Authors:

Fangzheng Yuan, PharmD Candidate 2018: St. Louis College of Pharmacy
Hannah Pope, PharmD, BCPS: Barnes-Jewish Hospital

Dual antiplatelet therapy (DAPT) is the mainstay of treatment in acute coronary syndromes (ACS). The use of DAPT is crucial in those who undergo percutaneous coronary intervention (PCI) and coronary artery stent implantation.¹ DAPT consists of low-dose aspirin and an oral P2Y₁₂ receptor inhibitor such as clopidogrel, prasugrel, or ticagrelor.² Premature discontinuation of DAPT has been associated with an increased risk of adverse events, including stent thrombosis and mortality.² Mortality rates of 19-30 % have been observed in patients who had DAPT discontinued early for a surgical procedure.^3-5 Studies have shown that over 4% of patients on DAPT will require non-cardiac surgery within one year after stent implantation.⁶ The optimal approach for managing the risk of potential catastrophic perioperative stent thrombosis and bleeding in patients requiring surgery during the recommended duration of DAPT remains uncertain.

In non-emergent cases, American College of Cardiology/American Heart Association recommended that DAPT be discontinued 5-7 days prior to surgical intervention. Current guidelines recommend that all elective surgeries be postponed until DAPT is complete.¹ Per these recommendations, non-cardiovascular, elective surgeries should be delayed for at least 30 days after bare metal stent (BMS) and 6 months after drug eluting stents (DES).² However, this is not always feasible and temporary administration of a short-acting antiplatelet agent, also known as bridging anti-platelet therapy, is warranted to minimize ischemic and bleeding events. 

An ideal bridging agent should achieve platelet inhibition similar to the oral P2Y₁₂ receptor inhibitors, with a rapid onset and short duration of action.⁷ Off-label use of the GPIIb/IIIa inhibitors, tirofiban and eptifibatide, as bridging agents has been advocated as an alternative to oral DAPT therapies, due to their pharmacokinetic profiles (Table 1).^7-10 Current evidence for this indication is limited and the optimal duration of therapy is unknown.

Cangrelor is an intravenous, non-thienopyridine adenosine triphosphate analogue that directly and reversibly binds to the P2Y₁₂ receptor.⁸ This differs from oral thienopyridines such as clopidogrel and prasugrel that require metabolic activation and bind irreversibly. Although not FDA approved for bridging therapy, the pharmacokinetic profile of cangrelor makes it an ideal bridging agent. It has a faster onset and offset than other agents considered for bridging (Table 1).^8-10 Due to its rapid inactivation in the circulation via dephosphorylation, cangrelor is less likely to accumulate and does not require renal dosing when compared to GPIIb/IIIa anti-platelet agents, which are eliminated as unchanged drug or partial metabolites.^8-10

Table 1. Pharmacokinetic profiles of bridging agents^8-10

	Cangrelor	Tirofiban	Eptifibatide
Administration	IV	IV	IV
Onset of action	Immediate	Immediate	Immediate
Mechanism of action	P2Y12 inhibition	GPIIb/IIIa inhibition	GPIIb/IIIa inhibition
Plasma t ½	3-5 min	2 hours	2.5 hours
Offset of action	1 hour	4-8 hours	4-6 hours
Renal dosing	No	Yes	Yes

To date, cangrelor is FDA approved as an adjunct to PCI. However, the phase II randomized, double-blind trial, Bridging anti-platelet therapy with cangrelor in patients undergoing cardiac surgery (BRIDGE trial), evaluated the hypothesis that cangrelor may be a safe and effective option to bridge patients from irreversible platelet P2Y₁₂ inhibitors to cardiac surgery.¹¹ Patients were randomized to cangrelor or placebo after an initial open-label, dose-finding phase that determined the dose of 0.75 mcg/kg/minute was necessary to achieve appropriate platelet inhibition in 10 patients. In stage 2 of the study, a greater proportion of patients (98.8%) treated with cangrelor achieved the goal of platelet reactivity units (PRU) <240 throughout the entire treatment period compared with placebo (RR=5.2, 95% CI 3.3-8.1, P<0.001). In addition, no significant differences were found in excessive coronary artery bypass grafting (CABG) surgery-related bleeding or major bleeding prior to surgery. However, minor bleeding episodes were numerically higher with the cangrelor group. Angiolio, et al. concluded that the cangrelor group had a higher rate of maintenance of platelet inhibition than the control group.¹¹

Firstenberg, et al. assessed the effects of preoperative cangrelor on the incidence of perioperative complications in the BRIDGE trial.¹² All patients received 2-7 days of therapy (cangrelor or control) and the therapy was discontinued 1-6 hours before the planned CABG. Pre- and post-operative outcomes, bleeding values, and transfusion rates were compared between the cangrelor and placebo groups. A multivariable logistic model was used to quantify bleeding risks. No significant difference was found in the rate of CABG-related bleeding (P=0.763) or in serious post-operative adverse events (p=0.454) between the cangrelor group and placebo group. Bridging patients with cangrelor prior to CABG effectively maintained platelet inhibition at <240 P2Y₁₂ PRU without increasing post-CABG bleeding or infusion needs. This analysis further suggests that cangrelor treatment is a potential strategy for bridging patients to a procedure and surgery.¹²

Overall, the pharmacokinetic profile and data from the BRIDGE trial suggest that cangrelor is a potential treatment option in patients that require DAPT discontinuation prior to a procedure or surgery. Cangrelor can be initiated at the dose of 0.75 mcg/kg/minute through IV administration until 1-6 hours before surgery. Signs and symptoms of bleeding should be monitored during therapy and the procedure. DAPT with an oral antiplatelet agent should be resumed as soon as possible post-surgery.

References

1. Levine GN, Bates ER, Bittl JA et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Thorac Cardiovasc Surg. 2016; 152(5):1243-1275. 
2. Song JW, Soh S, Shim J-K. Dual antiplatelet therapy and non-cardiac surgery: evolving issues and anesthetic implications. Korean Journal of Anesthesiology. 2017; 70(1):13-21.
3. Wilson SH, Fasseas P, Orford JL, et al. Clinical outcome of patients undergoing non-cardiac surgery in the two months following coronary stenting. J Am Coll Cardiol. 2003; 42(2):234-240.
4. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA. 2007; 297(2):159-168.
5. Ferrari E, Benhamou M, Cerboni P, Marcel B. Coronary syndromes following aspirin withdrawal: A special risk for late stent thrombosis. J Am Coll Cardiol. 2005; 45(3):456-459.
6. Berger PB, Kleiman NS, Pencina MJ et al. Frequency of major noncardiac surgery and subsequent adverse events in the year after drug-eluting stent placement results from the EVENT (Evaluation of Drug-Eluting Stents and Ischemic Events) Registry. JACC Cardiovasc Interv. 2010; 3(9):920-927.
7. Capodanno D, Angiolillo DJ. Management of antiplatelet therapy in patients with coronary artery disease requiring cardiac and noncardiac Surgery. Circulation. 2013; 128:2785-2798.
8. Cangrelor. Lexicomp Online, Lexi-Drugs Online, Riverwoods. IL. 2017; July 15, 2017.
9. Tirofiban. Lexicomp Online, Lexi-Drugs Online, Riverwoods. IL. 2017; July 15, 2017.
10. Eptifibatide. Lexicomp Online, Lexi-Drugs Online, Riverwoods. IL. 2017; July 15, 2017.
11. Angiolio DJ, Firstenberg MS, Price MJ, et al. Bridging anti-platelet therapy with the intravenous agent cangrelor in patients undergoing cardiac surgery. JAMA. 2012; 307(3):265-274. Firstenberg MS, Dyke CM, Angiolillo DJ, et al. Safety and efficacy of cangrelor, an intravenous, short-acting platelet inhibitor in patients requiring coronary artery bypass surgery. Heart Surg Forum. 2013.

Authors:
Diane McClaskey, RPh, BCPS: Assistant Director of Experiential Education-UMKC at MSU

Sarah Cook, PharmD: Clinical Pharmacist at SSM Health St. Joseph’s Hospital – St. Charles

Whether a pharmacy student or resident desiring to set themselves apart or a practicing pharmacist desiring to contribute in a broader way to the medical community, writing review articles for publication in a medical journal may be a desirable opportunity.  Megan Musselman, PharmD, MS, BCPS, BCCCP is a Clinical Pharmacist Specialist in Emergency Medicine/Critical Care at North Kansas City Hospital and has generously shared her best practices for developing, writing, and successfully submitting a literature review paper.  We hope this information will be helpful to those contemplating and actively working on research articles.  If you have any questions regarding the topic, please sent them to Sarah.Cook@ssmhealth.com and they will be forwarded on to Dr. Musselman. 

What is the best method of choosing a topic for a review article?
When choosing a topic for a review article, it is best to choose an area you have interest in and to identify an audience you are familiar with.  If you are interested in the topic, it will help you keep momentum as you work your way through the process.  In addition, if you identify a target audience, it helps you streamline your outline and appropriately highlight specific areas of that topic.  Oftentimes, the best review articles developed are secondary to your own review of the available literature when trying to answer a question that applies to your practice. 

How should you start the process of writing a literature review paper?
Start by conducting a thorough literature search and downloading relevant papers.   When conducting your search, keep track of your search terms so they can be replicated, if needed.  Tips for a successful search include using different keywords and database sources (i.e., Google Scholar, Medline, Scopus).  Additionally, look through the references of the articles that you have selected to find any additional literature that may pertain to your topic.

What are important steps to take while reading and evaluating the available literature?
When choosing and evaluating literature, be up-to-date but don’t forget the older studies.   Be careful using other published reviews as a frame of reference for your current review; it can sway your evaluation and critique of the available studies on the topic.  Try to maintain objectivity when writing your review, reducing any bias on the subject matter.  Most importantly, take notes while reading.  This will help you remember which literature you used when drafting your publication.  Nothing is more frustrating than when you cannot remember which body of literature you used for a specific section of your paper.

How do you choose which journal to pursue for publication?
It is always good to research which journals are out there that are tailored to your specific topic, and most importantly, which journals take review articles.  Some journals do not accept review articles and other journals only accept review articles from authors they have invited to write the review.  Also, it is usually a good choice to choose a journal that you are familiar and read often.  This will make formatting easier.

What is the next step once you have identified your target journal for submission?
A good review should have the following elements: it is worth the reader's time, timely, systematic, well written, focused, and critical. It also needs a good structure. The structure is usually dictated by the journal’s specific requirements.  Overall, a general introduction of the content and, toward the end, a recap of the main points covered along with take-home messages makes sense in terms of structuring reviews. For systematic reviews, there is a trend towards including information about how the literature was searched including which database, number of keywords, and time frame used to conduct the search.

What is necessary to effectively write a literature review article?
A good review does not just summarize the literature.  It takes it a step farther and discusses it critically, identifies methodological problems, and points out current gaps in the literature.  One thing to keep in mind when writing your review is to ask yourself if your publication will provide the reader with the major achievements in the reviewed field, the main areas of controversy or debate, and what outstanding research questions still exist.  While focus is an important feature of an effective review, this requirement has to be balanced with the need to make the review relevant to a broad audience. 

What are some successful tips to ensure final acceptance of your publication?
Normally all journals are peer-reviewed.  After your initial submission, feedback will be provided on ways to improve your publication.  Feedback is vital to writing a good review, and should be sought from a variety of colleagues and disciplines.   While the feedback process is vital to the final product being exemplary, it is oftentimes hard to be open-minded to the criticism.  Keep in mind that this may lead, in some cases, to conflicting views on the merits of the paper and on how to improve it, but such a situation is better than the absence of feedback.

Finally, if you have a best practice which you feel others in the state would benefit from reading about, please contact me – Sarah Cook, Vice Chair of the MSHP Newsletter Committee – at Sarah.Cook@ssmhealth.com.  

Author: Barb Kasper, PharmD, BCACP
MSHP Newsletter Committee Chair

The Newsletter Committee has compiled the results of our 2017 Newsletter Survey.  A total of 57 members responded to the survey.  Approximately 64% of respondents read the newsletter at least 75% of the time.  Of the recurring newsletter content, members read the featured clinical topics, public policy updates, and announcements most frequently.  A strong majority of respondents were interested in obtaining pharmacist CE through the MSHP Newsletter.  Areas for improvement included the overall presentation of content and consistent distribution to all members. 

The Newsletter Committee wishes to thank members for taking the time to provide feedback to enhance the newsletter.  The following changes have already taken place, or will be forthcoming, to better meet the needs of our members:

The Newsletter Committee welcomes continued member feedback, questions, or concerns.  Additionally, if you are interested in becoming a member of the Newsletter Committee, please direct correspondence to the Newsletter Committee Chair.  We appreciate your support of the MSHP Newsletter and look forward to continuing to serve the needs of our membership!

Author: Heather Taylor, PharmD
MSHP Membership Committee Chair

The Membership Committee would like to share some of the results from our 2017 Annual Membership Survey. Ninety-nine of our members responded to the survey.  An overwhelming majority of responders felt that the primary benefit of being a MSHP member was the networking with other pharmacists and health care professionals. 

 

Top Three Reasons for being involved in MSHP:

1. Networking
   
2. Professional Development
   
3. Affiliate chapter activities and Continuing Education
   

 

MSHP is doing a good job with the following:

1. Providing networking opportunities
   
2. Affording ample opportunities for involvement and leadership
   
3. Provides relevant and timely information
   
4. Effectively advances pharmacy practice in Missouri
   

 

MSHP activities that are most important to members:

1. Advocating for pharmacists and the profession at the state level
   
2. Providing opportunities for networking
   
3. Delivering high quality ongoing education
   
4. Providing opportunities for leadership and organizational involvement
   
5. Promoting health system pharmacy to the general public
   

 

Areas for MSHP to improve upon:

1. Offering more local/regional programming
   
2. Offering more social functions and networking opportunities
   

 

What should the top priorities for MSHP be this year?

1. Legislative issues
   
2. Education/programming
   
3. Professional development for pharmacists and technicians
   
4. Membership involvement
   

 

*Items in purple received > 50% of votes

 

The majority of members utilize Facebook and Instagram daily and are the most popular social media platforms. The majority of members would like to be notified on issues via email or online media. The majority of members feel they receive a good value for their membership dues.

 

We want to thank all the members that took the time to fill out the survey. We utilize these results at our strategic planning meeting in the summer to determine what to focus on for the upcoming year.   We are excited about all the changes that have been happening within MSHP over the past year and look forward to continuing to improve your membership experience!

Author: Sarah Bledsoe, PharmD, CPHIMS
MSHP Treasurer 

Each year, the Treasurer has the responsibility to report to the membership on MSHP’s financial condition. MSHP’s financial year is from July 1 through June 30, coinciding with our policy development process and timetable. This report describes MSHP’s past and projected financial performance.

Fiscal Year Ending June 30, 2017 – Actual

In March 2017, members of the internal audit team performed a review of MSHP’s finances covering June 2016 through December 2016. The audit cycle was shortened due to the transition to our new management companies occurring in June 2016. The audit found no significant deviations.

During the transition, MSHP’s primary checking and savings accounts were transferred to Enterprise Bank and Trust. MSHP also retains a CD with US Bank which is projected to mature in November 2018 at which time the Executive Board will review future investment strategies.

As of June 30, 2017, the organizations balance sheet reported our total assets at $143,115.87 with a net income of $25,870.64 for the fiscal year. It was noted by the MSHP Executive Board that these figures are significantly elevated due to pending expenses from the Spring 2017 ICHP-MSHP Meeting.

Fiscal Year Ending June 30, 2018 - Projected

In June 2017, the MSHP Executive Board approved the fiscal year 2017-2018 budget which is balanced with a $1505.00 surplus. Notable changes in the proposed budget included increased funding for the ASHP Midyear reception due to increased attendance and facility fees, increased management fees, and decreased conference call fees.

As this is my first report to the membership, I am honored to serve as your Treasurer. I am delighted to be part of an actively engaged Executive Board that is committed to supporting and advancing the profession of pharmacy. MSHP continues to be a strong and vibrant organization from a financial viewpoint and I am committed to continuing a tradition of financial responsibility.

Author: Elaine Ogden, PharmD, BCPS, BC-ADM 
MSHP Secretary

The MSHP Board of Directors (BOD) has been working diligently over the summer to transition the new board members in, establish a working budget, and review/update the strategic plan for the next year.  There are several great things the board is working on, listed throughout this edition of the MSHP Newsletter, but here are a few interesting facts not listed elsewhere!

July BOD Updates

• The FY17-18 budget was approved at the strategic planning meeting as well as finalized a few outstanding payments for the FY16-17 year.
• David Wolfrath has been appointed as the as MSHP representative to the Hospital Advisory Committee by the BOD
• MSHP has begun meeting with several thought leaders in Missouri on legislation relating to the Missouri Pharmacy Practice Advancement Act. The group met on July 11th in Columbia, MO and their purpose was to discuss verbiage changes to pharmacist’s scope of practice in the state of Missouri. The group will be reaching out to MPA and MHA to gain support to foster change. The group still would like to solicit feedback from other areas of practice such as long-term care and ambulatory care pharmacist to obtain support to give uniform voice in MO and hopingly get the bill on the docket early next year!

August BOD Updates

• The strategic plan was approved by the BOD
• The Website committee reported continual work on updating the MSHP website. If a link does not work, please reach out the Website Committee!
• The Education and Programming Committee provided updates for the Fall meeting as well as an introduction to the joint MSHP/KCHP meeting in May 2018
• MSHP has applied for ASHP re-affiliation

Author: Bert McClary, RPh

At the August meeting, the group discussed the practice advancement legislation proposal, agenda topics from the June 23 and July 12 BOP meetings and pharmacy/drug-related sections of SB 501 that become effective August 28.

Practice Advancement Legislation Group

• A multidisciplinary practice advancement group was convened in January and has met three times.  The MSHP Public Policy and Practice Advancement Initiative Committees are leaders in this effort.  The meetings are open and between 15 and 20 persons have participated in each meeting.  While most are MSHP members, there is regular attendance by MPA, BOP, UMKC and StLCOP.  LTC pharmacists have participated and an additional effort is being be made to have chain stores and nuclear pharmacies represented.
• At the August 25 meeting in Columbia, proposed pharmacy practice act language was agreed on that includes authority to prescribe drugs including controlled substances, removal of the requirement for a prescription to implement a medication therapy services protocol, and removal of the term medication therapeutic plan.  Language is also proposed to be changed in the controlled substances act to allow prescribing of controlled substances by pharmacists, which will provide the basis for a pharmacist DEA registration.
• Although MPA members and staff have participated in the group, the MPA board of directors has not yet voted to support or promote the legislation.  MPA retains a lobbyist and has a formal process for sponsoring legislation which their board requires to be followed, but they do wish to work together with the other organizations in this effort.  MSHP members have strongly recommended that support and sponsorship also be solicited from the Missouri Hospital Association, and MHA staff have expressed interest.  A meeting with MHA staff, who have considerable experience in promoting legislation, is being arranged.  All participants have emphasized that this must be a true collaborative effort that is supported by all pharmacy practice settings.
• The MSHP PAI members are continuing to refine a Q&A, and will develop examples of advanced practices that will show the patient care benefits of increased pharmacist participation in direct patient care.
• A chairperson had not been previously designated, and Daniel Good accepted a request to serve in this position.  Daniel is past-president of MSHP, serves on the MPA board of directors, is a member of the BOP Hospital Advisory Committee, has worked directly with MHA on pharmacy-related projects and will be able to coordinate this multidisciplinary group.
• A core “executive group” will meet on September 21 to make decisions on next steps to move the effort forward.

The Public Policy Committee meets by telephone conference the first Thursday of each month at 4:00 p.m.  The new chair is Amy Benson, Director of Pharmacy at Liberty Hospital.  If you would like to join the conversations and if there are public policy/regulatory issues that you would like to discuss, contact Amy at abenson@libertyhospital.org.

Author: Bert McClary, RPh

The HAC met in Jefferson City on August 7

• Class J Shared Services Rule.  An emergency amendment became effective August 7 that will allow a licensed pharmacy to deliver a filled and labeled prescription to another licensed pharmacy without being licensed under Class J if the medication is to be administered on the same premises as the receiving pharmacy.  This amendment was based on current problems caused when specialty pharmacies could not deliver medications to a pharmacy/clinic for administration to the patient at the clinic because it was not possible obtain a Class J permit between the two pharmacies. 
• The Board is working with DHSS, the Department of Mental Health and others to implement provisions of new legislation related to opioid abuse and misuse, including a standing order for naloxone, MoHealthNet billing, patient education, insurance and distribution of free supplies from DMH.
• New legislation allows hospitals to be licensed if they are in compliance with CMS Conditions of Participation, and places restrictions on DHSS hospital licensing rules.  The definition of licensed premises is unclear under the new requirements and is significant to BOP licensing regarding certain practice sites.  DHSS and MHA are working together to interpret the law and DHSS will make proposals for rule changes.  HAC will review the previously proposed changes to the DHSS pharmacy services and medication management rule and make a recommendation to DHSS regarding sections that should be implemented.
• Suggestions were made regarding proposed pharmacy practice advancement legislation, to be forwarded to the task force that is preparing the language.
• Proposed technician legislation was reviewed and concerns were expressed regarding the effect of sterile compounding being placed in the advanced technician category.  The potential for DHSS and BOP to propose a joint rule regarding technician activities was discussed, to be considered if the proposed legislation is not successful or if the final language is not satisfactory.
• Greg Teale was elected to serve as Chairman.
• Strategic review of committee operations was deferred to the next meeting, to include a more complete review of previous activities, membership, scope of authority and future topics.

Author: Bert McClary, RPh

The Board met on July 12 in open session with several MSHP members present and participating. 

• Governor-mandated public rule comment period.  Members of the public commented on rules including pharmacist CE for drug administration and maintenance of electronic prescription records.
• Draft legislation proposal for technicians.  There is concern that the governor’s office wants restriction of oversight by state agencies rather than expansion.  Topics discussed during the meeting for further changes in the proposal included age requirements, advanced technician roles, nuclear technician CE, registration of trainees, and oversight by pharmacist during training.  A final version was to be reviewed by the Board and presented to the Governor’s office in early August, but this version has not been publicly distributed.
• Other proposed legislation.  Additional proposals agreed to move forward included clarifying the role of third-party logistics providers and changing pharmacist CE to a biennial period rather than annual.
• Required rule review.  Although hospital pharmacist interest is usually focused on inpatient-related issues, more hospital pharmacists are showing interest in Board rules for outpatient pharmacy as well.  Board members were again reminded of the Governor’s request for a reduction in the number of mentions of “shall” and “must.”  Lengthy discussions were held regarding five rules scheduled under the previous Governor’s required Rule Review 2020, and seven draft rule proposals that are in process, including:
• • Compounding Standards of Practice.  Updating is needed, including consideration of USP 795.  Postpone for one year due to other priorities.
  • Nuclear.  A nuclear subcommittee will recommend minimum changes and wait for USP 825 requirements.
  • Standards of Operation.  Miscellaneous editorial and minor changes recommended.
  • Supervision.  A new rule proposal would address current supervision requirements and new concepts such as remote technician supervision.  Recommended to focus first on final verification of a prescription/order, considering technology and credentials and qualifications of technicians.  Later discussion of types and definitions of remote supervision.  Hospital pharmacists expressed concerns about expansion of remote hospital physician clinics with no pharmacy services onsite that could be addressed with remote supervision.
  • Administration by prescription order.  Removal of CE requirement.
  • Vaccines by protocol.  Change CE requirements to 2 hours per 2 years.
• A Governor’s Task Force on Boards and Commissions is still meeting with Boards and discussing possible changes such as combining various boards, inspector qualifications (e.g.: non-pharmacist inspectors), salaries, CE for staff, and technology.  Board staff emphasized the need for continuity and expertise of pharmacist inspectors and retaining separation from other medical professional boards.  Board member appointments are still anticipated this summer.
• Proposed Patient Safety Conference and Opioid Conference are still on hold.
• A webinar is scheduled to review new 2017 legislation, most of which will become effective August 28.  Legislation will also be reviewed in the August BOP Newsletter.
• Board Officers.  Christian Tadrus was elected President.  Christian is a past-president of MPA and a principal in the Missouri Pharmacist Care Network supporting advanced clinical practice in community pharmacy.  Although Christian does not support expanded technician roles, he has been a friend of hospital pharmacy and has represented community pharmacy in various Board hospital pharmacy issues for a number of years, including the Hospital Advisory Committee.  Doug Lang, a perennial hospital pharmacy promoter, is serving a new term on the Board after being absent for several years and was elected Vice President.

By John Neill, PharmD Candidate 2018, and Courtney Kominek, PharmD, BCPS, CPE

Gabapentin and pregabalin are widely     prescribed in chronic pain. Food and Drug Administration (FDA)-approved indications for gabapentin and pregabalin include post-herpetic neuralgia and epilepsy.1,2 In addition, pregabalin is FDA-approved for neuropathic pain (diabetic or spinal cord injury) and fibromyalgia.2 These gabapentinoids are frequently prescribed off-label for various reasons including post-operative pain, hot sweats, generalized anxiety disorder, and substance use disorders.3,4 Per the Controlled Substance Act, pregabalin is a Schedule V drug indicating it has the least likelihood for abuse among the 5 classes of controlled substances. Pregabalin was classified as a controlled substance based on the data from clinical trials. These trials showed that pregabalin causes positive psychic effects similar to alprazolam and diazepam, as well as acute euphoric effects seen at a higher proportion than expected.5 Gabapentin is not a controlled substance.3 Up until recently, gabapentin and pregabalin have been regarded as having low levels of abuse and being safe. This thought is rapidly changing and the reasoning behind this change will be described in this article.

Many drugs of abuse including alcohol, benzodiazepines, and non-benzodiazepine hypnotics display effects on gamma-aminobutyric acid (GABA) receptors.3 Gabapentinoids have structures that are similar to GABA, but they do not directly interact with GABA receptors or impact GABA uptake or production.6 It has been proposed that gabapentin may interfere with GABA metabolism, as well as cause the release of GABA allowing it to interact with its receptors.4 Gabapentinoids also reduce neurotransmitter release and the influx of calcium by binding to the alpha-2-delta subunit of voltage-gated calcium channels potentially causing their anticonvulsant, anxiolytic, and antinociceptive effects. It is believed, that not only do gabapentinoids cause euphoric effects most commonly attributed to GABA moderating drugs, but they may also cause dissociative effects through their interaction with the dopaminergic system.3 This dopaminergic relationship may also be the cause for the addictive potential of these drugs with the reward system being activated through this interaction. These dopaminergic effects are not typically seen with the other GABA modifying medications.3,4 In addition to the above effects associated with gabapentinoid abuse, other unexpected effects have been reported by abusers. These effects include relaxation and a high described as being similar to a high from marijuana, ‘zombie-like’ effects, and enhanced sociability.4

Gabapentinoid abuse is most common among the younger population, generally occurring in the 30s, on average. Risk factors for abusing gabapentinoids include a history of cocaine use, combination marijuana and benzodiazepine use at high rates, psychiatric patients, prisoners, and opioid abusers. The data for abuse rates for males vs. females is conflicting, with some studies showing higher rates in males, while others show higher rates in females. The prevalence of gabapentinoid abuse is much higher in this patient population and this problem has been on the rise in recent years. U.S. opioid abusers misused gabapentin and pregabalin as much as clonazepam and 2 times more than amphetamines. Gabapentinoid abuse is of particular concern in patients who currently abuse opioids or have a history of opioid abuse. Studies that have been done that have specifically assessed people with opioid use disorders and gabapentinoid abuse show pregabalin being abused at rates ranging from 3-68%, and gabapentin being abused at rates ranging from 15-22%. When comparing this to a study that showed the general population in the United Kingdom abusing pregabalin and gabapentin at rates of 1.1 and 0.5%, it shows you the alarming difference in rates of abuse between opioid use disorder patients and the general population.3Gabapentin dosing for post-herpetic neuralgia starts with 300 mg on day 1, 300 mg twice daily on day 2, and 300 mg three times daily on day 3, titrating up as needed to a max of 1800 mg/day; however, gabapentin may be dosed up to 3600 mg/day in divided doses for other conditions. Pregabalin dosing is recommended to start at 150 mg/day for all indications. This is typically divided into 2 to 3 doses per day. The general titration schedule is to increase to the max dose per indication based on tolerability and efficacy within 1 week. Max doses for pregabalin vary from 300 mg/day to 600 mg/day based on indication.2 Both medications require dosage adjustments for reduced renal function when creatinine clearance is below 60 mL/min.1,2.

Per individual case reports for gabapentinoid abusers, pregabalin abuse ranged anywhere between 800 to 7,500 mg per dose, with the median dose being 2,100 mg; and gabapentinoid abuse was anywhere between 1,000 and 12,000 mg per dose, with the median dose being 3,600 mg. These are typically single supratherapeutic doses when abused. Tachyphylaxis develops rapidly, so repeat abusers commonly increase the dose as they continue to abuse. U.S. poison centers have reported doses ranging up to 96,000 mg of gabapentin and 9,000 mg of pregabalin. No deaths occurred due to these high doses and outcomes were mostly mild to moderate. These reports indicate an advantageous adverse effect profile for these drugs; however, they are being seen on toxicology reports on an increasing basis. When pregabalin and gabapentin are used in conjunction with other central nervous system depressants, overdose deaths are more frequent.3

Typical abuse occurs via oral route, but intravenous routes, rectal plugging, smoking, and parachuting have been reported. Often times gabapentinoids are abused in conjunction with other drugs like alcohol, benzodiazepines, marijuana, opioids, lysergic acid diethylamide (LSD), selective-serotonin reuptake inhibitors, and quetiapine.3,4 People who abuse gabapentinoids typically acquire them with a legal prescription, from their family members or friends, or may purchase them online. Gabapentin on the black market ranges from $1 to $7 per pill.3

A concern related to gabapentinoid abuse is physical dependence and withdrawal symptoms. Withdrawal symptoms can be caused by sudden discontinuation of gabapentin or pregabalin. Withdrawal with gabapentinoids are very similar to what is seen with alcohol and benzodiazepine withdrawal, likely due to their effects on GABA.3 Symptoms that can result from alcohol and benzodiazepine withdrawal include anxiety, tremors, sweating, irritability, cognitive dysfunction, psychosis, and seizures, which can be life-threatening.7 Treatment for benzodiazepine and alcohol withdrawal involves using primarily benzodiazepines to help relieve symptoms. Benzodiazepine treatment for gabapentinoid withdrawal is ineffective, but fast relief can be attained by the administration of gabapentinoids. Re-administering gabapentinoids and slowly tapering the dose is the ideal way to treat gabapentinoid withdrawal.3

Some states have taken their own action to address this issue. The State Board of Pharmacy in Ohio made a rule effective on December, 1st 2016 requiring pharmacies, wholesalers, and prescribers to submit the specified dispensing, personal furnishing, or wholesale sale information on gabapentin to the Ohio Automated Rx Reporting System.8 In addition to the changes to gabapentin in Ohio, a rule went into effect in Kentucky on July 1, 2017 making gabapentin a Schedule V controlled substance resulting in the requirement of the administering and dispensing of gabapentin to be reported to Kentucky All Schedule Prescription Electronic Reporting (KASPER).9 It is highly likely that as time goes on more states will continue to adopt similar rules to help reduce the misuse and abuse of gabapentin.

Pharmacists are in a critical position to help reduce the spread of the abuse and misuse of pregabalin and gabapentin. Pharmacists can help raise awareness to this problem and make sure these medications are being used for legitimate purposes and that the doses are appropriate and do not exceed the maximum recommended dosages. It is important that pharmacists are aware of the warning signs of abuse such as frequent early refill request, patients requesting to pay out of pocket when they have insurance, multiple prescriptions for the same medication from different doctors, frequent transfers for that medication, and patients wanting their prescription early because it was ‘stolen or misplaced.’ We also need to pay particular attention to patients taking gabapentinoids who have substance abuse disorders, specifically people using opioids or with psychiatric issues.3

References

1.  Neurontin [package insert]. New York, NY: Pfizer; 2015.
   
2.  Lyrica [package insert]. New York, NY: Pfizer; 2016.
   
3.  Evoy KE, Morrison MD, Saklad SR. Abuse and misuse of pregabalin and gabapentin. Drugs. 2017;77:403.
   
4.  Schifano F. Misuse and abuse of pregabalin and gabapentin: cause for concern? CNS Drugs. 2014;28:491-496.
   
5.  Leonhart MM. Schedules of controlled substances: placement of pregabalin into Schedule V. DEA diversion website. https://www.deadiversion.usdoj.gov/fed_regs/rules/2005/fr0728.htm. July 2005. Accessed: June 27th, 2017.
   
6.  Gabapentin. Lexi-Comp OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; Accessed: June 27th, 2017.
   
7.  Freynhagen R, Backonja M, Schug S, et al. Pregabalin for the treatment of drug and alcohol withdrawal symptoms: a comprehensive review. CNS Drugs. 2016;30:1191.
   
8.  Reporting gabapentin to OARRS. State of Ohio Board of Pharmacy website. http://pharmacy.ohio.gov/Documents/Pubs/Special/OARRS/Reporting Gabapentin Products to OARRS – Effective 12-1-2016.pdf. July 2016. Accessed: June 28, 2017.
   
9.  KASPER (Kentucky All Schedule Prescription Electronic Reporting). Cabinet for Health and Family Services in Kentucky website. http://www.chfs.ky.gov/os/oig/KASPER.htm. June 2017. Accessed: July 6, 2017.