al. Old and new oral anticoagulants: food, herbal medicines and drug interactions. 

 2017;31(4):193-203. doi: 10.1016/j.blre.2017.02.001.

Coumadin [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co; 2017. 

packageinserts.bms.com/pi/pi_coumadin.pdf

Jiang X, Williams KM, Liauw WS, et al. Effect of St John’s wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. 

 2004;57:592—599. doi: 10.1111/j.1365-2125.2003.02051.x.

Wegrzyn E, Fudin J. Carefully assess bleeding risk in patients on antidepressants. 

pharmacytimes.com/publications/issue/2019/march2019/carefully-assess-bleeding-risk-in-patients-on-antidepressants

. Published March 19, 2019. Accessed September 23, 2019.

Stöllberger C, Finsterer J. Relevance of P-glycoprotein in stroke prevention with dabigatran, rivaroxaban, and apixaban. 

 2015;40(suppl 2):140-145. doi: 10.1007/s00059-014-4188-9.

Eliquis [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co; 2012. 

Xarelto [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals Inc; 2011. 

janssenlabels.com/package-insert/product-monograph/prescribing-information/XARELTO-pi.pdf

Savaysa [prescribing information]. Parsippany, NJ: Daiichi Sankyo Inc; 2015. www.

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Pradaxa [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2011. www.

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Drug development and drug interactions: table of substrates, inhibitors and inducers. FDA website. www.

fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers

Patients on this therapy should monitor their INR frequently, especially when adding other medications.

Watch for Interactions With Warfarin

The protein kinase inhibitor drug class has been rapidly expanding the past 5 years, reaching more than 40 individual medications. Protein kinase inhibitors, including tyrosine, serine, and threonine kinase inhibitors, can act on a variety of targets within the body to allow for targeted cancer treatment. As many of these new drugs are oral medications metabolized by the liver, it is important to consider drug drug interactions (DDIs) with many common medications. Protein kinase inhibitors have been documented to have pharmacodynamic and pharmacokinetic DDIs. These interactions can lead to malabsorption with altered gastric pH, deviations in metabolism by cytochrome (CYP) P450 enzymes, and interactions leading to QT prolongation.

The majority of protein kinase inhibitors undergo significant metabolism by CYP450 enzymes, particularly CYP450 3A4 (CYP3A4). When administered concurrently with inducers or inhibitors of CYP3A4, the plasma concentration of the kinase inhibitor may be altered. CYP3A4 inducers, such as carbamazepine, phenytoin, rifampin, and St John’s wort, decrease serum levels and reduce the overall area under the curve (AUC) of the substrate kinase inhibitor, resulting in decreased therapeutic efficacy. CYP3A4 inhibitors, such as antifungals (ketoconazole, itraconazole), certain antivirals (boceprevir, cobicistat, ritonavir, etc), grapefruit juice, and macrolide antibiotics (clarithromycin and erythromycin but not azithromycin), can lead to an increase in AUC of the substrate kinase inhibitor, resulting in greater toxicity and adverse events.

Table 1 illustrates recommendations for concomitant use of protein kinase inhibitors and CYP3A4 inducers and inhibitors, as obtained from FDA regulatory documents.

 A handful of kinase inhibitors have been shown to have minimal or no interaction with CYP3A4 inducers and inhibitors, and these are afatinib, alectinib, binimetinib, dacomitinib, lenvatinib, and trametinib.

Pharmacokinetically, many protein kinase inhibitors demonstrate pH-dependent solubility. Medications such as H2-receptor antagonists, proton pump inhibitors, and short-acting antacids actively increase gastric pH. This prevents pH-dependent absorption, which decreases the AUC and maximum concentration (Cmax) of the protein kinase inhibitor (table 2). A reduction in AUC and Cmax may lead to decreased efficacy and clinical outcomes. In many cases, avoiding concomitant use of gastric acid—reducing agents and protein kinase inhibitors and is recommended.

Many protein kinase inhibitors require transportation through various processes, including passive diffusion and adenosine triphosphate—binding cassette transporters, such as p-Glycoprotein (P-gp), thus leading to P-gp inhibition. Pharmacokinetically, known in vitro substrates of P-gp such as digoxin, fexofenadine, and quinidine may undergo an increase in AUC via P-gp inhibition with protein kinase inhibitor use. For example, the AUC of digoxin increases about 80% with concomitant use with lapatinib, which may affect its narrow therapeutic index.

 This has particular implications in the treatment of breast cancer, as many chemotherapy agents are substrates of P-gp. Pazopanib used with paclitaxel increased the exposure of paclitaxel by about 26%.

 Although results of preclinical studies illustrate that protein kinase inhibitors may possess some capability to counteract P-gp—mediated multidrug resistance, there is also a greater risk of adverse effects, because of the accumulation of cytotoxic drugs in the body.

 Although not completely elucidated, the potential for critical P-gp interactions between protein kinase inhibitors and chemotherapy in the treatment of breast cancer should be considered.

Several protein kinase inhibitors have been associated with the pharmacodynamic effect of prolonging the QT interval. Most protein kinase inhibitors have been evaluated for QT prolongation through well-documented clinical trials. According to an article from Drug Safety, the QT-prolonging effects of tyrosine kinase inhibitors may be due to “off-target class III electrophysiologic effects, possibly related to the presence of a fluorine-based pharmacophore.”

 Tasigna (nilotinib), in particular, has a boxed warning for QT prolongation, and medications associated with prolonging the QT interval should not be used in conjunction with Tasigna. Overall, evaluating the risk of QT prolongation associated with protein kinase inhibitors is critical in reducing the risk of DDI (table 2).

Concomitant administration of protein kinase inhibitors with gastric acid—reducing agents or inducers or inhibitors of CYP3A4 may have clinically significant effects on the serum concentration of the protein kinase inhibitor, leading to effects on efficacy and safety. Protein kinase inhibitor use and the potential for P-gp inhibition or induction should be considered, especially for narrow therapeutic index medications, including cytotoxic medications. Certain protein kinase inhibitors have also been shown to prolong the QTc interval; therefore, care should be taken when administering them simultaneously with other agents that can lead to QTc prolongation. By recognizing the pharmacokinetic and pharmacodynamic interactions of these particular groups of medications in combination with protein kinase inhibitors, pharmacists can recommend agents and/or doses that may be safer for the patient and provide appropriate therapeutic efficacy.

 is the associate chief of pharmacy services, the PGY-1 pharmacy residency director, and the PGY-2 pain and palliative care pharmacy residency coordinator at ASVMC. She coordinates and precepts in the VA Learning Opportunities Residency intern program and is an adjunct advanced pharmacy practice experience preceptor for ACPHS and Western New England University College of Pharmacy and Health Sciences in Springfield, Massachusetts.

Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, FFSMB,

van Leeuwen RW, van Gelder T, Mathijssen RH, Jansman FG. Drug-drug interactions with tyrosine-kinase inhibitors: a clinical perspective. 

. 2014;15(8):e315-e326. doi: 10.1016/S1470-2045(13)70579-5.

Drugs @FDA: FDA approved drug products. FDA website. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed 19 Jul 2019.

Beretta GL, Cassinelli G, Pennati M, Zuco V, Gatti L. Overcoming ABC transporter-mediated multidrug resistance: the dual role of tyrosine kinase inhibitors as multitargeting agents. 

. 2017;142:271-289. doi: 10.1016/j. ejmech.2017.07.062.

Shah RR, Morganroth J, Shah DR. Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarization (QT interval). 

 2013;36(5):295-316. doi: 10.1007/s40264-013-0047-5.

Medications in this drug class can alter the safety and efficacy of co-administered medications.

Keep an Eye on Protein Kinase Inhibitors

A lack of specific chemical targets related to migraine pathophysiology has led to limited efficacious treatments for migraine headaches. Therefore, the approach to migraine prophylaxis has been to investigate medications with primary indications other than migraines. Examples include beta-blockers; centrally acting alpha agonists; certain atypicals; selective serotonin reuptake inhibitors; various antidepressants, including serotonin-norepinephrine reuptake inhibitors, anticonvulsants, and tricyclic antidepressants; and others that have been used with variable efficacy. These medications have unique adverse effect (AE) profiles and toxicities that often result in poor compliance, further contributing to reduced treatment efficacy.

The 2012 American Academy of Neurology (AAN) guidelines for episodic migraine prevention in adults categorize medications by likelihood of effectiveness and evidence of ineffectiveness.

 These guidelines were reaffirmed by AAN in 2015, with a guideline update in progress.

An ideal migraine medication would target a chemical or receptor specific to the pathophysiology of migraines, with the ability to prevent and/or reduce active symptoms of the disease. The overall benefit to be obtained from the triptan medication class suffers from a stringent monthly dosing limit because of the risk for potentially serious AEs. Development of abortive medications that offer an improved safety profile would be useful to those who suffer from migraines. Many patients are also in need of effective preventive therapies that may be used on a regular basis to decrease their need for abortive medications. Not all patients with migraines benefit substantially from or require regular use of prophylactic migraine medication. Some indications for their use include contraindication, failure of, or intolerance to acute therapies; long-lasting or recurring migraines; or migraines that cause a decrease in quality of life or interfere with daily routine, despite the use of acute therapy.

 Calcitonin gene-related peptide (CGRP) inhibitors were developed to address the issue of inadequate preventive therapy.

A search of studies for biomarkers of migraine activity found that CGRP levels are elevated in individuals who experience migraines.

 CGRP is a neuropeptide that is released from and synthesized in trigeminal neurons as a potent vasodilator, facilitating increased intracranial pressures and nociceptive pain transmission due to excessive cerebral blood flow.

 Additional studies have tested the relationship between CGRP and migraines by assessing intravenous infusion of CGRP in humans, which produced lasting headaches in healthy individuals and migraine headaches in patients already suffering from the condition.

Three monoclonal antibodies targeting CGRP were released to the market recently—erenumab (Aimovig), fremanezumab (Ajovy), and galcanezumab (Emgality)&mdash;and approved by the FDA in 2018 for preventive treatment of migraines in adults.

Erenumab came to market on May 17, 2018, as the first CGRP available for use and the first medication approved for migraine headaches since onabotulinum-toxin A in 2010.

 It is a human immunoglobulin G2 (IgG2) that binds to the CGRP receptor and inhibits the action of CGRP. Erenumab is a monthly subcutaneous (SC) injection available as an auto-injector pen or syringe at a starting dose of 70 mg that can be tried at an increased dose of 140 mg in select patients. The medication is stored under refrigeration; must be left at room temperature for 30 minutes prior to administration into the abdomen, thigh, or upper arm; and is very well tolerated, with the most common AEs being injection-site reactions, constipation, and muscle cramp/spasm incidence of 6%, 1%, and less than 1%, respectively, in a study of 787 patients receiving the 70-mg dose.

Neutralizing antibodies produced by the human immune system can occur during treatment with monoclonal antibody drug products. Although 6.2% and 2.6% of patients experienced an emergence of anti-erenumab antibodies with either the 70- or 140-mg dose, respectively, just 2 of 1282 patients had neutralizing activity in vitro.

 However, at this time it cannot be inferred that neutralizing antibodies would affect the efficacy, pharmacokinetics, or safety of the medication until further studied.

Geriatric populations and those with creatinine clearance less than 30 mL/min were not sufficiently represented in trials, and there are no specific recommendations about how to treat these patients. Peak serum concentration is reached within 6 days, and the effective half-life of erenumab is about 28 days, reaching steady state concentration within 3 months using once-monthly dosing. The 2 main routes of elimination are nonsaturable proteolytic activity that results in cleavage of the antibody and saturable binding to the CGRP receptor.

Fremanezumab was approved on September 14, 2018, and is the only CGRP inhibitor that allows the flexibility of both monthly (225 mg) and every-3-month (675 mg) dosing options.

 Similar to erenumab, this medication is also a SC injection available in a prefilled syringe, which must be removed from the refrigerator 30 minutes prior to administration into the thigh, abdomen, or upper arm. Although erenumab is a fully human monoclonal antibody, it is humanized, meaning that it contains a small portion of murine protein in its structure. Another minor distinction between the 2 medications is that erenumab binds to the CGRP receptor and fremanezumab binds to the CGRP ligand, with the prevention of interaction between the 2 entities as a result in both cases. The only AE to occur at an incidence of 2% or greater was injection-site reactions (43% - 45% in fremanezumab vs 38% in a placebo).

Antifremanezumab antibodies were detected in 1.6% of patients in an ongoing open-label study and 0.4% of patients in a 3-month study. Within the open-label study, 17 of 30 patients with antidrug antibodies demonstrated neutralizing activity. However, because of differences in immunoassays and other factors in the analysis, comparing this statistic across CGRP inhibitors may not be accurate or appropriate. Time to max concentration after a single dose is about 5 to 7 days, and steady state is achieved after about 6 months in both monthly and quarterly dosingregimens.Themedicationisalsoeliminatedviaproteolytic cleavage activity.

Galcanezumab came to market on September 27, 2018.

 It is a human immunoglobulin G4 antibody also available as a single-dose prefilled pen or syringe that must be refrigerated and placed at room temperature 30 minutes prior to administering. This medication is the only one in the class with an initial loading dose of 240 mg followed by monthly SC doses of 120 mg administered in the abdomen, back of the upper arm, buttocks, or thigh. The loading dose allows for attainment of steady state concentration after just 1 dose. The time to max concentration is 5 days, with an elimination half-life of 27 days and a mechanism of elimination similar to erenumab. Geriatric patients with renal impairment did not have a large enough representation in trials to make definitive conclusions about efficacy and safety.

Eptinezumab by Alder Biopharmaceuticals is a fourth CGRP inhibitor, and it is on its way to market. There is no prescribing information available to the public at this time, as the medication is in investigational drug status. The biological license application was under review by the FDA as of April 22, 2019, with a decision regarding its approval expected in February 2020.

All 3 CGRP inhibitors on the market display similar efficacy in trials, with a reduction in migraine days per month by about 3 to 5 days compared with no therapy at baseline for patients with chronic migraines (15 or more migraine days per month) or episodic migraines (4-14 migraine days per month). Of note, the CGRP inhibitor mentioned have not been directly compared with one another within a trial, and limitations in interpretation of results between studies should be acknowledged.

Erenumab was the first to demonstrate the efficacy of CGRP inhibitors in 1 study of patients with chronic migraines and 2 studies of those with episodic migraines. In a 2017 study for episodic migraines conducted by Goadsby et al, the primary efficacy endpoint was change from baseline in mean monthly migraine days over months 4 to 6. The trial included 317 and 319 patients in the 70-mg and 140-mg erenumab groups, respectively, and 319 patients in the placebo group. Mean migraine frequency at baseline was 8.3 migraine days per month, which changed from baseline in the erenumab groups by —3.2 and –3.7 days per month, respectively. A change of –1.8 migraine days per month was observed for the placebo, resulting in a difference of –1.4 and –1.9 migraine days per month for the 70-mg and 140-mg doses (P <.001 for both erenumab groups compared with the placebo).

In the second study for episodic migraines, the primary endpoint was change from baseline in monthly migraine days as measured at month 3. Patients had a mean of 8 migraine days per month at baseline, with the 70-mg erenumab group experiencing a change of —2.9 migraine days compared with the baseline, which was a reduction of 1.0 day compared with the placebo (P <.001).

A third study of erenumab in episodic migraines, authored by Reuter et al and known as the LIBERTY trial, was a double-blind, multicenter, phase 3b, placebo-controlled randomized trial. It included patients who had failed 2 to 4 prophylactic therapies because of lack of efficacy, tolerability, or both. The trial period was 12 weeks, and an elderly subset of patients was not included. Patients in the erenumab arm received only the higher 140-mg monthly dose compared with the placebo. The primary endpoint was the proportion of patients achieving a 50% or greater reduction in mean monthly migraine days during weeks 9 to 12 of active treatment. With 121 participants in the erenumab group and 125 assigned to the placebo, 30% of erenumab patients met the primary endpoint compared with 14% in the placebo group (odds ratio, 2.7; CI, 1.4-5.2; P = .002). Safety and tolerability were statistically similar between the groups.

 These study results show that erenumab may provide benefit in patients with multiple treatment failures.

In a separate study for patients with chronic migraines, the primary endpoint was also the mean change in monthly migraine days at month 3. Mean migraine frequency was 18 days per month at baseline, with a change of —6.6 migraine days per month in the 70-mg and 140-mg treatment arms, with a difference of –2.5 days (P <.001) for both erenumab groups compared with the placebo.

To demonstrate efficacy with fremanezumab, a 3-month study was conducted in patients with chronic migraines, with a reduction in monthly migraine days of at least moderate severity from 12.8 to 8.2 in the 225-mg monthly group and from 13.2 to 8.9 in the 675-mg quarterly group. This was statistically significant compared with the placebo, which reduced migraines from 13.3 to 10.8 days.

 In 2018, Dodick et al published a 3-month study of 791 patients with episodic migraines, comparing fremanezumab 225-mg monthly and 675 mg quarterly. Fremanezumab 225 mg monthly resulted in a reduction of mean monthly migraine days from 8.9 to 4.9, and 675 mg every 3 months reduced monthly migraine days from 9.2 to 5.3. These were statistically significant compared with a reduction from 9.1 to 6.5 migraine days with the placebo.

 Of note, in the Dodick study, fremanezumab was being studied in patients suffering from cluster headaches. The manufacturer of fremanezumab analyzed early results and projected that the study would be unable to meet the primary endpoint, so it was suspended in April 2019.

Initial data available for galcanezumab included 1 study in patients with chronic migraines and 2 studies in patients with episodic migraines. Both episodic migraine studies were 6 months in length, with about 9.1 to 9.2 migraine days per month at the baseline for the active treatment and placebo arms. The mean change in migraine days from baseline for galcanezumab 120 mg in both studies were —4.7 and –4.3 days compared with –2.8 and –2.3 with placebo.

 In patients with chronic migraines, baseline monthly migraine days were 19.4 and 19.6 in the placebo and treatment groups, respectively. Over a 3-month period, galcanezumab showed a reduction in migraine days per month of 4.8 compared with the placebo group. All comparisons mentioned between the placebo and treatment were statistically significant.

Although CGRP inhibitors have displayed acceptable efficacy and safety, medication costs may result in delayed widespread use. Analysts originally projected that CGRP inhibitors would cost $8000 to $20,000 per year. However, likely in an effort to expand access, erenumab was brought to market at a wholesale acquisition cost of $6900 per year.

The Institute for Clinical and Economic Review (ICER) conducted a cost-effectiveness analysis for erenumab in April 2018 based on a price of $8500 per year. The institute calculated that it would cost $135,000 for 1 patient to gain 1 quality-adjusted life year compared with no treatment for migraines and that using erenumab would result in an additional $6000 in costs per patient to the health care system.

 With knowledge of the official pricing set below initial projections, ICER has since made a statement that erenumab is cost-effective once less expensive options have been trialed with data to support this price point.

ICER is a nonprofit, private organization without regulation by government entities and has a portion of its funding provided in connection with various third-party payers.

 Although ICER has been criticized for flaws in methodology and difficulty in applying results to the unique situations of some stakeholders based on assumptions used in the modeling,

 ICER addresses an unmet need for price and value transparency in the United States. The analyses that it produces allow manufacturers, payers, the public, and other stakeholders to gain another perspective on value, with a primary goal of keeping the cost of US health care down while using efficacious therapy.

As patients exhaust options for preventive therapy and continue to have debilitating events, patients may consider the out-of-pocket cost of CGRP inhibitors to be worth the relief of their symptoms. In line with ICER recommendations, CGRP inhibitor use likely will be supported by payers for use in patients who have been refractory to full trials of standard-of-care preventive medications or in those who are contraindicated to the use of standard-of-care medications.

Pharmacists should familiarize themselves with counseling on administration and storage, the indications for use of preventive migraine therapy, pharmacokinetics of CGRP inhibitors (see table

), the possibility of development of antidrug antibodies, and the uncertainty of how that affects efficacy and safety, being aware of the cost both to the health care system and patients.

CGRP inhibitors offer a unique mechanism that is more targeted to the pathophysiology of migraines than any guideline-recommended medication preceding them. The short-term AE profile of CGRPs is relatively benign in comparison to nonspecific treatments for migraine. Dose adjustments for hepatic or renal impairment are not required, and drug interactions are generally nonexistent with injected monoclonal antibodies, as they are not metabolized through the cytochrome P450 enzyme system.

Although CGRPs have their own limitations, most notably cost, lack of long-term safety data, and lack of robust head-to-head trials with current standard of care, they are a long-awaited class that may only be the tip of the iceberg for breakthrough migraine treatments. The development of CGRP inhibitors may prove to be a catalyst in encouraging pharmaceutical companies to invest in the further development of medications that will provide great advances in the quality of life of those with migraines.

, recently completed a PGY-1 pharmacy practice residency at the New Mexico Veterans Affairs Health Care System in Albuquerque and has accepted a position as an outpatient clinical pharmacist for the Veterans Affairs Greater Los Angeles Healthcare System in California.

 is CEO and founder of Remitigate LLC and the owner and managing editor of paindr.com. He is also an adjunct associate professor at Western New England College of Pharmacy and Health Sciences, an adjunct associate professor of pharmacy practice and pain management at Albany College of Pharmacy and Health Sciences, and the director of the PGY-2 pain residency at Albany Stratton VA Medical Center in New York.

Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society

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Bellamy JL, Cady RK, Durham PL. Salivary levels of CGRP and VIP in rhinosinusitis and migraine patients. 

Durham PL, Dong PX, Belasco KT, et al. Neuronal expression and regulation of CGRP promoter activity following viral gene transfer into cultured trigeminal ganglia neurons. 

Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play a causative role in migraine. 

Aimovig (erenumab-aooe) [prescribing information]. Thousand Oaks, CA: Amgen Inc; 2018. 

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Ajovy (fremanezumab-vfrm) [prescribing information]. North Wales, PA: Teva Pharmaceuticals; 2018. 

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Emgality (galcanezumab-gnlm) [prescribing information]. Indianapolis, IN: Eli Lilly and Co; 2018. 

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Goadsby PJ, Reuter U, Hallström Y, et al. A controlled trial of erenumab for episodic migraine. 

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Sources of funding. Institute for Clinical and Economic Review website. 

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Calcitonin gene-related peptide inhibitors are integral to preventing these powerful headaches.