In a session on “old drugs reinvented” at the 2019 annual meeting of the American College of Clinical Pharmacy (ACCP), experts explored the histories of these two medications—gabapentin and ketamine—and detailed what clinicians should know about their benefits and potential for abuse.

‘But It’s Nonaddictive’

Gabapentin has long been touted as a safe and nonaddictive drug. Its only official FDA approvals are for certain types of seizures and postherpetic neuralgia, but it’s frequently prescribed to treat everything from headaches and other conditions such as restless legs syndrome and anxiety.

“Our review of 19 common off-label uses for gabapentin found that there is little to no evidence to support its efficacy in many of those conditions, yet we continue to see its frequent off-label prescription,” said Kirk Evoy, PharmD, a clinical assistant professor in the Pharmacotherapy Division of the College of Pharmacy at the University of Texas at Austin (Subst Abuse 2018;12:1178221818801311). Another review found that gabapentin prescribing increased by 64% between 2012 and 2016, as prescribers sought nonopioid alternative approaches to chronic pain management (N Engl J Med 2017;377[5]:411-414).

“Practitioners tend to think of it as a benign drug with few side effects—possibly as a safer alternative to opioid therapy—so they can justify a trial of it to improve symptoms,” Dr. Evoy said. “But we have started to see increasing evidence of abuse and harm [which] gets little publicity compared to the larger opioid crisis.”

Between 2012 and 2016, 576 adverse drug events—106 fatal—related to gabapentin abuse were reported to the FDA Adverse Event Reporting System, according to an analysis by Dr. Evoy and his colleagues (Res Social Adm Pharm 2019;15[8]:953-958).


Patients with existing opioid use disorders are most likely to abuse gabapentin, Dr. Evoy noted. “In an analysis of insurance claims data, we found that criteria for sustained overuse were met by 2% of 44,148 patients treated with gabapentin without opioids and by 11.7% of 15,335 patients treated with concomitant gabapentin [and] opioids,” he said (Pharmacotherapy 2018;38[4]:436-443). Without opioids in the mix, he added, a patient history of other addiction did not predict overuse of gabapentin.

The study also showed that patients who were overusing opioids and gabapentinoids had more than a fourfold increased risk for hospitalization compared with the no-overuse cohort (Drug Saf 2018;41[2]:213-228). Another study found that patients taking both drugs had a 49% higher risk for a fatal overdose than those taking opioids alone, Dr. Evoy noted (PLoS Med 2017;14[10]:e1002396).

States have begun to recognize the growing risk for gabapentinoid abuse. As of October, five—Kentucky, Michigan, Tennessee, Virginia and West Virginia—had added it to their roster of controlled substances, with several other states considering a similar move at press time.

“There are pros and cons to scheduling,” Dr. Evoy said. “Gabapentin is the sixth most commonly prescribed drug in the country. We use it all the time for pain in patients with uncontrolled diabetes and neuropathy. It’s inexpensive and generally safe. So, is all the extra work with making it a schedule drug justified by the current level of concern? In the general population, abuse of gabapentin seems to be low but growing quickly, so I think more study of the benefits and drawbacks of scheduling is needed. But when these drugs are not on the controlled substance schedule, they need to be managed carefully, with mitigation efforts targeted at the highest risk patients.”

The FDA is taking the risks posed by gabapentinoids seriously. In late December, the agency announced that it would require new warnings about respiratory depression to be added to the prescribing information of gabapentinoids.

Kyle E. Hultgren, PharmD, the director of the Center for Medication Safety Advancement at Purdue College of Pharmacy, in West Lafayette, Ind., agreed that pharmacists need to heed the risks posed by gabapentin. “Pharmacists should be vigilant as they would with any substance that has an abuse potential. Keep an eye on dosing and refill patterns. Have they been increasing rapidly? Make sure there’s a balance in how the patients are taking it, and what they’re taking it with.”

A New Role for ‘Special K’

Although gabapentin may be a relatively recent drug of abuse to emerge, clinicians have long been aware of the abuse potential of ketamine, which has been a Schedule III federally controlled substance since 1999. Considered a dissociative anesthetic, ketamine experienced a surge of popularity as a club drug in the 1980s and 1990s. Its hallucinogenic effects include a sense of floating and dissociation, while larger doses sometimes produce what users call a “K-hole”—a sort of out-of-body, near-death experience. It has also been employed as a common date rape drug.

Until recently, the primary use of ketamine has been as an IV anesthetic for specific patients, such as in cases of shock or hypotension, in patients with reactive airway disease, in burn patients, and in prehospital and battlefield medicine (Anesth Essays Res 2014;8[3]:283-290). But in March 2019, the FDA approved a new nasal spray form of ketamine, esketamine (Spravato, Janssen), for treatment-resistant depression.

Some clinicians also have found significant benefit in treating depression and post-traumatic stress disorder using ketamine either via IV infusion or oral dosing, said Jessica Geiger, PharmD, a clinical pharmacist on the palliative care team at OhioHealth Riverside Methodist Hospital, in Columbus.

“A major problem with treating depression is the lag time in drug efficacy,” Dr. Geiger said. “Up to 60% of patients with depression may not respond to initial treatment, and it can be months before these patients see any benefit. But patients given ketamine have relief in hours to days, compared with weeks to months with most traditional antidepressants.”

Psychotomimetic adverse events are dose-dependent and more likely at higher doses (>1.5 mg/kg), she noted. They are less frequent with oral versus IV administration and can be mitigated by premedication with haloperidol or lorazepam. Other adverse effects include urinary frequency and dysuria, and respiratory depression at high/anesthetic doses. Relative contraindications include severe cardiovascular disease, uncontrolled hypertension, a recent cardiovascular event, thyroid conditions and elevated intraocular or intracranial pressure.

The biggest barrier to the use of ketamine for depression is financial, Dr. Geiger noted. “The nasal spray is a great option but cost-prohibitive at $590 to $885 per treatment, with a dosing schedule of twice weekly during the three-week induction phase and once weekly for weeks 5 to 8,” he said. After the eighth week, dosing can be weekly or stepped down to every other week. “IV infusion, in contrast, is inexpensive, at $10.00 per 500 mg of solution, and rapid acting with long duration—but it doesn’t have FDA approval. I’ve used ketamine very successfully in my practice for pain and depression, but among patients who are already in the hospital. In the ambulatory setting, we see more barriers.”

An advantage of ketamine for depression is its efficacy in patients in an acute crisis, Dr. Hultgren noted. “These are patients who may be at the highest risk of self-harm, and it is very helpful to be able to stabilize them in a matter of days as opposed to weeks or months.”