Are you prescribing these commonly misused drugs?

A fine line exists between therapeutic and supratherapeutic medication dosages, and crossing the Rubicon—intentionally or not—can be lethal. For instance, many older patients engaged in polypharmacy end up ingesting too many psychiatric medications, leading to delirium—a form of acute brain failure that increases risk of death and predicts poorer long-term cognition and function. Physicians should be aware of overprescribing these and other medications.

The following is a list of drugs that are commonly taken in excess:

Psychotropic medications

A study published in the Journal of the American Geriatrics Society highlights the dangers of psychotropic medications at high doses. Researchers crunched data from a prospective cohort of patients aged 65 years and older who visited the emergency department (ED) of an academic medical center. Using a liquid chromatography-mass spectrometry-based platform, they assessed levels of opioids, benzodiazepines, antidepressants, antipsychotics, and amphetamines.

The team found that 66 of 158 patients were delirious in the ED, with supratherapeutic psychotropic drug levels found in the blood of 17% of delirious patients and 4% of nondelirious patients. Supratherapeutic levels of psychotropic drugs were related to a longer duration of delirium. Disconcertingly, of the 15 medications measured in supratherapeutic doses, 60% were prescribed at the same or higher doses at the time of discharge.

The authors concluded that the platform used to test for supratherapeutic psychotropic drug levels “may provide useful, timely clinical information to the inpatient team regarding circulating medications that require dose adjustments prior to hospital discharge.”

They added, “Future studies should include a randomized controlled trial with a larger sample size and an evaluation of long-term outcomes of supratherapeutic drug levels based on deprescribing.” 

Gabapentinoids

Pregabalin and gabapentin misuse are emerging as causes for consternation among clinicians, as demonstrated by the results of a systematic review published in Drugs.  

After perusing 59 studies, investigators found increasing numbers of patients are self-administering gabapentinoid doses that are higher than recommended. In the general population, 1.6% of individuals misused the drug, with prevalence of misuse among opioid misusers ranging between 3% and 68%. Risk factors for misuse include psychiatric illness and a history of opioid or other substance misuse.

“While effects of excessively high doses are generally non-lethal, gabapentinoids are increasingly being identified in post-mortem toxicology analyses,” the authors wrote. “Prescribers should be aware of high-risk populations and monitor for signs of abuse.”

In more disturbing news, gabapentin has made its way to the streets, with reports of it being used to “cut” heroin, according to an article published in the British Journal of General Practice. In fact, misusers of the drug with no history of neuropathic pain now request “gabbies” from street dealers.

“Unfortunately, our clinical experience suggests that gabapentin is now prevalent as a drug of abuse,” the authors wrote. “The drug’s effects vary with the user, dosage, past experience, psychiatric history, and expectations. Individuals describe varying experiences with gabapentin abuse, including: euphoria, improved sociability, a marijuana-like ‘high’, relaxation, and sense of calm, although not all reports are positive (for example, ‘zombie-like’ effects).”

Acetaminophen

Throughout the world, people self-administer acetaminophen (also known as paracetamol) to relieve pain and fever. But, this drug can be very dangerous, even after moderate consumption, according to the results of a systematic review published in the British Journal of Clinical Pharmacology.

The researchers mined databases for 199 cases of  repeated supratherapeutic paracetamol ingestion (RSPI). They found severe liver damage evidenced by liver enzymes in 93% of cases, with 99% of cases involving children aged 6 years or less exhibiting severe liver damage. Liver failure occurred in 64% of cases, and of those patients with liver failure, 39% died. In 36% of cases, US thresholds for maximum ingested daily paracetamol doses were not met, with 49% of these patients developing liver failure and 14% dying. Importantly, no cases of liver damage occurred in patients with paracetamol concentrations concentration < 20 mg l−1 and a normal ALT/AST on initial presentation or when RSPI was first suspected.  These metrics, however, were available only for 40% of cases.

“[T]here are many reported cases of supratherapeutic paracetamol ingestion associated with severe hepatotoxicity or death, especially in younger children,” wrote the authors. 

“Thresholds based on weight‐adjusted daily paracetamol doses may be of limited value in risk stratification as cases with severe liver outcomes are reported after doses apparently below currently recommended thresholds. A low or undetectable paracetamol concentration associated with normal transaminases activity on initial assessment of RSPI appears to indicate a low probability of subsequent severe liver damage, but numbers of cases studied are limited and further data should be collected to quantify this risk more accurately,” they concluded.

Loperamide

Due to its over-the-counter status to treat diarrhea, it’s tempting to assume that loperamide is safe, and it is—when used in doses approved by the FDA. Bad actors, however, have picked up on its opioid properties and spread this information on recreational drug forums online. As such, poison control centers have recently noted a doubling of cases of overdose ever since 2014, according to the authors of a dyad of case reports published in the Journal of Community Hospital Internal Medicine Perspectives.

Loperamide exerts peripheral mu receptor agonism in the gastrointestinal tract, which is why it is used to assuage gastrointestinal disturbance, but these same opioid properties can lead to euphoria when the drug is misused. At one time, loperamide was a Schedule V drug and called “poor man’s methadone,” with certain people using the drug to help with opioid withdrawal. But, in the absence of tolerance development at supratherapeutic doses, the FDA pulled its Schedule V status.

Importantly, in supratherapeutic doses, the drug can cause cardiotoxicity and dysrhythmias, which were evident on post-marketing analysis. Consequently, the FDA in 2016 slapped a warning on the drug. 

“Given the opioid epidemic in the USA, the increasing recognition of the abuse potential and the easy availability of loperamide, an extensive history of over-the-counter medications is a must at the time of admission in order to suspect and diagnose loperamide cardiotoxicity,” the authors wrote. “Early consultation with a poison control center is a necessary adjunct to providing the safest, most effective care.”

ADHD medications

Amphetamines are a popular prescription for treating attention-deficit hyperactivity disorder (ADHD). But in supratherapeutic amounts, these drugs can lead to choreiform movements in children and adults. In one case report of a 10-year-old who accidentally received an extra dose of lisdexamfetamine dimesylate (Vyvanse), the boy experienced acute chorea of the arms, legs, and trunk, which resolved in 48 hours after treatment with haloperidol.

Another harrowing case cited by the authors involved an 8-month-old baby exposed to his stepbrother’s mixed amphetamine salts (Adderall XR), subsequently manifesting acute chorea. Fortunately, the baby recovered, but only after a 72-hour stay in the pediatric ICU.

“Benzodiazepines, diphenhydramine, benztropine, and opioids did not suppress the chorea in either case,” the researchers wrote in Pediatric Neurology. “Our cases demonstrate that choreiform movements of sustained duration can occur in children with acute supratherapeutic ingestions of amphetamine-derived medications.”

Bottom line

Even with the most common prescriptions and over-the-counter formulations, there can be too much of a good thing. Clinicians should continually ask about medication history and dosages, as well as keep tabs on prescription patterns with scrutiny paid to possible polypharmacy and supratherapeutic intake. Finally, on discharge from the hospital, it’s a good idea to check for supratherapeutic doses of current medications—especially psychotropics—and consult with other prescribing physicians and the clinical pharmacist when prudent.