The Journal of Emergency Medicine, Vol. 29, No. 3, pp. 265–271, 2005
`Copyright © 2005 Elsevier Inc.
`Printed in the USA. All rights reserved
`0736-4679/05 $–see front matter
`
`doi:10.1016/j.jemermed.2005.03.007
`
`Original
`Contributions
`
`EFFICACY OF INTRANASAL NALOXONE AS A NEEDLELESS ALTERNATIVE FOR
`TREATMENT OF OPIOID OVERDOSE IN THE PREHOSPITAL SETTING
`
`Erik D. Barton, MD, MS,* Christopher B. Colwell, MD,† Timothy Wolfe, MD,* Dave Fosnocht, MD,*
`Craig Gravitz, EMT-P,† Tamara Bryan, EMT-P,† Will Dunn, EMT-P,† Jeff Benson, EMT-P,† and
`Jeff Bailey, EMT-P†
`
`*Division of Emergency Medicine, Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, Utah and
`†Department of Emergency Medicine and Denver Paramedic Divison, Denver Health Medical Center, Denver, Colorado
`Reprint Address: Erik D. Barton, MD, MS, University of Utah, Division of Emergency Medicine, 175 North Medical Drive East,
`1150 Moran Building, Salt Lake City, UT 84132
`
`e Abstract—Prehospital providers are at increased risk
`for blood-borne exposure and disease due to the nature of
`their environment. The use if intranasal (i.n.) medications
`in high-risk populations may limit this risk of exposure. To
`determine the efficacy of i.n. naloxone in the treatment of
`suspected opiate overdose patients in the prehospital set-
`ting, a prospective, nonrandomized trial of administering
`i.n. naloxone by paramedics to patients with suspected
`opiate overdoses over a 6-month period was performed. All
`adult patients encountered in the prehospital setting as
`suspected opiate overdose (OD), found down (FD), or with
`altered mental status (AMS) who met the criteria for nal-
`oxone administration were included in the study. i.n. nal-
`oxone (2 mg) was administered immediately upon patient
`contact and before i.v. insertion and administration of i.v.
`naloxone (2 mg). Patients were then treated by EMS pro-
`tocol. The main outcome measures were: time of i.n. nal-
`oxone administration, time of i.v. naloxone administration,
`time of appropriate patient response as reported by para-
`medics. Ninety-five patients received i.n. naloxone and were
`included in the study. A total of 52 patients responded to
`naloxone by either i.n. or i.v., with 43 (83%) responding to
`i.n. naloxone alone. Seven patients (16%) in this group
`required further doses of i.v. naloxone. In conclusion, i.n.
`
`Dr. Wolfe is the Vice president and Medical Director of
`Wolfe Tory Medical, Inc, the company that supplied the Mu-
`cosal Atomizer Devices (MAD®) for the study.
`
`naloxone is a novel alternative method for drug adminis-
`tration in high-risk patients in the prehospital setting with
`good overall effectiveness. The use of this route is further
`discussed in relation to efficacy of treatment and minimiz-
`ing
`the
`risk of blood-borne
`exposures
`to EMS
`personnel. © 2005 Elsevier Inc.
`
`e Keywords—Prehospital;
`dose; exposure; needlestick
`
`intranasal; naloxone; over-
`
`INTRODUCTION
`
`In 1991, the Occupational Safety and Health Adminis-
`tration (OSHA) published the Occupational Exposure to
`Bloodborne Pathogens standard. This regulation outlines
`employer requirements necessary for the implementation
`of an exposure control plan to reduce or eliminate haz-
`ards from bloodborne pathogens and infectious materials
`(1). The regulation specifically targets engineering con-
`trols as a primary means of eliminating or minimizing
`employee exposures. These controls include implemen-
`tation of safer medical devices such as needleless sys-
`tems and shielded needles. Despite advances in medical
`device technology that reduce needlestick risk, employee
`exposures continue to be of concern. Frequency of these
`
`RECEIVED: 7 July 2004; FINAL SUBMISSION RECEIVED: 19 January 2005;
`ACCEPTED: 21 March 2005
`
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`266
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`E. D. Barton et al.
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`long-term
`exposures remains high, and the potential
`mental and physical health effects can be severe (2–5).
`In response to the continued prevalence of bloodborne
`pathogen exposures from accidental sharps injuries in the
`workplace, OSHA developed The Needlestick Safety
`and Prevention Act (Pub. L. 106-430), which was signed
`into law in November 2000 and became effective in
`April 2001 (6). It set forth in greater detail the require-
`ments for employers to identify, evaluate, and implement
`safer medical devices.
`Most recently, needleless technology has been imple-
`mented in hospitals, clinics, and other healthcare offices. To
`date, however, very few needleless systems are being used
`in the prehospital setting. Ambulances, including air and
`ground programs, rarely find one needleless system that has
`universal compatibility with the various devices used in the
`hospitals they service. For this reason, most prehospital
`providers still rely on needle-type devices to access periph-
`eral intravenous (i.v.) lines and to administer subcutaneous
`(s.q.), and intramuscular (i.m.) medications.
`Intranasal (i.n.) medication delivery is an alternate de-
`livery route for injectable medications. When used with
`carefully selected medications, this delivery route has the
`advantage of rapid onset, high plasma bioavailability, direct
`transport to the central nervous system (CNS) across the
`olfactory mucosa, elimination of first pass metabolism and,
`perhaps most importantly, elimination of all needles (7–13).
`Access to the nose is also relatively immediate, especially
`in the prehospital setting where access to extremities
`through clothing can be highly variable from one patient to
`the next. Intranasal medication administration in the emer-
`gent setting is a rapid and a safe method for both the patient
`and the provider that has been underutilized to date.
`We investigated the use of i.n. naloxone (Narcan®) by
`paramedics to assess its efficacy and safety as an alter-
`native (needleless) medication delivery route. Narcan is
`commonly used in patients suffering from a suspected
`opioid overdose. These patients often have limited pe-
`ripheral venous access, making the intranasal route po-
`tentially very advantageous. The preliminary data, pub-
`lished in January 2002, was very promising (14). This
`study reports the final data from that series and makes the
`recommendation that the intranasal route should be con-
`sidered as a safer method of administering naloxone in
`high-risk patients encountered in the field. Additionally,
`we will briefly discuss other intranasal medications that
`hold promise in the prehospital setting.
`
`METHODS
`
`Study Design
`
`This study was performed by the Denver Health Para-
`medic Division as a prospective evaluation of intranasal
`
`Figure 1. The Mucosal Atomizer Device (MAD®) attached to
`a syringe showing the spray pattern of medication.
`
`naloxone in all patients who presented with potential
`opiate drug intoxication. The study was performed from
`February 1 to August 30, 2001 as part of a Paramedic
`Division Quality Assurance Evaluation of i.n. naloxone.
`There was an interruption in the study (March to June)
`due to a national shortage of naloxone in the 2 mg/2 mL
`concentration doses. Data collection occurred for a total
`of 3 months during the study period. All paramedics
`went through a brief training curriculum that taught the
`use of the i.n. naloxone device and the appropriate doc-
`umentation required before the start of the study. Insti-
`tutional Review Board (IRB) approval was granted (pro-
`tocol #01-635).
`
`Procedure
`
`All adult patients (⬎ 14 years) encountered in the field
`with a prehospital encounter diagnosis of “altered mental
`status” (AMS), “found down” (FD), or “suspected opioid
`overdose” (OD) were eligible for the study. The standard
`protocol called for these patients to have an i.v. placed
`and to receive i.v. naloxone (1–2 mg) based on the
`paramedic’s assessment of a possible overdose. For the
`study this protocol was modified so that these patients
`initially had 2 mg of intranasal naloxone administered
`using a disposable Mucosal Atomizer Device (MAD®,
`Wolfe-Tory Medical, Inc., Salt Lake City, UT) (Figure
`1). One mL of the 1 mg/mL naloxone solution was
`administered into each naris by inserting the MAD®
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`approximately ¼ to ½ inch, for a total volume of 2 mL.
`Immediately after i.n. naloxone, the standard protocol
`including airway management, i.v. line placement and
`i.v. medications was followed. The standard protocol
`was discontinued only if the patient responded and no
`further treatment was required. Data sheets were com-
`pleted for all patients (Figure 2) and included: times of
`initial patient encounter, i.n. naloxone administration,
`i.v. insertion, i.v. naloxone administration, and patient
`response. In addition, paramedics were asked to report
`any obvious abnormalities noted in the patient’s nasal
`mucosa (such as bleeding, deformity, mucus, etc.) at the
`time of i.n. drug administration.
`
`Outcomes
`
`The number of patients responding to i.n. naloxone,
`defined as a significant improvement in level of con-
`sciousness as determined by paramedics, before i.v. ad-
`ministration of a second dose of naloxone was recorded.
`Additionally, the time of response to naloxone (to the
`nearest minute) was measured by paramedics. Results
`were analyzed using McNewmar Change test and two-
`tailed t-tests for independent samples.
`
`RESULTS
`
`Ninety-five patients met study criteria and received i.n.
`naloxone. Fifty-two of these patients responded to either
`i.n. or i.v. naloxone (“Naloxone Responders”). Table 1
`lists the category to which the paramedics assigned the
`patients and the percentage that responded to naloxone.
`The majority of patients (63%) were suspected of having
`an opiate overdose upon initial assessment by the para-
`medic. Three patients were assigned to two categories.
`Forty-three (83%) of the 52 “Naloxone Responders” (p
`⫽ 0.0011) awoke with intranasal naloxone before the
`paramedics could administer the naloxone intravenously.
`Table 2 lists mean and median response times from
`paramedic arrival and from drug administration for all
`naloxone responders. Twelve of the 43 i.n. “Naloxone
`Responders” (29%) received no i.v. placement in the
`field after i.n. naloxone delivery. Seven patients (16%) in
`the i.n. naloxone response group required additional
`doses of i.v. naloxone after initial response due to “re-
`current somnolence” or “slow response,” whereas 36
`patients (84%) required no further naloxone therapy
`(69% of all “Naloxone Responders”). None of the “Nal-
`oxone Responders” was reported to have severe with-
`drawal reactions from either i.v. or i.n. naloxone.
`There were nine patients (17%) who responded only
`to i.v. naloxone and not to i.n. naloxone. Five of these
`
`nine (56%) i.n. nonresponder patients had “epistaxis”
`(2), “nasal mucus” (1), “trauma” (1), or “septal abnor-
`mality” (1), as noted by paramedics. None of the i.n.
`naloxone responders had any nasal abnormality noted by
`paramedics.
`
`DISCUSSION
`
`With the increasing seroprevalence of bloodborne patho-
`gens, accidental needle sticks now pose a life-changing
`and possibly life-ending event to heath care providers.
`This risk is especially high in the Emergency Medical
`Services (EMS) environment. Marcus et al. found a
`human immunodeficiency virus (HIV) seroprevalence
`rate of 4.1 to 8.9 per 100 patient visits in three inner-city
`Emergency Department (ED) populations (15). The an-
`nual blood contact for an individual EMS worker has
`been estimated to be as high as 12.3 per year in popula-
`tions where over 90% of patients’ HIV status are un-
`known (16). There is much concern that this high expo-
`sure rate can result
`in viral seroconversion of EMS
`providers. Valenzuela et al. reported a fivefold higher
`prevalence of Hepatitis B (HBV) infection in paramedics
`than that observed in a comparable population from the
`same city in 1985 (17). Pepe et al. confirmed this corre-
`lation in Houston EMS personnel, noting a strong asso-
`ciation between years of employment and the rate of
`HBV infections (18). Although there is less risk today
`with the advent of HBV vaccines and use of universal
`precautions, the risk for other exposures remains signif-
`icant.
`An especially high-risk patient population to EMS
`providers is the intravenous drug abuser (IVDA). These
`patients have HIV, HBV and Hepatitis C (HBC) sero-
`prevalence rates that are far higher than the baseline
`population and the serostatus is typically unknown to
`EMS workers (19). In addition, EMS personnel com-
`monly are involved in their care for life-threatening
`illnesses such as respiratory arrest from opiate overdose.
`Because opiate overdose patients rarely need an i.v. for
`any reason beyond the administration of naloxone (20 –
`22), a needleless method of administering naloxone
`would eliminate needlestick risk and potential transmis-
`sion of bloodborne pathogens.
`As this study demonstrates, such a delivery method
`exists. Like nitroglycerine, which is rapidly absorbed
`across mucosal membranes, naloxone also easily crosses
`the mucosal membranes. After intranasal mucosal ad-
`ministration, naloxone exhibits opiate antagonist effects
`almost as rapidly as the i.v. route with a bioavailability
`and clinical response approaching 100% in animal and
`human studies (7–9). The current series is a report of
`routine i.n. naloxone use in the emergent setting of opiate
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`Figure 2. Paramedic recording sheet for Prehospital Intranasal Narcan study.
`
`overdose. This study shows that intranasal naloxone is a
`clinically effective, rapid, needleless approach for ad-
`ministering naloxone to patients suffering an opiate over-
`
`dose and is easily implemented in the prehospital setting.
`Our results demonstrate an 83% response rate to i.n.
`naloxone in patients suffering an opiate overdose. In
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`Table 3. Intranasal Medications Previously Studied for
`Systemic Indications [adapted from Barton, et al.
`(3)]
`
`Table 1. Numbers of Patients who Presented with Altered
`Mental Status (AMS), Found Down (FD) or as a
`Suspected Opiate Overdose (OD), and the
`Number of Patients who Responded to Naloxone
`(“Naloxone Responders”)
`
`Indication
`
`Total patients (n ⫽ 95)
`
`AMS
`(n ⫽ 40)
`
`FD
`(n ⫽ 20)
`
`OD
`(n ⫽ 38)
`
`Analgesia
`
`Medications
`
`Fentanyl
`Diamorphine
`Sufentanil
`Buprenorphine
`Meclizine
`Metoclopramide
`Hydralazine
`Nifedipine
`Nitroglycerine
`Propranolol
`Verapamil
`Atropine
`Epinephrine
`Lidocaine
`Naloxone
`Butorphanol
`Dihydroergotamine
`Lidocaine
`Sumatriptan
`Dextrose
`Glucagon
`Diazepam
`Ketamine
`Midazolam
`Diazepam
`Midazolam
`Gentamycin
`Neostigmine
`
`Antiemetics
`
`Antihypertensives
`
`Cardiac arrest/ACLS
`
`Drug overdose
`Headache therapy
`
`Hypoglycemia
`
`Sedation
`
`Seizures
`
`Miscellaneous
`
`“Naloxone responders”
`
`11 (22%)
`
`8 (15%)
`
`33 (63%)
`
`Note: three patients were listed in two categories.
`
`actual practice, response rates to i.n. naloxone may be
`greater than 83%. By study design, no delays for i.v.
`naloxone were allowed, resulting in a number of cases
`where i.v. naloxone was administered shortly after i.n.
`naloxone due to rapid i.v. placement. Four of the nine
`patients (44%) reported to have responded only to i.v.
`naloxone received the i.v. dose within 4 min or less after
`the i.n. dose. Because i.n. naloxone often takes 4 min to
`arouse a patient, some of these patients may have re-
`sponded to i.n. naloxone but were identified as nonre-
`sponders because they received i.v. naloxone within such
`a short time period.
`When comparing time of response to i.n. naloxone to
`other routes of administration, it seems to be equivalent.
`Median times from arrival at the patient’s side to clinical
`response (8.0 min i.n. vs. 10.0 min i.v.) and from drug
`administration to clinical response (3.0 min i.n. vs. 3.0
`min i.v.) were not significantly different between i.n.
`delivery and i.v. delivery. These median times to clinical
`response after naloxone administration are similar to
`those previously reported for intravenous naloxone and
`subcutaneous naloxone (23). Wanger et al. found that the
`median time from ambulance arrival to patient response
`(defined at a RR ⬎ 10) was 9.3 (⫾ 4.2) minutes for i.v.
`naloxone, and 9.6 (⫾ 4.58) min for s.q. naloxone. The
`median times from drug administration to clinical re-
`sponse were 3.8 min for i.v. naloxone and 5.5 min for s.q.
`naloxone. The authors conclude that the delay in re-
`
`Table 2. Intranasal (i.n.) and Intravenous (i.v.) “Naloxone
`Responders” in the Prehospital Setting
`
`Response Times in minutes (⫾ SD)
`
`n ⫽ 52
`
`Initial contact
`
`i.n. Naloxone
`
`43 (83%)
`
`i.v. Naloxone
`
`9 (17%)
`
`p Value
`
`0.0011
`
`9.9 (⫾ 4.4)
`(median 8.0)
`12.8 (⫾ 7.6)
`(median 10.0)
`(ns)
`
`Drug
`administration
`
`4.2 (⫾ 2.7)
`(median 3.0)
`3.7 (⫾ 2.3)
`(median 3.0)
`(ns)
`
`Note: times reported from initial patient contact and from drug
`administration to observed response.
`
`sponse to s.q. administration was compensated for by the
`time it took to establish i.v. access, making the delivery
`routes equivalent in efficacy. We believe the same logic
`applies to i.n. delivery with the added safety advantage
`that no needle is used.
`Intranasal naloxone is not the only medication holding
`promise for needlestick risk reduction and improved
`patient care in the prehospital setting. Table 3 gives a
`listing of a number of medications routinely used in the
`EMS setting that are effective when delivered intrana-
`sally. One of the most important is i.n. midazolam for
`seizure control. A number of studies have demonstrated
`that emergent seizure control with i.n. midazolam is as
`effective as the long-held standard of intravenous diaz-
`epam and superior to rectal diazepam (24 –27). Lahat et
`al. found i.n. midazolam to provide equivalent control of
`pediatric seizures compared to i.v. diazepam (28). In
`addition, due to the time it took to start an i.v. in a seizing
`child, the i.n. midazolam group (6.1 min) had a signifi-
`cant reduction in total time to seizure cessation compared
`to the i.v. diazepam group (8 min). Fisgin et al. noted a
`much better control of pediatric seizures using i.n. mi-
`dazolam (87% cessation) when compared to rectal diaz-
`epam (60% cessation) (24).
`Transmucosal drug delivery is emerging as a promis-
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`ing method of delivering medications directly to the
`blood stream. This method of delivery can eliminate the
`need for intravenous catheters, and effective drug levels
`can be delivered rapidly for a number of important med-
`ications. The nasal route is a particularity attractive area
`to deliver transmucosal medications due to the large
`absorptive surface (180 cm2), rich vascular plexus, blood
`flow rates that approach that of the brain, and rapid
`absorptive properties that allow titration of medication
`effect (29). Utilizing an “atomized” delivery system that
`enhances mucosal surface coverage and optimizes parti-
`cle size for nasal distribution also increases drug absorp-
`tion (30). Atomization provides a larger surface coverage
`to nonciliated surfaces for better absorption. Addition-
`ally, with nasal breathing, nearly all particles with a size
`of 10 –20 ␮m (“atomized”) are deposited on the nasal
`mucosa, those less than 2 ␮m pass through the nasal
`cavity and deposit in the lungs, whereas larger droplets
`often coalesce and run out of the nasal cavity.
`Nasal drug administration also offers a number of
`advantages over parenteral and oral drug administration.
`The obvious advantage of nasal medication delivery over
`parenteral delivery is the elimination of an injection. This
`not only eliminates the risk of a needle stick exposure to
`the provider, but also eliminates the pain of injection
`experienced by the patient. The latter advantage is espe-
`cially attractive in the pediatric setting. In addition, in-
`tranasal drug administration does not require sterile tech-
`nique, clinical skills required for placing intravenous
`catheters or injecting medications, and it is immediately
`and readily available in almost all patients. Finally, for a
`number of parenteral medications, the rate and extent of
`absorption and plasma concentration vs. time profiles
`when the drug is delivered intranasally are comparable to
`those obtained by intravenous administration (31–35).
`However, nasal drug delivery is not without its own
`problems. As demonstrated in our study, the clinical effect
`of i.n. drug delivery is not 100%. Even if an optimized
`medication form, concentration and delivery system are
`used, i.n. delivery will not always work due to uncontrol-
`lable patient factors. A patient’s nasal blood flow and nasal
`mucosal characteristics have significant impact on drug
`absorption (36). If the patient used a street drug or OTC
`medication that decreases nasal blood flow (alpha agonists
`and anticholinergics), then the absorption of the therapeutic
`medication is likely reduced. Similarly, significant amounts
`of nasal secretions or nasal bleeding may inhibit drug ab-
`sorption, and using higher drug volumes to try to overcome
`these factors would cause runoff into the hypopharynx and
`out of the nostril, making the extra medication volume
`unavailable for absorption.
`The results of this study are important in terms of risk
`reduction to EMS providers. Accidental needle sticks,
`especially those resulting from a source patient who is an
`
`i.v. drug abuser, are emotionally draining for employees
`as well as their families. Months of distress are spent
`worrying about the possibility of contracting HIV, hep-
`atitis B or C, and concerns regarding prevention of any
`possible transmission to the employee’s spouse (2– 4). In
`addition, the medications used for postexposure prophy-
`laxis for HIV are expensive and frequently result in
`major side effects (5). By administering naloxone intra-
`nasally, needlestick risk is eliminated. Prehospital sys-
`tems in major metropolitan areas recognize the safety
`advantages of intranasal naloxone and are just now start-
`ing to implement this delivery route in their standard
`protocols for altered mental status and opiate overdose
`(37). These protocol changes will improve the safety of
`the work environment and eliminate the professional,
`personal, and family turmoil that might occur should a
`provider incur a needle stick from an i.v. drug abuser.
`
`LIMITATIONS
`
`There were significant limitations in designing such a
`study for use in the prehospital setting. First, because the
`efficacy of i.n. naloxone in the treatment of opiate over-
`dose was an unknown, we were required to follow our
`standard procedure of rescue breathing, i.v. initiation and
`administration of i.v. naloxone in all patients encoun-
`tered. The only adjustment to this protocol was to first
`administer i.n. naloxone before i.v. start. In some situa-
`tions we may have administered i.v. naloxone before the
`i.n. drug had a chance to take effect. An ideal setting
`would have been the requirement to wait 5 min after i.n.
`drug delivery before i.v. naloxone was administered and
`provide rescue breathing with bagging if needed. This
`would have allowed us to be more certain of the clinical
`efficacy of i.n. naloxone. Despite this limitation, we still
`found an 83% response rate to i.n. naloxone.
`A second limitation was the reliance on the subjective
`reporting from paramedics who were required to record
`times, administer medications, and assess appropriate pa-
`tient responses. Although paramedics did an exemplary job,
`this type of data collection is subject to recording errors in
`such an uncontrolled setting. Additionally, times were re-
`corded to the nearest minute, which may have limited exact
`analysis and statistical significance of the data.
`A third limitation was lack of randomization or blind-
`ing. Patients were not randomized nor was drug admin-
`istration blinded to the provider who was assessing pa-
`tient response. Rather, we chose a “staged” protocol so
`that medical care of the patient would not be diminished
`if there was no response to the i.n. medication.
`Finally, we did not look at confirmatory studies dem-
`onstrating the presence of opiate metabolites in the
`bloodstream of all patients who responded to i.n. or i.v.
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`naloxone upon hospital arrival. Because there are other
`overdose situations that may respond to naloxone, this
`could be a confounding variable in our study.
`
`CONCLUSION
`
`Several medications could be considered for routine in-
`tranasal administration in the prehospital setting. We
`have attempted to demonstrate the effectiveness of one
`medication, naloxone, with our study demonstrating an
`83% response when used intranasally. Our recommen-
`dation is that i.n. naloxone should be considered in EMS
`settings as first-line therapy for opioid overdose patients,
`using parenteral naloxone as a secondary treatment, es-
`pecially in high risk populations. The advantages to
`incorporating i.n. naloxone into a prehospital protocol
`include both 1) a rapid reversal of opioid overdose in a
`majority of patients, and 2) limiting the risk of needle-
`stick exposures. By employing intranasal medication ad-
`ministration with selected medications, bloodborne ex-
`posures may be reduced in prehospital practice.
`
`REFERENCES
`
`1. Occupational exposure to bloodborne pathogens—OSHA. Final
`Rule. Fed Regist 1991;56:64004 –182.
`2. Howsepian AA. Post-traumatic stress disorder following needle-
`stick contaminated with suspected HIV-positive blood. Gen Hosp
`Psychiatry 1998;20:123– 4.
`3. Hershey N. Recovery for emotional distress from fear of AIDS
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