NALOXONE-ASSOCIATED PATIENT VIOLENCE:
`
`AN OVERLOOKED TOXICITY?
`
`Gary M. Gaddis and William A. Watson
`
`OBJECTIVE: To report two cases of a previously unreported adverse
`effect, violent patient behavior, after the reversal of sedation by
`intravenous naloxone.
`DESIGN: Case report.
`PATIENTS/INTERVENTIONS: Responses of two individuals who had
`reversal of sedation by intravenous naloxone are compared.
`RESULTS: Placement of patient restraints before the administration of
`intravenous naloxone to obtunded or unconscious patients can make
`an important contribution to the safety of patients, healthcare
`personnel, and public safety personnel, as illustrated by the violent
`reaction of one unrestrained patient after naloxone administration.
`CONCLUSIONS: Patient restraint should be considered before naloxone
`administration to protect the patient and healthcare workers. In the
`prehospital setting, limiting the use of naloxone to patients with
`decreased mental status and respiratory depression would decrease
`the likelihood of naloxone-induced violent behavior.
`
`Ann Pharmacother 1992;26:196-8.
`
`NALOXONE has generally been associated with very few ad(cid:173)
`verse effects.r-s Yealy et al. evaluated the adverse gastroin(cid:173)
`testinal, cardiovascular, and neurologic effects of naloxone
`after prehospital administration in 813 patients with de(cid:173)
`creased consciousness. The adverse effects noted were de(cid:173)
`creased systolic blood pressure (BP) (2 patients), increased
`systolic BP (I), vomiting (2), and tonic-clonic seizure (I).
`Most of these effects occurred in patients with concomitant
`confounding factors, such as recent ipecac ingestion or a
`prior history of seizures,"
`Violent or aggressive patient behavior after naloxone re(cid:173)
`versal of sedation secondary to opioids has not previously
`been reported. 2,3,5,6 When healthcare providers are unpre(cid:173)
`pared, such violent behavior can be a hazard both to pro(cid:173)
`viders and patients. Two cases at our institution illustrate
`contrasting outcomes following naloxone administration
`with subsequent violent patient behavior. These cases sug(cid:173)
`gest that planning for physical control or restraint of pa(cid:173)
`tients prior to naloxone administration can prevent injury
`to both patients and personnel.
`
`CASE REPORTS
`
`CASE I
`Paramedicswere called to the residenceof a 35-year-oldman af(cid:173)
`ter he was observed by his family 10 have a decreased level of
`
`GARY M. GADDIS, M.D., Ph.D., is a Staff Physician and an Assistant Professor,
`Department of Emergency Medicine, School of Medicine; and WILLIAM A. W AT·
`SON, Pharm.D., DABAT, is a Clinical Associate Professor, Department of Emer(cid:173)
`gency Medicine and Division of Pharmacy Practice, Schools of Medicine and Phar(cid:173)
`macy, University of Missouri-Kansas City, Kansas City, MO. Reprinls: Gary M.
`Gaddis, M.D., Ph.D., Department of Emergency Medicine, Truman Medical Center.
`2301 Holmes. Kansas City, MO 64108.
`
`consciousness. Family members suspected a drug overdose and
`indicated that the patient had no significant past medical, neuro(cid:173)
`logic, or psychiatrichistory.The patient was initiallycooperative
`and admitted smoking marijuana laced with phencyclidine
`(PCP). He complainedof dizzinessand numbness.He was assist(cid:173)
`ed, but walked without incidentfrom the front porch of his horne
`to the ambulance. At that time his heart rate was 100 beats/min,
`respiratory rate was 18 breaths/min, and BP was 180/110rnrnHg.
`Paramedicsobtained intravenous access and performeda Dextro(cid:173)
`stick,measuring a blood glucoseconcentration of 4.4--6.7 mmol/l;
`The patient was breathing spontaneously and had a gag reflex.
`Before contacting the base station physician, the paramedic ad(cid:173)
`ministered naloxone 2.0 mg iv bolus, later citing as his rationale
`standing orders permitting the administrationof naloxone for al(cid:173)
`tered mental status, as well as a curiosity regarding whether the
`patient's altered mental status was narcotic-related. The patient
`abruptly became extremely violent and disconnected his intra(cid:173)
`venous line. Paramedics, fearing for their safety, called their dis(cid:173)
`patcher for assistance. Because of his continued and escalating
`violent behavior, more than ten police and fire personnel were
`called to the scene to physically subdue the patient with limited
`success. A base station order by a resident physician for di(cid:173)
`azepam 5 mg im had little effect. Butorphanol tartrate 2 mg im
`ordered by the staff attendingphysiciansedated the patientover a
`period of approximatelyfive minutes. Four-point restraints were
`placed on the patient in the ambulance,and he was transportedto
`the emergencydepartment(ED) withoutfurther incident.
`Upon arrival at the ED, the patient was placed prone in four(cid:173)
`point leather restraints. Heart rate was 100beats/min,respirations
`were 24 breaths/min, BP was 172/98 mm Hg, and electronically
`recordedoral temperaturewas 100.3OF. General physical exami(cid:173)
`nationrevealed a muscular,well-developed male with no signs of
`trauma. Needle track marks were noted in the antecubitalfossae.
`The patient was alert; oriented to person, place, and time; and
`moved all four extremitieswell. He had no gross sensorydeficits.
`Facies was symmetric and his speech was clear. No nystagmus
`was noted. The cardiac monitor showed a regular sinus rhythm
`between 90 and 105 beats/min. Accucheck blood glucose con(cid:173)
`centration was 11.1 mmol/L. Urine was negative for blood by
`dipstick. Urine toxicologic screening was not obtained at this
`time. However,on a return visit for diffuse body aches three days
`later, the patient's urine was positive for PCP and benzodiaze(cid:173)
`pines, and negative for opiates.
`Two hours after arrivalfor his initialvisit, the patientwas calm
`and the restraintswere removed. He was alert, fully oriented,ap(cid:173)
`propriate, and requested to be discharged. He denied homicidal
`or suicidal ideation or any knowledge of narcotic ingestion.The
`patient was dischargedtwo and a half hours after arrival,after be(cid:173)
`ing wamed about the risks of PCP use. At this time he was polite
`and thanked us for his care.
`
`CASE 2
`A 31-year-oldwoman was brought by a friend to the ED because
`"she looked blue" and had nearly stopped breathing. The friend
`was unaware of any recent narcotic use by the patient, but stated
`that the patient had a prior history of narcotic abuse. There was
`no historyof neurologicor psychiatricabnormalities.
`
`196 • The AnnalsofPharmacotherapy
`
`•
`
`1992 February, Volume 26
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`

`

`The patient's initial respiratory rate was 4-6 breaths/min, and
`a gag reflex could not be elicited. She received ventilatory sup(cid:173)
`port via bag-valve-mask and had an intravenous line placed. A
`brief physical survey was significant for 1.5-mm reactive pupils,
`perioral and acral cyanosis, poor responsiveness to pain, and an(cid:173)
`tecubital needle tracks. In anticipation of narcotic reversal by
`naloxone, the patient was placed in four-point restraints.
`Naloxone 2.0 mg iv bolus was administered. Within 60 sec(cid:173)
`onds the patient was fully awake and combative with slurred
`speech. Her pupils widened to 3.5 mm. Piloerection of the skin
`was noted, and the patient yawned repeatedly while complaining
`that she felt cold. A brisk gag reflex returned. Pulse oximetry
`documented 97% oxygen saturation.
`Because she had been restrained before naloxone was adminis(cid:173)
`tered, the patient posed no safety threat to herself, other patients,
`or personnel in the ED After about five minutes she was no longer
`combative and subsequently volunteered that she had "shot hero(cid:173)
`in" to relieve toothache pain unalleviated by acetaminophen. She
`was observed for a five-hour period after receiving activated char(cid:173)
`coal 50 g. No repeat doses of naloxone were required. The pilo(cid:173)
`erection and yawning ceased approximately two hours after the
`naloxone was administered. The patient's urine drug screen was
`positive for acetaminophen, ethanol, and opiates. Her serum ac(cid:173)
`etaminophen concentration was 0 and her blood alcohol concen(cid:173)
`tration was 59 mmol/L, She was discharged to a dental clinic for
`treatment, and went home from there without incident.
`
`Sudden reversal of central nervous system (CNS) de(cid:173)
`pression by naloxone may unmask or precipitate unex(cid:173)
`pected violent patient behavior. The mechanisms involved
`may be related to the physical discomfort of withdrawal,
`the confusion of awakening in an unexpected setting,
`anger at losing the altered mental status "high," the effects
`of other concomitantly ingested medications no longer
`opposed by narcotics, underlying personality disorder(s),
`or other causes. The precipitation of violent behavior can
`place both the patient and medical personnel at risk for
`avoidable injury. This risk can be minimized by preemp(cid:173)
`tive placement of restraints when feasible, as illustrated by
`case 2. Because of our experience with the patient de(cid:173)
`scribed in case 1, we have begun to more actively discour(cid:173)
`age the routine prehospital administration of naloxone to
`patients with diminished levels of consciousness unless
`respiratory depression is also present. The general medical
`prehospital standing paramedic orders have since been re(cid:173)
`vised to reflect this change.
`It is unclear whether case 1 represents a reversal of opi(cid:173)
`ate toxicity or PCP toxicity by naloxone. Studies in hu(cid:173)
`mans suggest that naloxone can decrease the anesthetic ef(cid:173)
`fects of ketamine, a PCP analog.' The patient in case 1 be(cid:173)
`came combative with purposeful activity after intravenous
`naloxone administration, and was resedated after intramus(cid:173)
`cular butorphanol administration. Because a drug screen
`was not performed at the initial hospital visit, a definitive
`determination of whether opiates were involved could not
`be made.
`The 2-mg dose of naloxone administered to the two pa(cid:173)
`tients we have described is the most commonly recom(cid:173)
`mended dose. Although 2 mg was greater than the mean
`dose used by Yealy et al. it was not greater than the highest
`dose administered by these investigators (2.4 mg)." It re(cid:173)
`mains unclear whether the magnitude of the dose adminis(cid:173)
`tered to our patients correlates with the development of
`combative or violent behavior. The proper dosing of nalox(cid:173)
`one remains controversial.v?
`The choice of sedative used and its route of administra(cid:173)
`tion for the first patient, after he became violent and dis-
`
`CaseReports
`
`continued his intravenous access line, was limited by the
`availability of only two injectable agents with CNS depres(cid:173)
`sant effects (diazepam and butorphanol) in the paramedics'
`drug boxes and by the lack of any intravenous access. It
`has long been known that diazepam absorption after intra(cid:173)
`muscular injection is slow and quite variable, hence, the
`lack of efficacy of this medication is readily explained.
`Violent patient behavior is a clinically relevant adverse ef(cid:173)
`fect readily anticipatable, but previously not reported follow(cid:173)
`ing naloxone administration. Combative behavior should be
`added to the list of previously documented adverse effects of
`naloxone administration. These include hypertension," pul(cid:173)
`monary edema,' emesis," seizures," cardiac dysrhythmias,"
`and cardiac arrest." To prevent violent patient behavior and
`potential physical injury, we suggest that patient restraints
`be used before the administration of naloxone in the ED or
`prehospital setting. We also suggest that paramedics' stand(cid:173)
`ing orders be revised, if necessary, to encourage prehospital
`naloxone administration only for cases involving respirato(cid:173)
`ry depression of sufficient severity to cause the paramedic
`to consider endotracheal intubation of the patient. ~
`
`References
`I. Handal KA, Schauben JL, Salamone FR. Naloxone. Ann EmergMed
`1983;12:438-45.
`2. McNicholas LF, Martin WR. New and experimental therapeutic roles
`for naloxone and related opioid antagonists.Drugs 1984;27:81-93.
`3. Buchwald A. Naloxone use. Side effects may occur (letter).Ann Emerg
`Med 1988;17:765.
`4. Neal JM. Complications of naloxone (letter). Ann Emerg Med 1988;17:
`765-6.
`5. Kunkel DB. Narcoticantagonistupdate.EmergMed 1987;19(5):97-108.
`6. Yealy OM, Paris PM, Kaplan RM, Heller MB, Marini SE. The safe(cid:173)
`ty of prehospital naloxone administration by paramedics. Ann Emerg
`Med 1990;19:902-5.
`7. Stella L, Crescenti A, Torri G. Effect of naloxone on the loss of con(cid:173)
`sciousness induced by iv anesthetic agents in man. Br J Anaesth 1984;
`56:369-73.
`8. Azar I, Turndorf H. Severe hypertension and multiple atrial premature
`contractionsfollowing naloxone therapy.AnesthAnalg 1979;58:524-5.
`9. Schwartz JA, Koenigsberg MD. Naloxone-induced pulmonary edema.
`Ann EmergMed 1987;16:1294-6.
`10. Kobrinsky NL, Pruden PB, Cheang MS, Levitt M, Bishop AJ,
`Tenenbein M. Increased nausea and vomiting induced by naloxone in
`patients receiving cancer chemotherapy. Am J PediatrHemato/lOneol
`1988;10:206-8.
`II. Mariani PJ. Seizure associated with low dose naloxone. Am J Emerg
`Med 1989;7:127-9.
`12. Michaelis LL, Hickey PR, Clark TA, Dixon WM. Ventricular irri(cid:173)
`tability associated with the use of naloxone hydrochloride.Ann Thorae
`Surg 1974;18:608-14.
`13. Andree RA. Sudden death following naloxone administration. Anesth
`Analg 1980;59:782-4.
`
`EXTRACfO
`
`Comportamiento violento 0 agresivo con el usa de naloxona intravenosa
`para revertir sedaci6n no ha sido informado aun, Informamos dos casos
`de comportamiento violento despues de la administraci6n de naloxona y
`se contrasta el manejo clfnico y el resultado de estos casos. Se sugiere
`restringir al paciente de sus movimientos antes de administrar naloxona
`para proteger al paciente y al personal de la salud. En el marco
`prehospitalario, limitar el uso de naloxona a pacientes con condici6n
`mental disminuida y depresi6n respiratoria disminuye la probabilidad de
`un comportamiento violento inducido por naloxona.
`
`RAFAELA MENA DE GIRALDI
`
`The AnnalsofPharmacotherapy
`
`•
`
`1992 February, Volume 26 •
`
`197
`
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`Page 2
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`

`

`RESUME
`
`Aucun comportement agressif n' a ete rapporte apres avoir renverse la
`sedation chez 813 patients aI'aide du naloxone administre par voie
`intraveineuse lors d'une recente revision d'une sene de cas sur ces effets
`secondaires. Nous rapportons ici deux cas de comportement agressif
`apres I' administration de naloxone. L' approche clinique et les resultats
`de ces cas sont mis en contraste. Dans les deux cas on suggere de
`
`restraindre les mouvements du patient avant de lui administrer Ie
`naloxone afm de Ie proteger lui ainsi que les intervenants de la sante.
`Dans un contexte prehospitalier, limiter I'usage du naloxone chez les
`patients ayant un statui mental altere et une detresse respiratoire
`dirninuerait la possibilite d'induire des comportements agressifs avec Ie
`naloxone.
`
`CHANTAL GUEVREMONT
`
`SHORT REPORTS
`
`TOPICAL TREATMENT WITH MINOXIDIL 2% AND SMOKING INTOLERANCE
`
`Akiva Trattner and Aryeh Ingber
`
`OBJECTIVE: To report smoking intolerance that occurred in two
`patients while they were treated with minoxidil.
`DATA SYNTHESIS: Minoxidil is a potent vasodilator useful in treating
`severe hypertension. Topical minoxidil was approved as a treatment
`for androgenital alopecia. Only few side effects have been reported
`during treatment with topical minoxidil, most of them localized skin
`reactions. Two of our patients developed smoking intolerance
`during treatment with topical minoxidil for androgenital alopecia.
`The relation between treatment with minoxidil and smoking
`intolerance was emphasized by stopping treatment and the
`disappearance of the smoking intolerance, and then by rechallenge
`in both patients.
`CONCLUStONS: Topical minoxidil may cause smoking intolerance;
`further studies are needed to evaluation this side effect.
`
`Ann Pharmacother 1992;26: 198-9.
`
`MINOXIDll.. IS A POTENT VASODll..ATOR used in the treatment
`of severe hypertension. Hypertrichosis (excessive hair
`growth) occurs in nearly all patients treated with oral minox(cid:173)
`idil for more than four weeks. This side effect has been eval(cid:173)
`uated in some controlled studies and minoxidil has been
`proven to be effective in the treatment of male pattern bald(cid:173)
`ness. This drug (in the form of a topical 2% solution) was
`approved by the Food and Drug Administration in August
`1988 for the treatment of men with androgenetic alopecia at
`the vertex region of the scalp. t Only a few adverse effects
`
`AKIVA TRATTNER, M.D., is an Instructor of Dermatology; and ARYEH ING(cid:173)
`BER, M.D., is a Senior Lecturer of Dermatology, Sackler School of Medicine, Tel(cid:173)
`Aviv University, Tel-Aviv, Israel. Reprints: Akiva Trattner, M.D., Kedumim, D.N.
`Shornron, 44856, Israel.
`
`have been reported with the use of topical minoxidil. These
`include localized skin reactions (e.g., irritation, pruritus,
`burning, allergic contact dermatitisj'< and systemic reac(cid:173)
`tions such as headaches,' noncardiac substernal chest pain,2,3
`dizziness and weakness, taste alteration.' impotence.v minor
`electrocardiographic changes," and a mild increase in blood
`pressure after discontinuation of therapy.'
`We report on two patients who developed smoking in(cid:173)
`tolerance during topical treatment with minoxidil. We con(cid:173)
`ducted a search of the literature (Medline) and consulted
`with the manufacturer of the product (Rogaine, Upjohn).
`To our knowledge, this is the first report dealing with this
`side effect.
`
`CASE REPORTS
`
`CASE 1
`A 42-year-old man with male pattern alopecia of ten years' dura(cid:173)
`tion, but otherwise healthy, had a 25-year history of smoking 40
`cigarettes/day, He was on no medication. He began treatment
`with topical minoxidil 2% 1 mL bid. Laboratory studies (hemo(cid:173)
`gram, automated chemistry panel [SMA-12l, urinalysis, and
`electrocardiogram) were within normal limits. Three weeks after
`the initiation of treatment, the patient reported an intolerance to
`smoking. He experienced an unpleasant taste sensation when
`smoking, but reported no other taste alterations or change in ap(cid:173)
`petite. He stopped the treatment after only three weeks. Three
`days later the smoking intolerance disappeared and he began to
`smoke again. A week later he resumed the topical minoxidil ap(cid:173)
`plications and the phenomenon of smoking intolerance reap(cid:173)
`peared within 48 hours. The patient continued minoxidil treat(cid:173)
`ment for five months and completely stopped smoking. He is
`continuing the treatment on a long-term basis and is pleased
`
`198 • The Annals ofPharmacotherapy
`
`•
`
`1992 February. Volume 26
`
`Opiant Exhibit 2010
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`Page 3
`
`