Thursday, February 11, 2016

Gabapentin Misuse: A Growing Challenge

With the opioid abuse epidemic that we clinicians in the emergency department encounter as part of our daily practice, the movement towards the use of alternative agents continues to evolve for the management of pain in our patients. In taking advantage of traditional and novel mechanisms of action of these agents, acute pain in patients in the emergency department may be managed appropriately without posing the risk of introducing opioid-naive patients to opioids or worse, exacerbating pain that is inadequately treated with opioids in the first place.

For patients who may present with neuropathic pain, one agent that has been advocated in recent years is gabapentin (GBP), which is considered to be an off-label use of this agent. In fact, it is said that this agent possesses far more off-label indications than those approved by the FDA, the former which include diabetic neuropathy, trigeminal neuralgia, and maintenance of abstinence secondary to drug and alcohol withdrawal (1). Anecdotally speaking, a modest proportion of patients who present to the emergency department at my institution are on GBP as chronic outpatient therapy for these and other conditions.
In terms of its activity, although it is structurally similar to gamma aminobutyric acid, GBP does not exert its action associated with the management of neuropathic pain within this system. It functions by binding to the alpha-2/delta subunit at voltage-gated sensitive calcium channels that leads to modulation of the influx of calcium, which ultimately reduces the extent of pain associated with neuropathy by minimizing the release of excitatory neurotransmitters responsible for this sensation such as glutamate, norepinephrine, and substance P (2-4).

The latest Cochrane review related to the utility of GBP for the management of neuropathic pain and fibromyalgia has suggested that it may indeed be beneficial in some patients for these conditions, but as is the case with these somewhat challenging conditions, it may be difficult to predict who may actually benefit from treatment, with the risk of adverse events leading to some patients being unable to tolerate treatment with GBP altogether (5).

However, recent literature has suggested while GBP is widely prescribed for a multitude of conditions in patients across the globe, there is a concern for misuse (and abuse) of GBP that is seemingly on the rise, and should not go unrecognized.

Et tu, gabapentin?

In one review, of those cohort of patients with established recognition of opioid abuse, the misuse of GBP within this population is estimated to occur at a rate of upwards of 22%, and among this subgroup, between 40 and 65% of patients had a prescription for GBP for predominantly off-label use (6). Substantial misuse of GBP has been noted to occur within England, Scotland, and Finland (7-10), but observations of misuse are being increasingly reported to take place in the United States. In fact, a recently published prospective analysis of 503 subjects in Kentucky who reported diversion and non-medical use prescription opioids highlights that 15% of patients utilized GBP to achieve a state of being "high" in 2014, which represents a nearly 3000% increase in this trend compared to 2008 (11).

In most cases, higher than prescribed doses are often utilized for this purpose, and the descriptions of patient experiences related to the "high" experienced with GBP are eerily not dissimilar to those related to opioids and benzodiazepines (6, 12). Furthermore, GBP has been reported to be used as a means to potentiate the "high" associated with misuse of other agents, including buprenorphine and methadone (8, 13).

The incidence of withdrawal is also not uncommon with GBP, with signs and symptoms occurring as early as 24 hours and as late as 7 days following abrupt cessation of therapy. Signs and symptoms consistent with GBP withdrawal include agitation, confusion, disorientation, diaphoresis, hypertension, and insomnia (12). In addition, there is one documented case in the literature thus far of neonatal withdrawal secondary to gabapentin (14).

Interestingly enough, as discussed in a previous blog post written by Craig, the "evil stepsister" of GBP, pregabalin, which shares some structural similarities to its sister compound, is categorized as a schedule V substance in the United States. This certainly begs the question as to whether the same should apply to GBP itself.

Part of the challenge related to this issue is that GBP has traditionally held a long reputation of being a relatively inexpensive medication that is widely available, safe, and effective and not capable of misuse or diversion. However, this claim to fame of minimal to no abuse potential associated with GBP has never been formally evaluated nor established in a controlled clinical environment since its approval by the FDA in 1993. Time will tell whether this will occur in the future, given the growing challenges and issues that GBP has posed to countries across in the EU and the increased recognition of these same issues here in the United States.

References:
  1. Mack A. Examination of the evidence for off-label use of gabapentin. J Manag Care Pharm 2003; 9(6):559-68.
  2. Stahl SM. Anticonvulsants as anxiolytics, part 2: Pregabalin and gabapentin as alpha(2)delta ligands at voltage-gated calcium channels. J Clin Psychiatry 2004; 65(4):460-1.
  3. Bockbrader HN, Wesche D, Miller R, et al. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet 2010; 49(10):661-9.
  4. Kukkar A, Bali A, Singh N, et al. Implications and mechanism of action of gabapentin in neuropathic pain. Arch Pharm Res 2013; 36(3):237-51.
  5. Moore RA, Wiffen PJ, Derry S, et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2014; 4:CD007938.
  6. Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse, and diversion: A systematic review. Addiction 2016 [Epub ahead of print].
  7. Kapil V, Green JL, Le Lait MC, et al. Misuse of the γ-aminobutyric acid analogues baclofen, gabapentin and pregabalin in the UK. Br J Clin Pharmacol 2014;78(1):190-1.
  8. Baird CR, Fox P, Colvin LA. Gabapentinoid abuse in order to potentiate the effect of methadone: A survey among substance misusers. Eur Addict Res 2014; 20(3):115-8.
  9. Smith BH, Higgins C, Baldacchino A, et al. Substance misuse of gabapentin. Br J Gen Pract  2012; 62(601):406-7.
  10. Häkkinen M, Vuori E, Kalso E, et al. Profiles of pregabalin and gabapentin abuse by postmortem toxicology. Forensic Sci Int. 2014; 241:1-6.
  11. Smith RV, Lofwall MR, Havens JR. Abuse and diversion of gabapentin among nonmedical prescription opioid users in Appalachian Kentucky. Am J Psychiatry 2015; 172(5):487-8.
  12. Mersfelder TL, Nichols WH. Gabapentin: Abuse, dependence, and withdrawal. Ann Pharmacother 2015 [Epub ahead of print].
  13. Reeves RR, Ladner ME. Potentiation of the effect of buprenorphine/naloxone with gabapentin or quetiapine. Am J Psychiatry 2014; 171(6):691.
  14. Carrasco M, Rai SC, Bearer CF, et al. Neonatal gabapentin withdrawal syndrome. Pediatr Neurol 2015; 53(5):445-47.