Gabapentin: The Everything Drug

According to the National Institute of Drug Abuse, there are more than 115 people dying from opioid overdoses every day in the United States.¹ However, opioids are not the only drugs contributing to the staggering amount of overdose deaths. One drug in particular whose usage has been on the rise is gabapentin. In 2017, gabapentin was implicated in more than one-third of overdose deaths in Kentucky.² Gabapentin was first approved by the FDA in January, 1994 as an antiepileptic medication.³ Since then, its usage has skyrocketed. In 2015, there were over 43 million prescriptions written for gabapentin, and it is currently the seventh-most prescribed medication in the United States.⁴

Figure 1: Gabapentin prescription rates (in millions) between the years of 2004 and 2015.⁴

           

            The rise in gabapentin prescriptions is mainly due to the drug company Pfizer promoting their brand-name gabapentin (Neurontin) to physicians for a plethora of off-label uses. Due to this mass-marketing, gabapentin is now prescribed not only for epilepsy, but for anxiety, trigeminal neuralgia, restless legs syndrome, diabetic neuropathy, migraines, insomnia, bipolar disorder, and many other conditions.⁵ Some analysts have stated that “up to 90 percent of Neurontin prescriptions were for off-label uses.”⁶

            Pfizer’s mass-marketing campaign to physicians was so voracious that a felony case was settled against them in 2004.⁶ According to the San Francisco Chronicle, Pfizer “agreed to plead guilty to two felonies and pay $430 million in penalties to settle charges that it fraudulently promoted the drug Neurontin for a string of unapproved uses.”⁶ Ironically, the FDA approved Neurontin to be sold as generic gabapentin in the same year, making it more readily available and more affordable. Coupled with the rise in prescriptions, gabapentin’s potential for abuse has caused it to be added to the DEA’s list of controlled substances in Kentucky, Ohio, and West Virginia in 2017.³

             Gabapentin’s potential for abuse lies mainly in its mechanism of action. Although its molecular structure closely resembles the neurotransmitter GABA, it does not directly act on GABA receptors.⁷ Its proposed mechanism is that it mainly binds to voltage-gated calcium channels on glutamatergic neurons.⁷ By closing the voltage-gated calcium channels, less glutamate is released from presynaptic neurons, therefore lowering the excitation level of the postsynaptic neurons. This contributes to gabapentin’s perceived analgesic or anxiolytic/sedative effects.

            Although gabapentin has shown some efficacy in treating conditions like epilepsy, its off-label usage is unlike any other medication on the market today. Even after debunking many of its off-label uses and being placed on the DEA’s controlled substances list in 3 states, gabapentin prescriptions are still being given out at an alarming rate. Gabapentin’s contribution to drug overdoses should not be overlooked, especially with the opioid epidemic the U.S. is currently experiencing. Instead of being a first-line course of action, both physicians and patients should question the efficacy of gabapentin before beginning treatment.

 

References:

1. National Institute on Drug Abuse. (2018, March 06). Opioid Overdose Crisis. Retrieved from https://www.drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis

2. Gabapentin Abuse. (n.d.). Retrieved from https://www.pewtrusts.org/en/research-and-analysis/blogs/stateline/2018/05/10/abuse-of-opioid-alternative-gabapentin-is-on-the-rise

3. Honarmand, A., Safavi, M., & Zare, M. (2011). Gabapentin: An update of its pharmacological properties and therapeutic use in epilepsy. Journal of Research in Medical Sciences, 16(8), 1062-1069.

4. (n.d.). Retrieved from https://www.addictionpro.com/article/prescription-drug-abuse/states-eye-adding-gabapentin-controlled-substance-list

5. Fukada, C., Kohler, J., Boon, H., Austin, Z., & Krahn, M. (2012). Prescribing gabapentin off label: Perspectives from psychiatry, pain and neurology specialists. Canadian Pharmacists Journal, 145(6), 280-284.

6. Tansey, B. (2012, January 28). Huge penalty in drug fraud / Pfizer settles felony case in Neurontin off-label promotion. Retrieved from https://www.sfgate.com/business/article/Huge-penalty-in-drug-fraud-Pfizer-settles-2759293.php

7. Taylor, C. P. (1997). Mechanisms of action of gabapentin. Revue Neurologique, 153(1), 39-45.

 

By Hart Foley, Master of Medical Sciences Student, University of Kentucky

Selective Serotonin Reuptake Inhibitors



        In the 1970s, the discovery that serotonin played a significant role in mood disorders initiated efforts to develop Selective Serotonin Reuptake Inhibitors (SSRIs). Monoamine oxidase (MAO) inhibitors and tricyclic antidepressants (TCA) had been used to treat major depressive disorder since the late 1950s. Both of these classes of drugs were developed serendipitously; MOAs were discovered originally for treatment of tuberculosis and TCAs were initially intended for patients suffering from schizophrenia. MAO enzymes break down amines such as neurotransmitters, and their inhibition results in the increase of neurotransmitter concentrations in the presynaptic terminal. TCAs contain a core of three benzene rings and inhibit both neurotransmitter transporter and receptor functions. Although these medications were mildly effective, they had a narrow therapeutic index and long list of serious side effects.¹

           

 

Figure 1. Mechanism of Action of Selective Serotonin Reuptake Inhibitors⁷

 

In the clinic, SSRIs proved to be much more tolerable than MAO inhibitors and TCAs for patients based on their specificity for serotonin receptors.² They bind only serotonin transporters and increase the amount of serotonin in the synapse. Over time, the serotonin receptor 5HT1A is downregulated and even more serotonin is released. This mechanism explains why these medications take a few weeks to show full effect.³ SSRIs were initially thought to be free of side effects and could be used by children and elderly populations.

 

            However, as clinical use increased, the side effects of SSRIs became more apparent. It is possible that the dosages used in early clinical trials were relatively low and at levels that did not exert observable side effects. It is also possible that side effects were not reported as they relied on self-report measures which often lack accuracy. The most significant adverse side effects of SSRIs are serotonin syndrome, sexual dysfunction, and weight gain, but appetite and sleep may be affected. Serotonin syndrome can result from overdose and presents with muscle spasms, increased heart rate, and possible psychosis. If a patient abruptly stops taking SSRIs, discontinuation syndrome may ensue. This is similar to withdrawal, so patients should be weaned off these medications.² A 2005 study showed patients who tapered their SSRI medications exhibited half the symptoms of discontinuation syndrome than those who stopped taking them abruptly. Tapering schedules were developed by patients, general practitioners, and psychiatrists, with periods varying from two weeks to four months.⁴

 

            The controversy on the efficacy of SSRIs prevails. Irving Kirsch is a psychologist and a researcher of the Placebo Studies Program at Harvard Medical School. In a 60 Minutes special, Kirsch argued that the placebo effect, not the actual chemical substance of antidepressants, accounted for patients’ improvement By performing a meta-analysis, he concluded that SSRIs were only effective with severe levels of depression. However, Dr. Michael Thase of the University of Pennsylvania School of Medicine disagreed, saying that by focusing on research, Kirsch was overlooking the success of SSRIs seen in clinic. Although the efficacy Thase observes is low, more success is seen in the mildly and moderately depressed than what is shown in the research.⁵ A newer meta-analysis conducted by Hieronymus et al. compared paroxetine and citalopram (information was requested for fluoxetine and sertraline but was not received) and refuted this placebo effect. More research is needed to provide conclusive evidence on SSRI efficacy, but this study was able to provide support for the pharmacodynamic effects of these drugs.⁶

 

1. Hillhouse, T. M., & Porter, J. H. (2015). A brief history on the development of antidepressant drugs: From monoamines to glutamate. Experimental and Clinical Psychopharmacology, 23(1). http://doi.org/10.1037/a0038550
2. Ferguson, J. M. (2001). SSRI Antidepressant Medications: Adverse Effects and Tolerability. The Primary Care Companion to the Journal of Clinical Psychiatry, 3(1), 22-27. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC181155/#i1523-5998-003-01-0022-b11
3. Guzman, F. (n.d.). Mechanism of Action of SSRIs. Retrieved from https://psychopharmacologyinstitute.com/antidepressants/ssris/mechanism-action-ssris/
4. van Geffen, E. C. G., Hugtenberg, J. G., Heerdink, E. R., van Hulten, R. P., & Egberts, A. C. G. (2005). Discontinuation symptoms in users of selective serotonin reuptake inhibitors in clinical practice: tapering versus abrupt discontinuation. European Journal of Clinical Pharmacology, 61, 303-307. https://doi.org/10.1007/s00228-005-0921-x
5. Stahl, L. (Interviewer), Kirsch, I. & Thase, M. (Interviewees). (2012, February 19). Treating Depression: Is there a Placebo Effect? [Interview Transcript]. Retrieved from https://www.cbsnews.com/news/treating-depression-is-there-a-placebo-effect/
6. Hieronymus, F., Lisinski, A., Nilsson, S., & Eriksson, E. (2017). Efficacy of selective serotonin reuptake inhibitors in the absence of side effects: a mega-analysis of citalopram and paroxetine in adult depression. Molecular Psychiatry. https://doi.org/10.1038/mp.2017.147
7. Lattimore, K. A. , Donn, S., Kaciroti, N., Kemper, A. R., Neal, C. R., & Vázquez, D. (2005). Selective Serotonin Reuptake Inhibitor (SSRI) Use during Pregnancy and Effects on the Fetus and Newborn: A Meta-Analysis. Journal of Perinatology, 25, 595-604. doi:10.1038/sj.jp.7211352.

 

By Catie White, Master of Medical Sciences Student, University of Kentucky

 

Weakening the Immune System: How Immunosuppressants Help Save Lives

The immune system is designed to aid in protection against potential infection and disease from invasion of foreign bodies. One example of how this defense mechanism becomes problematic, however, is when the ‘foreign’ tissue is a necessity for one’s survival – as in the case of organ transplantation.

                Organ transplants, especially kidney transplantations, impact many lives each year. According to the Kidney Alliance of Kentucky, “there are over 750 people in Kentucky waiting for a life saving kidney transplant.”¹ The University of Kentucky Transplant Center set a record for the most transplants performed by any Kentucky medical center in a single year with 208 total transplants in 2017 – of those, 101 were kidney transplants, 43 were heart transplants, 41 were liver transplants, and 23 were lung transplants². The basis for transplant ‘success’ is the ability to use drugs that suppress the immune system (called immunosuppressants) in a manner in which the immune system does not recognize and/or target the foreign organ to allow for successful donated organ function.

                Immunosuppressants are a highly specialized class of drugs that are essential in the organ transplant process. They not only function as a hinderance to organ rejection but are also used to treat graft versus host disease and reduce damage to tissues in autoimmune and other inflammatory diseases³. There are several classes of immunosuppressants in this particular drug family, including corticosteroids, calcineurin inhibitors, mTOR (mammalian target of rapamycin) inhibitors, IMDH (inosine monophosphate dehydrogenase) inhibitors, biologics, and monoclonal antibodies⁴.

Some examples of the most common classes of immunosuppressants involved in organ transplantation are calcineurin inhibitors and IMDH inhibitors. Calcineurin acts to catalyze reactions associated with T cell activation in the immune response; inhibitors of calcineurin bind to immunophilin proteins to block its effect and prevent NFAT (nuclear factor of activated T-cells) activation⁴. The result is a reduction in production of cytokine IL-2 and proliferating T cells⁶. In contrast, IMDH inhibitors perform by blocking the inosine monophosphate dehydrogenase pathway, an important enzyme involved in cell interactions and DNA replication⁴. This results in a reduction of infiltrating immune cells during potential transplant rejection⁷. Prograf (tacrolimus) and Mycophenolate mofetil (MMF) are two commonly prescribed combination immunosuppressant drugs to prevent organ rejection for transplant patients; they fall under the calcineurin inhibitor and IMDH inhibitor classes respectively⁸. There are several other immunosuppressant drugs being used in similar clinical settings that fall under different subcategories according to other pathways used to target the immune system.

 

Immunosuppressive Drugs. (n.d.). Retrieved from https://step1.medbullets.com/immunology/105068/immunosuppressive-drugs

Like any drug, there are side effects/precautions when taking immunosuppressants. By weakening the immune system, patients are more susceptible to infection and illness while taking immunosuppressants. Those taking these types of drugs may also be subject to delayed wound healing for similar reasons. Doctors often prescribe antibiotics in addition to these medications to help prevent such problems and advise patients to limit their interactions/possibilities of introducing bacteria into their compromised environment³. These risks can be especially troublesome because transplant recipients must often take these drugs for the rest of their lives to ensure the viability and protection of the donated organ.

                While the immune system is normally a beneficial protective mechanism, it can be detrimental to the successful integration of a transplanted organ. It is quite interesting to explore the mechanisms that scientists, chemists, pharmacologists, and other teams have utilized to suppress this system in order to help save the lives of many people through organ transplantation.

References:

1. How To Help: Be a Living Kidney Donor. (n.d.). Retrieved from https://www.khaky.org/how-to-help/living-kidney-donor.html

2. UK Transplant Center Sets New State Record for Total Transplants in 2017. (2018, January 08). Retrieved from https://uknow.uky.edu/uk-healthcare/uk-transplant-center-sets-new-state-record-total-transplants-2017

3. Immunosuppressants in Organ Transplantation. (2014, March 13). Retrieved from https://www.myvmc.com/treatments/immunosuppressants-in-organ-transplantation/

4. Immunosuppressants. (n.d.). Retrieved from https://www.amboss.com/us/knowledge/Immunosuppressants

5. Immunosuppressive Drugs. (n.d.). Retrieved from https://step1.medbullets.com/immunology/105068/immunosuppressive-drugs

6. P. (2006, August 01). Immunosuppressants - mechanisms of action and monitoring | Australian Prescriber. Retrieved from https://www.nps.org.au/australian-prescriber/articles/immunosuppressants-mechanisms-of-action-and-monitoring

7. Blaheta, R. A., Leckel, K., Wittig, B., Zenker, D., Oppermann, E., Harder, S., . . . Markus, B. H. (1998, December). Inhibition of endothelial receptor expression and of T-cell ligand activity by mycophenolate mofetil. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/10342739

8. Giorgi, A., & Gregory, P. (2016, December 7). About Immunosuppressant Drugs. Retrieved from https://www.healthline.com/health/immunosuppressant-drugs#drug-list

By Caitlin Seward, Master of Medical Sciences Student, University of Kentucky