4/3/2018. Gabapentin: The Wonder Drug (?) Objectives. Outline

Transcription

1 Gabapentin: The Wonder Drug (?) Andrew J. Garcia, MD - Hospice and Palliative Care Fellow University of Minnesota Hospice & Palliative Medicine Fellowship Objectives Discuss current FDA approved uses for gabapentin Discuss current understood mechanism of action for gabapentin Illustrate via a case presentation, a novel use for gabapentin Discuss current research supporting gabapentin use an anti-inflammatory Outline Introduce case presentation Discussion of gabapentin Present research supporting the anti-inflammatory properties of gabapentin Wrap up case presentation 1

2 Disclosures Will be discuss off-label uses of gabapentin No financial disclosures Case 50 y/o F diagnosed with choroidal malignant melanoma presenting to the palliative care clinic for pain control CC: left eye pain w/associated headaches Ongoing for the past several months Characterizes pain as stabbing, sudden, and sharp, experiences photophobia and has been unable to achieve any good sleep for past several weeks as is now seeing disco lights even with eyes closed Case (cont.) Past Medical History: Anxiety and depression, untreated Past Surgical History: C/section, hysterectomy L eye clips during initial diagnosis of malignancy Family Medical History: Unknown cancer in maternal grandmother Thyroid disease in sister 2

3 Case (cont.) Medication Regimen at time of visit: Diphenhydramine 50 mg caps 3-4 per day Ibuprofen 200 mg tabs 6-8 at a time about 4 times/day Excedrin Tension headache (Acetaminophen-caffeine) 4-6 per day Melatonin Gummies 4-6 per night Zzz-quil liquid (Diphenhydramine) 1-2 tsp per night Oxycodone 5 mg tabs 4-6 per day Case (cont.) Vitals: BP: 124/78 HR: 89, RR: 16, T: 98.7 F, Ht: 5 4, Wt: 154lbs Physical Exam: Gen: alert, appears fatigued, in no acute distress HEENT: NC/AT, EOMI, MOM, PERRLA, Left eye w/surrounding erythema and some moderate inflammation Cardio: RRR, normal s1/s2, no m/r/g Lungs: Clear to auscultation Abd: BS+, soft, non tender Neuro: A&O x 3, CN II-XII grossly intact, no focal deficits noted Psych: Appears anxious/frustrated, mood down, affect normal, speech/thoughts coherent Suggestions from here? 3

4 Gabapentin Structural analog of GABA (yamino butyric acid) First approved for use in 1993/94 Main indication then, partial seizures Current FDA approved uses: Post-herpetic neuralgia Seizures, partial onset Other Current (Off label) uses Diabetic Neuropathy Chemo induced neuropathy Trigeminal neuralgia HIV neuropathy Cancer Pain Fibromyalgia Pain after burns Complex regional pain syndrome Alcohol dependence Alcohol withdrawal Brachioradial pruritus Cough, chronic Hiccups Hot flashes Post operative pain (adjunct) Restless leg syndrome Social anxiety disorder Uremic pruritus Usual Dosing Varies mainly based on what it is being used for Doses most commonly range from 1,800 3,600 mg daily (in divided doses) Doses can be as low as 300 mg/day Doses >1,800 mg not shown to be generally more effective No set way to titrate to max effective dose, based largely on provider preference/comfort and patient tolerance 4

5 GABA Neurotransmitter that is widely distributed throughout the CNS Exerts postsynaptic inhibition GABA(A) receptor complex has binding sites for GABA Also for benzodiazepines and phenobarbital Principal role is to reduce neuronal excitability Gabapentin: Mechanism of action As mentioned it is a structural analog of GABA There is no evidence that it blocks GABA uptake or its metabolism What it does do: Targets voltage gated calcium channels Those with the alpha-2,delta 1 subunit specifically These channels presumed to play a role in pain modulation as they decrease neuronal activity when inhibited Possibly alter microglia function Typical Inflammatory Response Non specific response to injury Mediated by both functional and molecular responses Recruitment and/or activation of inflammatory cells Macrophages, neutrophils, etc., Release of inflammatory mediators Cytokines (TNF-a) Interleukins (IL-1B, IL-6) Enzymes (COXs) Prostaglandins (PGE2) 5

6 Back to the case Initial plan Medications advised to stop: Diphenhydramine Melatonin Acetaminophen-caffeine headache medicine Zzz-quil (Diphenhydramine) Initial plan (cont.) Medication plan to begin following: Tylenol 1,00 mg PO TID Ibuprofen 800 mg PO TID w/meals Oxycodone mg PO q4h PRN Gabapentin 300 mg PO qhs x 3 nights, then increase to 600 mg PO qhs thereafter Hydroxyzine 50 mg PO qhs PRN, in the event above medications do not provide adequate relief to facilitate sleep 6

7 Support for starting Gabapentin in this patient Article: Gabapentin Attenuates Ocular Inflammation: In Vitro and In Vivo studies Studied the effect of LPS stimulated rabbit corneal cells and endotoxin-induced uveitis Measured levels of TNF-a, IL-1B, cpla2x, COX-2, and PGE2 in the cells with and without gabapentin treatment Gabapentin was found to significantly attenuate cytokine production, cpla2 activation, COX-2 expression and PGE2 levels Anfuso CD, Olivieri M, Fidilio A, et al. Gabapentin Attenuates Ocular Inflammation:andStudies. Front Pharmacol. 2017;8:173. Abdel-Salam and Sleem et al found that: Systemic administration of gabapentin resulted in the antinociceptive effects in different acute pain models Increased nociceptive threshold of thermal or electrical stimuli Reduced the inflammatory edematogenic response with lower doses (25 and 50mg/kg) more effectively than higher doses (100mg/kg) Abdel-salam OM, Sleem AA. Study of the analgesic, anti-inflammatory, and gastric effects of gabapentin. Drug Discov Ther. 2009;3(1): Dias, et al found that gabapentin was able to reduce the following in mice experimental models: Anti-inflammatory mediator activity Neutrophil migration Pro-inflammatory cytokines levels Concentrations of MDA and GSH Overall felt that gabapentin could likely be used to improve tissue resistance to damage during inflammatory conditions Dias JM, De brito TV, De aguiar magalhães D, et al. Gabapentin, a synthetic analogue of gamma aminobutyric acid, reverses systemic acute inflammation and oxidative stress in mice. Inflammation. 2014;37(5):

8 Starmer et al, showed that patients who received gabapentin for pain management during chemoradiotherapy (CRT) for head and neck cancers were able to: Use fewer opioids overall Less PEG dependence Have excellent long-term swallowing outcomes Improve patient perceived quality of life Starmer HM, Yang W, Gourin CG, et al. One-Year Swallowing Outcomes in Patients Treated with Prophylactic Gabapentin During Radiation-Based Treatment for Oropharyngeal Cancer. Dysphagia. 2017;32(3): Zhai et. al, conducted a systematic review and meta-analysis of RCT s and non-rct s to evaluate efficacy and safety of gabapentin vs placebo for pain control after surgery Found that gabapentin: Has an effective analgesic effect Has an opioid sparing effects in acute post-op pain management No increased SE (ex. Dizziness or pruritus) Zhai L, Song Z, Liu K. The Effect of Gabapentin on Acute Postoperative Pain in Patients Undergoing Total Knee Arthroplasty: A Meta-Analysis. Medicine (Baltimore). 2016;95(20):e3673. Conclusion Very similar and encouraging results across various studies showing gabapentin may very well play a bigger role as antiinflammatory agent than currently given credit for Can and should be considered as an adjunct medication for pain control both due to acute injury and planned surgery, for it s possible anti-inflammatory properties and opioid sparing effects 8

9 Patient Follow up At 2 week follow up, reported significant relief in terms of eye pain, headaches, and inability to sleep due to these factors Current gabapentin use is 600 mg BID (total 1,200 mg daily) Under recommended 1,800 mg/day In line with research showing lower doses more effective as an anti-inflammatory (??) Continues with chemotherapy for now metastatic malignant choroidal melanoma, doing well clinically overall Thank You Questions? 9

10 References Abdel-salam OM, Sleem AA. Study of the analgesic, anti-inflammatory, and gastric effects of gabapentin. Drug Discov Ther. 2009;3(1): Anfuso CD, Olivieri M, Fidilio A, et al. Gabapentin Attenuates Ocular Inflammation:andStudies. Front Pharmacol. 2017;8:173. Dias JM, De brito TV, De aguiar magalhães D, et al. Gabapentin, a synthetic analogue of gamma aminobutyric acid, reverses systemic acute inflammation and oxidative stress in mice. Inflammation. 2014;37(5): Starmer HM, Yang W, Gourin CG, et al. One-Year Swallowing Outcomes in Patients Treated with Prophylactic Gabapentin During Radiation-Based Treatment for Oropharyngeal Cancer. Dysphagia. 2017;32(3): Yang JL, Xu B, Li SS, et al. Gabapentin reduces CX3CL1 signaling and blocks spinal microglial activation in monoarthritic rats. Mol Brain. 2012;5:18. Kane CM, Mulvey MR, Wright S, Craigs C, Wright JM, Bennett MI. Opioids combined with antidepressants or antiepileptic drugs for cancer pain: Systematic review and meta-analysis. Palliat Med. 2018;32(1): Ashburn MA, Fleisher LA. The Role of Gabapentin in Multimodal Postoperative Pain Management. JAMA Surg. 2017; Lee BS, Jun IG, Kim SH, Park JY. Intrathecal gabapentin increases interleukin-10 expression and inhibits pro-inflammatory cytokine in a rat model of neuropathic pain. J Korean Med Sci. 2013;28(2): Starmer HM, Yang W, Raval R, et al. Effect of gabapentin on swallowing during and after chemoradiation for oropharyngeal squamous cell cancer. Dysphagia. 2014;29(3): Zhai L, Song Z, Liu K. The Effect of Gabapentin on Acute Postoperative Pain in Patients Undergoing Total Knee Arthroplasty: A Meta-Analysis. Medicine (Baltimore). 2016;95(20):e