Abstract
To The Editor:
D
Case Report
A 22-year-old female was admitted to our hospital for evaluation of a possible intra-abdominal abscess following transplanted kidney removal at an outside institution. She had a history of three prior renal transplants, the first occurring at 3 years of age. Her latest transplanted kidney failed>1 year prior, and she was dependent on intermittent hemodialysis. Psychiatric consultation diagnosed her with a mood disorder secondary to her medical condition, and did not find an Axis II diagnosis. Global Assessment of Functioning was rated to be 50–55. Input from a pain medicine specialist was requested for acute or chronic abdominal pain management. The patient was requesting intravenous diphenhydramine 50 mg every 4 hours for pruritus provoked by multiple triggers, including narcotics, intravenous antibiotics, blood transfusion, and dialysis. Historically, she had been treated with intravenous diphenhydramine starting at 8 years of age, with initial doses of 25 mg intravenously. At her current outpatient hemodialysis appointments (three times weekly), she received one 50 mg intravenous dose prior to the start of dialysis, and a second 50 mg dose at the conclusion of each dialysis session.
While hospitalized, she requested that diphenhydramine be administered while she was awake to observe the administration, and demanded that rapid intravenous injection be followed by saline flush. She became visibly upset when she was not awoken for her scheduled diphenhydramine doses. After observing this behavior, the intravenous diphenhydramine was discontinued, and she was offered oral diphenhydramine to treat pruritus instead. She subsequently displayed further anger, stating “I demand to have my IV Benadryl.” When told that intravenous delivery was no longer indicated, she denied secondary or euphoric effects of diphenhydramine. Although she was offered oral diphenhydramine to treat pruritus, and prevent withdrawal, she continued to demand intravenous diphenhydramine. She threatened to refuse intravenous antibiotics and dialysis. The patient was not listed for renal transplant for multiple reasons, including the need for further testing such as stress echocardiogram, vascular computed tomography study, and Pap smear. The patient's demand for diphenhydramine was also listed as requiring treatment prior to transplantation.
After hospital discharge, the patient did not complete the required testing for transplantation at our institution, and did not return follow-up phone calls. Notification of her death was received, having occurred 10 months after her hospital discharge. The cause of death was not available.
The patient had consented to research via Minnesota Research Authorization, and institutional review board (IRB) approval was obtained.
Discussion
Diphenhydramine is a first generation antihistamine of the ethanolamine family. A competitive inhibitor of H1-receptors, diphenhydramine also has anticholinergic/antimuscarinic and antiserotonergic activity. Clinical pediatric uses include treatment of pruritus, allergies, nausea, vomiting, and extrapyramidal side effects. Diphenhydramine is also used to induce sedation, provide anxiolysis, and treat insomnia.
A dopaminergic-reward mechanism explaining diphenhydramine abuse has been theorized; however, animal studies have not found increased extracellular dopamine levels after diphenhydramine injection in rhesus monkeys (Banks et al. 2009). Rats will self-administer intravenously delivered diphenhydramine, however (O'Connor et al. 2011).
Overdose of diphenhydramine can lead to hallucinations, excitement, ataxia, lack of coordination, confusion, fixed dilated pupils with flushed face, sinus tachycardia, urinary retention, and dry mouth, and fever may also be present (similar to in atropine poisoning) (Brunton et al. 2011). Death from cardiorespiratory collapse can occur in 2–18 hours. The clinical antidote to diphenhydramine toxicity is sodium bicarbonate (high dose 200 mEq) and cardiorespiratory support (Jang et al. 2010).
The pharmacokinetics and dynamics of diphenhydramine differ in children and in adults. A study by Simons in 1990 studied the efficacy and average elimination of diphenhydramine in three age groups. Twenty-one fasting subjects were divided into three age groups: elderly (mean age 69.4), young adult (mean age 31.5), and children (mean age 8.9). The oral diphenhydramine syrup was given at a dose of 1.25 mg/kg; Serum diphenhydramine concentration was measured hourly for 6 hours, every 2 hours for 12 hours, and then at 24 hours and 72 hours. Efficacy was diagnosed by maximum weal suppression and maximum flare suppression, which were 5 and 6 hours for elderly, 6 and 4 hours for young adult, and 2 and 2 hours for children, respectively. Complete elimination was 13.5 hours in elderly, 9.2 hours in young adults, and 5.4 hours in children. Therefore, children have more rapid onset of efficacy and faster metabolism of diphenhydramine than do young adults and elderly populations (Simons et al. 1990; Brunton et al. 2011).
Diphenhydramine has been previously thought to have low abuse risk (Griffiths and Johnson 2005). A postmarketing survey based review of hypnotic medication in adults showed less risk with diphenhydramine than with benzodiazepines (Jaffe et al. 2004). A comprehensive study of medications used in anesthesia by Zacny and Galinkin concluded that histamine receptor blocking medication abuse liability is, “at best equivocal.” (Zacny and Galinkin 1999). Animal behavioral studies, however, raise questions about the abuse potential of antihistamines. Data, which include self-administration, drug discrimination, and conditioned place preference, show that antihistamines have potential for abuse (Halpert et al. 2002). Rhesus monkeys have shown reinforcing behavior with H1 antihistamines (Beardsley and Balster 1992). Reinforcing effects of diphenhydramine may be more likely with intravenous administration. Rats will self-administer intravenously delivered diphenhydramine, but will not self-administer diphenhydramine drink solution (O'Connor et al. 2011).
Injectable diphenhydramine is indicated only when oral administration is impractical, for example, in rare, but reported, drug allergy with oral formulation (Brunton et al. 2011). Official Pfizer recommendations in the packaging insert note that intravenous injection rates should not exceed 25 mg/min in either adults or children.
Because of the clinical observation of addiction behavior in adolescents, and the different metabolism of diphenhydramine in children and adults, children and adolescents may represent a vulnerable population for diphenhydramine misuse. Young adults have listed calming effects, mild euphoria, and ability to stop tremors (Gracious et al. 2010) as reinforcing effects of antihistamine misuse. Diphenhydramine dependence has been documented in mentally ill patients taking antipsychotic medications, in whom diphenhydramine was administered to treat the cholinergic and extrapyramidal side effects of antipsychotics (Gracious et al. 2010). Despite this, reports of abuse are rare: Only nine case reports of human diphenhydramine abuse exist in the literature between 1986 and 2013 (Jaffe et al. 2004; Thomas et al. 2009; Lin et al. 2010). In pilots who died during aviation accidents, the most common drug found on toxicology screen was diphenhydramine (Canfield et al. 2012). A review of 252 admissions to the Regional Poisoning Treatment Centre in Edinburgh during 1971 and 1972 showed that diphenhydramine with methaqualone (Mandrax) was the third most common drug abused; only barbiturates and lysergide (LSD) had higher abuse rates. Five chronically ill adolescents and children who exhibited drug-seeking behavior with diphenhydramine have been reported (Dinndorf et al. 1998).These young patients were also treated with other medications of high abuse liability (including narcotics and benzodiazepines), but they displayed drug-seeking behavior with diphenhydramine alone. Dinnedorf et al. recommended that the oral dose be given preferentially to intravenous dosing, to prevent abuse. If the intravenous formulation had to be used, they recommend using the lowest effective dose (0.5 mg/kg [maximum 25 mg] every 6 hours) to be given over a slow infusion of 20 minutes or longer, to decrease abuse liability (Dinndorf et al. 1998).
Withdrawal symptoms in patients abusing diphenhydramine include worsening of insomnia, rhinorrhea, nausea, irritability, restlessness, abdominal cramps, sweating, and diarrhea (Feldman and Behar 1986; de Nesnera 1996; Gracious et al. 2010). In patients taking large daily diphenhydramine doses, judicious tapering remains the treatment of choice for prevention of withdrawal. The oral formulation of diphenhydramine for tapering purposes is as effective as the intravenous one. One report of withdrawal treatment with naltrexone exists (Gracious et al. 2010); however, the naltrexone was used in addition to a gentle antihistamine taper. More evidence is needed to support the use of naltrexone for antihistamine withdrawal treatment.
Conclusions
Despite the initial studies that have shown low abuse potential for diphenhydramine, some patients may be susceptible to abuse. Young adults, adolescents, and children are the most reported subjects, possibly secondary to the significantly different metabolism demonstrated by young adults and children as opposed to the elderly. Chronically ill adolescents are potentially at the greatest risk for iatrogenic diphenhydramine addiction. To prevent abuse of diphenhydramine, oral dosing should be used, if possible. If intravenous diphenhydramine is necessary, the lowest effective dose via slow infusion should be used. Judicious use of intravenous diphenhydramine may decrease incidence of inadvertent diphenhydramine abuse.
Footnotes
Disclosures
No competing financial interests exist.