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InFocus: Medications Surprisingly Linked with Opioids

Roberts, James, R., MD

doi: 10.1097/01.EEM.0000533731.00189.87
InFocus

Dr. Roberts is a professor of emergency medicine and toxicology at the Drexel University College of Medicine in Philadelphia. Read the Procedural Pause, a blog by Dr. Roberts and his daughter, Martha Roberts, ACNP, PNP, at http://bit.ly/EMN-ProceduralPause, and read his past columns at http://bit.ly/EMN-InFocus.

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Figure

Opioid addiction used to be so straightforward—it was either street heroin or a variety of opioids prescribed by clinicians. Opioid addiction now has a much wider spectrum, far greater than various additives and impurities in street drugs and even new prescription opioids.

I discussed last month the potential abuse of loperamide (Imodium and generics), an opioid receptor mu agonist that has been used to quell opioid withdrawal or as an opioid substitute. (“Reports of Loperamide ODs Reveal a New Cardiotoxic Opioid,” EMN 2018;40[4]:8; http://bit.ly/EMN-InFocus.) Massively large doses of loperamide are used—up to 200 tablets a day. The drug is usually benign, but it has been associated with cardiac toxicity. Many physicians are unaware of the use of loperamide as an opioid substitute. It does not show up on any drug screen, and its use can go unsuspected.

Two other prescription medications are associated with opioid addiction, pregabalin (Lyrica) and gabapentin (Neurontin and others). Both have been used for many clinical indications, but many physicians do not associate them with abuse and would not be called upon to write a pregabalin or gabapentin prescription. A red flag should be raised, however, if a patient asks for these medications.

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Abuse of Gabapentin Is Associated with Opioid Addiction

Bastiaens L, et al.

Psychiatr Q

2016;87(4):763

The authors of this study evaluated the extent of gabapentin misuse in a jail population, and attempted to determine if gabapentin use is specific for those with an opioid abuse disorder. Patients in a community correctional center were diagnosed with a psychiatric disease and an opioid use disorder. All 250 individuals, mostly Caucasian men, had a chronic substance abuse disorder involving numerous opioids, often in combination with other drugs or alcohol. The most common psychiatric disorders were depression and attention deficit hyperactivity disorder.

Table

Table

Sixty-two percent of respondents admitted by questionnaire to some type of additional prescription drug misuse. Opioid abuse was reported in 55 percent. Twenty-six percent of the 145 patients with an opioid use disorder endorsed gabapentin use, compared with only four percent of those without opioid use. This statistical difference confirmed a growing concern about gabapentin misuse in opioid-addicted patients who obtain it illegally, overuse it, and malinger to obtain it from clinicians, many while they are incarcerated. The authors believe that gabapentin abuse is common in the opioid-addicted population.

Comment: Two gabapentinoids, pregabalin and gabapentin, are being increasingly prescribed for a wide range of clinical conditions. Pregabalin, FDA-approved for fibromyalgia, is widely advertised and touted by media ads. It is considered to have low addictive potential in general, but significant misuse of this medication and of the related gabapentin in opioid-addicted individuals has recently been reported. (Addiction 2016;111[7]:1160.) Originally developed and FDA-approved for use as an anticonvulsant and for post-herpetic neuralgia, the gabapentinoids are widely prescribed off-label for multiple conditions. (See table.) Curiously, these drugs do not appear on published lists of abused drugs, and neither would they be detected in a routine urine drug screen for drugs of abuse.

The exact mechanism of action is unclear, but gabapentinoids in the central nervous system combine with calcium channels and are GABA analogues. This accounts for anticonvulsant, anxiolytic, and sleep-modulating activities. Pregabalin and gabapentin have similar action, but pregabalin has much higher potency, higher bioavailability, and likely a higher addiction potential. No specific antidote exists for gabapentinoid toxicity.

Gabapentinoids produce euphoria reminiscent of opioids, as well as sedation, relaxation, and calmness. Users report a pleasurable high similar to cocaine, amphetamines, MDMA, and marijuana.

Most gabapentinoids are obtained from clinicians, but they are available on the street. Gabapentinoid abuse seems to be somewhat of a well-kept secret of drug abusers, especially opioid addicts. One wonders if most prescribers are aware of the abuse potential of these medications. Abuse of gabapentinoids is apparently worldwide, not just in the United States, and some countries apparently have black markets for gabapentinoids.

A number of studies have indicated that patients often administer higher-than-recommended doses of prescribed gabapentinoids to achieve a euphoric high. (Am J Psychiatry 2015;172[5]:487.) The prevalence of abuse is rather high—up to 68 percent of opioid abusers use them, and psychiatric comorbidities appear to increase their abuse.

The use of gabapentinoids to potentiate the high obtained from methadone has recently been reported. (Eur Addict Res 2014;20[3]:115.) One study found that 22 percent of methadone users admitted abusing gabapentinoids to enhance euphoria.

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An Acute Gabapentin Fatality: A Case Report with Postmortem Concentrations

Cantrell FL, et al.

Int J Legal Med

2015;129(4):771

These authors report a rare gabapentin fatality and results of a postmortem analysis. Death from gabapentin has been reported occasionally, but this is one of a few cases of gabapentin as the sole agent, with much lower peripheral blood levels than previously reported. Gabapentin has few adverse effects in therapeutic doses. Common side effects include dizziness, fatigue, drowsiness, weight gain, and peripheral edema. Even with intentional abuse, serious side effects are rare.

A 47-year-old woman was found dead at work with a bottle of 600 mg tablets of gabapentin; 26 tablets were missing. The patient was addicted to prescription pain medications secondary to a motor vehicle crash, and was also prescribed hydrocodone with acetaminophen. She reported wheezing, coughing, and shortness of breath prior to her death.

An extensive postmortem toxicology analysis was performed. Pulmonary congestion was the only contributory pathology found in the autopsy. The only substance found on postmortem blood analysis was gabapentin in a concentration of 37 mg/L. No acetaminophen or hydrocodone was identified. The gabapentin level found in this analysis was lower than those previously reported as lethal. The cause of death was attributed to gabapentin toxicity.

Comment: Gabapentinoids are generally considered safe, and death from these drugs alone has been rarely reported. Postmortem blood levels are difficult to interpret, and the actual level is not always associated with a specific outcome. This case, however, is consistent with death solely from gabapentin, likely from respiratory arrest.

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Populations at Risk

Prescription drug abuse in correctional institutions is an interesting and rather common scenario. Prisoners are a unique group that is frequently baseline opioid-addicted, and they often abuse seemingly benign prescription medications while incarcerated. Most clinicians are not familiar with the drug information apparently known to many inmates, and uninitiated clinicians can easily be duped into prescribing medications that don't seem to be ripe for abuse. It has been known for some time that cocaine users in prison often requested gabapentin for a number of abnormalities, and would even pulverize and snort it to get high.

It's difficult to get opioids prescribed in prison, but psychiatric medications are apparently more readily available. Inmates often learn to ask for specific drugs, and unworried clinicians, thinking that the requests are benign or only psychiatric medications, frequently prescribe a variety of sought-after medications. Quetiapine (Seroquel), for example, was commonly prescribed to inmates at their request, but this drug has been highlighted as a potentially abusive medication. It has been taken off the formulary in many prisons.

Table

Table

Many inmates have serious psychiatric disorders, probably more than in mental hospitals throughout the country. It is difficult for correctional facilities to meet the growing mental health needs of inmates. The sheer number of inmates requiring extensive and complicated psychiatric care often overwhelm medical facilities and psychiatrists. Prisoners are also well known to malinger to get medications. An amazing 75 percent of prisoners have substance abuse disorders, alcohol use disorders, or both, and up to 50 percent have personality disorders. In fact, only about one in four prisoners has neither a substance abuse nor a psychiatric disorder, a rather shocking statistic. There is little information in the literature about how to treat such patients.

Prisoners in a Florida correctional facility often requested gabapentin and snorted it for its euphoria and altered mental status. A California correctional facility removed five medications from the jail formulary because of abuse potential: quetiapine, gabapentin, bupropion, trihexyphenidyl (Artane), and tricyclic antidepressants.

Emergency physicians would rarely initiate the use of gabapentinoids, but a request for a refill of a prior prescription should raise concern. Until recently pregabalin and gabapentin were just a few of the medications that the practicing emergency clinician would not view as highly abusable.

A gabapentin withdrawal symptom has been described, but it is generally not life-threatening or associated with serious side effects. Similar to alcohol and benzodiazepine withdrawal, gabapentinoid withdrawal may go undiagnosed in the ED.

Reader Feedback: Readers are invited to ask specific questions and offer personal experiences, comments, or observations on InFocus topics. Literature references are appreciated. Pertinent responses will be published in a future issue. Please send comments to emn@lww.com.

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Learning Objectives for This Month's CME Activity: After participating in this CME activity, readers should be better able to diagnose gabapentinoid abuse in patients, especially those with a history of opioid use.

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The History of Gabapentin

Read an editorial by Mark Mosley, MD, about why you shouldn't use gabapentin. Page 6.

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