Appropriate Gabapentin Dosing for Neuropathic Pain

DECEMBER 19, 2017
Neuropathic pain is a chronic debilitating pain syndrome that is complex to treat. Current medication management for neuropathic pain includes select neuromodulating agents such as anticonvulsants, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, and certain opioids.1,2 Gabapentin remains among the most commonly used anticonvulsants for neuropathic pain. 

The established therapeutic dosing for gabapentin in neuropathic pain trials is 1800-3600 mg/day in 3 divided doses in patients with normal renal function.3 This means the minimum effective dose is 600 mg 3 times a day. Renal adjustments are recommended in patients with CrCl below 60 mL/min. For patients on dialysis, gabapentin can often be 3 times weekly following dialysis.4,5

Several cross-sectional studies have reported gabapentin being used in subtherapeutic doses among most patients.6-8 In a retrospective analysis of 939 patients with post-herpetic neuralgia, the mean daily dose of gabapentin was 826 mg.7 In another 2-year retrospective study of 151 veterans with various neuropathic pain syndromes, the median daily dose for gabapentin was 900 mg.8 In both studies, the most prevalent gabapentin dosing was half the therapeutic dosing.

The cornerstones of effective pharmacotherapy are the right patient, the right drug, and the right dose. If an analgesic medication is being used at a suboptimal dose, oftentimes a knee-jerk reaction is to add another analgesic for synergy. While this may well be indicated under appropriate circumstances, it is inappropriate without maximizing the dose of each single agent with careful attention to dose titration in order to minimize toxicity of each add-on. Consider for example a patient who starts low dose gabapentin that was not properly titrated, returns for follow-up and is given an additional prescription for duloxetine for neuropathic pain since gabapentin “does not work,” assuming there are no tolerability issues. This adds to polypharmacy, increased costs, and the pain remains inadequately treated.
Pharmacists as medication experts can collaborate with prescribers to optimize the rational use of gabapentin in neuropathic pain. First, let’s take a look into the pharmacology of gabapentin.

Gabapentin is a gaba aminobutyric acid (GABA) analogue anticonvulsant but does not exhibit any significant agonistic effects at the GABA receptor.9 Gabapentin inhibits the alpha-2-delta subunit of the N-type voltage-gated calcium channels. Receptor binding causes presynaptic inhibition of excitatory neurotransmitter release (i.e. glutamate) thereby attenuating neuropathic pain.

Gabapentin’s counterpart, pregabalin, shares the same mechanism of action but there are key pharmacologic differences between both medications. Gabapentin has saturable, non-linear absorption kinetics, where bioavailability decreases as the dose increases.10 Following oral administration, gabapentin’s bioavailability is 60%, 47%, 34%, and 33%, following 900, 1200, 2400, and 3600 mg/day in 3 divided doses, respectively. On the other hand, pregabalin has ≥90% bioavailability irrespective of the dose, leading to more predictable kinetics. Pregabalin boasts a binding affinity for the alpha-2-delta receptor that is six times greater than that of gabapentin. 

What Every Patient Should Know
Patients should be aware of the therapeutic dosing for neuropathic pain to establish realistic expectations and improve compliance and likelihood of remaining on therapy. The conversation may be as follows: “Gabapentin may reduce nerve pain at 600 mg 3 times a day but patients usually start on a low dose to make sure they tolerate it and is then increased slowly to give the body a chance to get used to it.  If dose increases along the titration cause intolerable side effects such as dizziness or drowsiness, this can often be overcome by reducing back to the previous dose and escalating more slowly over a longer period of time.” Patients should be encouraged to follow-up with their prescriber for continued titration.

Gabapentin Is Not a “PRN” Medication
Another mishap with gabapentin that contributes to treatment failure is when patients take it on an as needed basis. Gabapentin exhibits its activity by impeding calcium trafficking and is required to be present at the alpha-2-delta receptor for 17-20 hours in order to ensure efficacy.11 Therefore, gabapentin needs to be taken around the clock to exert its analgesic effects rather than used on an as needed basis. This is another area that pharmacists can educate patients at initiation of therapy to improve compliance. 

Gabapentin Abuse
Despite its therapeutic role in neuropathic pain, gabapentin produces psychoactive effects and has an abuse liability.  Gabapentin abuse typically involves taking higher doses in a single administration. The median single dose for gabapentin abuse is 3600 mg, which is 3 times the maximum recommended single dose of 1200 mg.12 Risk factors for gabapentin abuse include current or previous opioid abuse, previous cocaine use, and/or concurrent use of benzodiazepines or cannabis. Alcohol use disorder is not generally a predictor of gabapentin abuse.12 

In conclusion, pharmacists as medication experts are well-poised to educate prescribers and patients on therapeutic dosing of gabapentin to optimize its rational and appropriate use for treating neuropathic pain.

This commentary was collaboratively written with Shannon Donovan and Dr. Mena Raouf.

Shannon Donovan is a 2018 PharmD candidate at Albany College of Pharmacy and Health Sciences in Alabany NY and is a pharmacy intern at CVS.

Mena Raouf is a PGY-2 pain and palliative care resident at the Stratton VA Medical Center in Albany, NY. He completed his PGY-1 residency at the VA Tennessee Valley Healthcare System in Nashville TN and received his PharmD from the Albany College of Pharmacy and Health Sciences.


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


References:
1.       O’Connor AB, Dworkin RH. Treatment of neuropathic pain: an overview of recent guidelines. Am J Med 2009;122(Suppl):S22–32.
2.       Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162-73.
3.       Backonja M, Glanzman RL. Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clin Ther. 2003 Jan;25(1):81-104.
4.      Neurontin® (gabapentin) [package insert] New York, NY: Parke Davis; 2015.
5.      Raouf M, Atkinson TJ, Crumb MW, Fudin J. Rational dosing of gabapentin and pregabalin in chronic kidney disease. J Pain Rese. 2017;10:275-278.
6.       Oneschuk D, al-Shahri MZ.The pattern of gabapentin use in a tertiary palliative care unit. J Palliat Care. 2003 Fall;19(3):185-7.
7.       Johnson P, Becker L, Halpern R et al. Real-world treatment of post-herpetic neuralgia with gabapentin or pregabalin. Clin Drug Investig. 2013 Jan;33(1):35-44.
8.       Raouf M, Crumb MW, Baker JW, Bramell J, Atkinson TJ. A two-year retrospective study of neuropathic pain management with gabapentin or pregabalin–Are we optimizing use in clinical practice? P-69 at PAINWeek, Las Vegas, NV. September 8, 2017.
9.       Patel R, Dickenson AH. Mechanisms of the gabapentinoids and alpha 2 delta-1 calcium channel subunit in neuropathic pain. Pharmacol Res Perspect. 2016;4(2):e00205. doi: 10.1002/prp2.205.
10.    Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinetics. 2010;49(10):661-9.
11.   Heblich F, Tran Van Minh A, Hendrich J et al. Time course and specificity of the pharmacological disruption of the trafficking of voltage-gated calcium channels by gabapentin. Channels (Austin). 2008 Jan-Feb;2(1):4-9.
12.   Evoy KE, Morrison MD, Saklad SR. Abuse and Misuse of Pregabalin and Gabapentin. Drugs. 2017 Mar;77(4):403-426
 



Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP
Dr. Jeff Fudin graduated from Albany College of Pharmacy & Health Sciences with a BS and PharmD. He is a Diplomate to the Academy of Integrative Pain Management, a Fellow to ACCP and ASHP, and a member of several other professional organizations. He is President and Director, Scientific and Clinical Affairs for Remitigate, LLC (remitigate.com), a software platform for interpreting urine drug screens (Urintel) and risk for opioid-induced respiratory depression (Naloxotel). Dr. Fudin is a section editor for Pain Medicine and serves on the editorial board for Practical Pain Management. He practices as a clinical pharmacy specialist (WOC) and director of PGY-2 pharmacy pain residency programs at the Stratton Veterans Administration Medical Center in Albany, New York and has academic affiliations with Western New England University and Albany Colleges of Pharmacy.
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