J Am Board Fam Pract: first published as 10.3122/jabfm.7.5.417 on 1 September 1994. Downloaded from Use Of Transdermal Nicotine Systems In A Possible Suicide Attempt

Norman Montalto, DO, Carolyn C. Brackett, PharmD, and Todd Sobol, MD

Background: Transdennal drug delivery systems, a relatively recent development, are well accepted by physicians and patients because of reliability and ease of administration. The patch resen'oirs, however, contain large quantities of drug, and the potential for considerable toxicity exists if they are used incorrectly. A case is presented of an apparent suicide attempt that involved the use of nicotine transdennal patches. Methods: This case report involved a patient seen in the emergency department by one of the authors. Data were obtained from the patient's medical record while maintaining confidentiality. Results: The drug overdose was a potentially serious one. The patient recovered fully after an uneventful hospital course. Conclusions: Transdennal drug delivery systems now deliver many drugs, several of which are quite potent. Intentional or unintentional misuse of the systems can result in toxicity. The physician and phannacist should carefully instruct each patient in the appropriate use and handling of transdennal drug delivery systems. (J Am Board Fam Pract 1994; 7:417-20.)

WIth the advancement of transdermal technol­ ing," "toxicology," "treatment," "management," ogy, such pharmaceutical agents as estrogen, sco­ and "contaminant." polamine, nitroglycerin, fentanyl, and recently nicotine can be administered by the transdermal Background route. Transdermal administration is not typi­ Nicotine is one of the most toxic of all poisons cally associated with acute drug overdosage, but and acts with great rapidity. It is well absorbed the following case appears to illustrate an attempt from the gastrointestinal and respiratory tracts at suicide using trans dermal nicotine patches in and through intact skin. Percutaneous absorption combination with ingestion of other substances. occurs many times more rapidly with the free Following the case presentation, we discuss the alkaloid than with any of its acid salts.1•2 symptoms and the treatment of nicotine toxicity The major effects of nicotine, in addition to and recommend safety guidelines to consider local caustic action, are transient stimulation and http://www.jabfm.org/ when prescribing transdermal nicotine therapy. then subsequent depression or paralysis of the central nervous system, all peripheral autonomic Methods ganglia, and motor end-plates in skeletal muscles. The case report was developed from informa­ Nicotine exerts an excitatory effect on smooth tion described by the attending physician and muscle, which could be responsible for the vaso­ from the patient's medical record. The patient's constriction and gastrointestinal hypermotility on 23 September 2021 by guest. Protected copyright. confidentiality was maintained. References that are observed following toxic exposures. 1 Fa­ for background literature were obtained from talities are traditionally believed to result from bibliography review, MEDLINE, and Interna­ respiratory arrest secondary to muscle paralysis, tional Pharmaceutical Abstracts. Key words used although there is now evidence that central de­ to search included "nicotine," "toxicity," "poison- pressant effects might contribute as well.2•3 A lethal dose of nicotine in adult humans is es­ timated to be 30 to 60 mg or 0.5 to 1.0 mglkg. Submitted, revised, 1 April 1994. From the Department of Family Medicine (NM), The Ohio Tolerance to the toxic effects of the alkaloid can State University Medical Center; the College of Pharmacy be acquired by habitual smokers, however, and (CCB), The Ohio State University, Columbus; and the Depan­ persons ingesting as much as 2.0 g of nicotine ment of Emergency Medicine (TS), Wright State University have survived.4 In fatal poisonings death is rapid, School of Medicine, Dayton, OH. Address reprint requests to Carolyn C. Brackett, PharmD, 500 W. 12th Avenue, Columbus, usually occurring within 1 hour and occasion­ OH43210. ally within 5 minutes. 1 Artificial ventilation and

Transdermal Nicotine 417 J Am Board Fam Pract: first published as 10.3122/jabfm.7.5.417 on 1 September 1994. Downloaded from circulatory support are often effective in prevent­ place is 11 to 12 hours, which reflects continued ing death, and some patients have experienced percutaneous absorption of drug, and following complete recovery within hours.l-4 removal of a nicotine patch, absorption continues Most fatalities associated with nicotine poison­ for several more hours, indicating the persistence ing occurred in the 1920s and 1930s, when con­ of a cutaneous reservoir of drug. IS Plasma nico­ centrated nicotine solutions were commonly used tine levels in nonsmoking volunteers are unde­ as insecticides, and reports of fatal poisonings fre­ tectable in 10 to 12 hours following patch removal quently involved the mistaking of nicotine solu­ but would be expected to decrease more rapidly in tions for other medications.2 Between 1930 and smokers whose hepatic enzymes have been in­ 1935,288 nicotine-associated fatalities occurred duced by the polycyclic aromatic hydrocarbon in the United States.5 Nonfatal poisonings were components of smoke. much more common than fatalities, however, Four nicotine transdermal patches are cur­ with some serious illnesses resulting from percu­ rently approved for use and marketed in the taneous exposure through clothing to as little as United States: Nicotrol (Parke-Davis), Nicoderm 7.5 mL of concentrated nicotine solution.5-9 (Marion Merrell Dow), Habitrol (Basel-Ciba­ Symptoms of nicotine toxicity are manifested Geigy), and Prostep (Lederle). All of the patches primarily by the gastrointestinal tract and the are applied every 24 hours, for 24 hours, except central nervous system. Features of gastrointes­ for Nicotrol, which is applied every 24 hours tinal cholinergic overstimulation are prominent but removed at bedtime, for an effective appli­ and include severe nausea, vomiting, salivation, cation time of approximately 16 hours. All patch and diarrhea. Central nervous system signs and strengths contain varying amounts of nicotine symptoms include headache, dizziness, confusion, (Table 1), but all brands contain nicotine as the seizures, and coma. In addition to central nervous free alkaloid, which is the form most readily system and gastrointestinal manifestations, severe absorbed through the skin.l°-I3 nicotine toxicity results in increased heart rate Percutaneous absorption from the drug-im­ and blood pressure and respiratory muscle paraly­ pregnated patch reservoir is generally excellent, sis, which are the events that can cause death. but to maintain a drug gradient across the system Treatment of nicotine poisoning includes re­ membranes, a substantial amount of drug must moving external sources of exposure, decontami­ remain in the controlled-release system after nating the gastrointestinal tract if vomiting and the 16-hour or 24-hour administration period diarrhea have not occurred, administering oxy­ (fable 1). For this reason safe disposal of the used gen, and supporting respiration and circulation, if patch is of the utmost importance, because chil­ http://www.jabfm.org/ necessary. In cases of nicotine toxicity caused by dren or pets discovering the used patch could be transdermal patches, removing the patches and poisoned by the remaining nicotine. washing the application sites with water only are recommended. The use of soap can actually drive Case Report nicotine on the skin surface further into the skin, A 15-year-old girl had a reported history of ad­

thus increasing the amount absorbed. IO-I3 Signs justment disorder with depressive features and at­ on 23 September 2021 by guest. Protected copyright. of toxicity are self-limiting, and recovery usu­ tention deficit disorder. She had a history of three ally occurs rapidly following discontinuation of previous suicide attempts. On the evening of ad­ exposure. mission to the emergency department she was Nicotine is eliminated primarily by the liver, found unresponsive, lying on her bed. She was and approximately 20 metabolites have been last seen at 4 PM in her usual state of health. Her identified. Following intravenous infusion, the parents discovered her at 6:45 PM and telephoned plasma half-life of nicotine is 1 to 2 hours in indi­ for emergency services. On arrival, the para­ viduals with normal hepatic function. The lung medics found the patient responsive only to deep and kidney also metabolize small amounts of the pain. She had placed 14 Habitrol patches on her drug. During percutaneous absorption of nico­ chest, abdomen, buttocks, and extremities. It is un­ tine, no important metabolism occurs in the skin. known how long the patches were in place. Para­ Nicotine has a large volume of distribution of 2 to medical personnel removed 12 of the patches, and 3 Ukg.14 Plasma half-life with a nicotine patch in the 2 remaining were removed in the emergency

418 JABFP Sept.-Oct.1994 Vol. 7 No.5 J Am Board Fam Pract: first published as 10.3122/jabfm.7.5.417 on 1 September 1994. Downloaded from Table 1. Characteristics of Nicotine Transdermal Systems.

Nicotine Dose Time to Peak Plasma Residual Nicotine Maximum Plasma Absorbed Concentration Total Nicotine (mg) after Concentration Product (mgl24 hr)lO-13 (hours)IO-13 Content (mg)lO-13 24 hours lO- 13 (ng/mL)

Nicoderm 21 2-4 114 83 23 (Marion Merrell Dow) 14 78 60 17 7 36 26 8 Habitrol 21 5-6 52.5 31.5 17 (Basel) 14 35 21 12 7 17 10.5 7 ProStep 22 8 30 8 16 (Lederle) 11 IS 4 ND Nicotrol 15* 8 24.9 6 13 (Parke-Davis) 10* 16.6 4 7 S* 8.3 2 3.5

ND=NoData *Nicotine absorbed over 16 hours

department. The size and milligram strength of cardiac, respiratory, and mental status monitoring the patches were not known. On examination at and supportive care. Her recovery was rapid and the emergency facility her respirations were regu­ without complication; she was discharged after 48 lar at 12/min, blood pressure was 170/92 mmlHg, hours to the psychiatric unit for further care. and pulse was 60 beats/min. Her skin was cool and clammy. She continued to be responsive only Discussion to deep pain, which elicited withdrawal. Her pu­ Although neither a urinary cotinine level (the pri­ pils were dilated with normal light reflex. Gas­ mary metabolite of nicotine) nor a blood nicotine trointestinal signs were not present and were not level were obtained, this case serves to draw atten­ reported by paramedics during transport. The re­ tion to a potentially serious or fatal situation. We mainder of her examination was unremarkable. are reluctant to claim that this patient's physical The patient was washed with soap and water examination and presentation are consistent with and received activated charcoal by oro gastric nicotine toxicity. Evidence to support nicotine tube. Approximately 45 minutes after arrival at toxicity would have included vomiting, diarrhea, http://www.jabfm.org/ the emergency department, she regained con­ salivation, tachycardia, coma, and a rapid return sciousness and slowly returned to her base-line to base-line mental status after removal of mental status. On further questioning, the patient patches. The patient did appear comatose, experi­ admitted she had also ingested "small" quantities enced a rapid recovery, and had an elevated blood of her mother's other medications obtained from pressure that decreased over several hours, and a medicine cabinet, which included ranitidine, al­ these findings do suggest nicotine toxicity. Inter­ prazolam, co-trimoxazole, and ibuprofen. Blood estingly, multiple substances were claimed to have on 23 September 2021 by guest. Protected copyright. concentrations for these medications were not been ingested, but they were not detected, and obtained. A laboratory toxicology determination other substances were detected but not suspected. was positive for amphetamine and negative for Nevertheless, the use of nicotine patches as a ethanol, acetaminophen, and benzodiazepines. source of drug overdose was undeniable and po­ Initial laboratory data included white cell count tentially very toxic. 9500/IJ..L, hemoglobin 14.1 g/dL, and hematocrit It is important for the clinician to recall that 43.7 percent; liver function tests were within nor­ there are differences among the patches in nico­ mal limits. Arterial blood gases on 6 L of oxygen tine absorption rates and bioavailability (fable 1). were pH 7.40, pC02 37.0 mmHg, p02 97 Contact time with the skin is important, and al­ mmHg, bicarbonate 23 mEq/L, oxygen satura­ though plasma nicotine levels were not measured, tion 98 percent. An electrocardiogram revealed if our patient had had the patches on for more sinus bradycardia. She was admitted to the inten­ than a few hours, the absorption could have been sive care unit, where her hospital course included extensive. Absorption of nicotine from a transder-

Transdermal Nicotine 419 J Am Board Fam Pract: first published as 10.3122/jabfm.7.5.417 on 1 September 1994. Downloaded from mal patch is also influenced by application site, moving a patch, do not touch your eyes or and data indicate that absorption rate is slightly nose before washing your hands. more rapid from sites over the chest. 11 The im­ 7. The most common side effect of the nicotine portance of patch placement with regard to toxic­ patch is irritation of the skin under and sur­ ity is unknown. rounding the patch. If this irritation is severe, In light of the potential for unpleasant or seri­ remove the patch and contact your physician. ous toxicity resulting from intentional or unin­ 8. Nicotine in any form is not safe to use during tentional misuse of nicotine patches, we recom­ pregnancy. If you are pregnant or suspect you mend that the following guidelines be given to all may be pregnant, discontinue use of nicotine patients receiving trans dermal nicotine therapy: immediately and contact your physician.

1. Do not use tobacco products while being treated with nicotine replacement patches. References Blood nicotine levels remain elevated for 6 to 1. Gosselin RE, Smith RP, Hodge HC. Clinical toxi- cology of commercial products. 5th ed. Baltimore: 12 hours after removal of a patch. I2 -15 Toxic Williams & Wilkins, 1984:311-4. side effects or serious adverse reactions, such 2. Haddad LM, Winchester ]E Clinical management as nausea, increase in blood pressure, dizzi- of poisoning and drug overdose. Philadelphia: WB ness, abdominal pain, sweating, or chest pain, Saunders, 1983:513-5. can occur. If you experience any of these reac- 3. Brady ME, Ritschel WA, Saelinger DA, Cacini W, tions, contact your physician. Patterson AJ. Animal model and pharmacokinetic in- terpretation of nicotine poisoning in man.lnt] Clin 2. Be certain that your physician and pharmacist Pharmacol Biopharm 1979; 17:12-7. are aware of all medications you are taking. 4. Franke FE, Thomas]E. The treatment of acute Many commonly used medications can nicotine poisoning.]AMA 1936; 106:507-12. change the rate at which the body is able to 5. Lockhard LP. Nicotine poisonings. Br Med] 1933; excrete nicotine that is absorbed from the 1:246-7. 6. McNally WD. A report of seven cases of nicotine patch. The consequences could be either poisoning.] Lab Clin Med 1922; 8:83-5. increased side effects from the nicotine or a 7. Von Ahn B. A further case of paroxysmal auricular failure of the patch to control your urge to fibrillation in acute nicotine poisoning. Acta Med smoke. Scand 1953; 145:28-33. 3. Patches are medication, as are tablets or cap- 8. Faulkner ]M. Nicotine poisoning by absorption Ii sules; store them well out of reach of children through the skin.]AMA 1933; 100:1664-5. I 9. Wilson GB. Nicotine poisoning by absorption http://www.jabfm.org/ "~ ~ and pets. through the skin. Br Med] 1930; 2:601-2. J 4. Dispose of used patches carefully by first 10. Nicotrol product information. Morris Plains, NJ: folding them with the sticky sides together Parke-Davis Laboratories, 1992. and then wrapping them in the package from 11. Nicoderm product information. Kansas City, MO: which the new patch was removed. Dispose Marion Merrell Dow, 1992. 12. Habitrol product information. Summit, NJ: Basel of used patches safely, away from children and Pharmaceuticals, 1992. on 23 September 2021 by guest. Protected copyright. pets. Call a poison control center, physician, 13. Prostep product information. Wayne, NJ: Lederle pharmacist, or hospital emergency depart- Laboratories, 1992. ment if you have questions. 14. Beeman]A, Hunter we. Fatal nicotine poisoning: 5. Trim, but do not shave hair at the intended a report of twenty-four cases. Arch Patho11937; application site. Irritation caused by shaving 24:481-5. 15. Mulligan SC, Masterson]G, Devane]G, Kelly]G. can increase nicotine absorption. Clinical and pharmacokinetic properties of a trans- 6. To remove nicotine after application, wash dermal nicotine patch. Clin Pharmacol Ther 1990; hands with water only. After applying or re- 47:331-7.

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