`P,inled in G'~al B,ilain.
`
`0022_39'6/92 SS .OO .. ,00
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`
`NASAL ADMINISTRATION OF NALOXONE FOR DETECTION
`OF OPIATE DEPENDENCE
`
`NORBERT LOIMER, PETER HOFMANN and HAROON RASHID C HAUDHRY·
`
`Psychiatrische Universitatsklinik Wien. Waehringer Guerlel 18-20 A- I09O Vienna . Austria and +King Edward
`Medical College, Punjab University, Lahore, Pakistan
`
`(Received \4 January 1991; accepted in final form 7 August 1991)
`
`Summary-In clinical trials, nasally applied nalo){one was used to identify opiate dependence in
`humans for the first time. Wit hdrawal distress was recorded, and pupillary response, pulse rate
`and blood pressure measured. A significant increase in withdrawal distress and pupillary dilation
`was observed after nasal administration of Img (I mg/400~) nalo){one in all subjects who also showed
`opiate-positive urine samples. In control subjecls. no reaclion to naloxone was observed. It may
`be concluded that the nasal route for naloxone administration is as effective as the parenteral rou te.
`This test is sensitive enough to identify the physically-dependent opiate user and might have a role
`in emergency medicine and withdrawal treatment.
`
`Introduction
`
`Up TILL the present time, naloxone has been used intravenously, intramuscularly or
`subcutaneously for a variety of indications, e.g. as diagnostic tool for opiate dependence
`(Wang, Wiesen, Lamid, & Roth, 1974; Peachey & Lei, 1988), for emergency use, for opiate
`detoxification treatment, for shock treatment and in the management of postoperative
`narcotic depression and narcotic overdosage (Martin, 1976). The most rapid onset of action
`is achieved by intravenous administration. Unfortunately, the oral route, which is the least
`invasive and most acceptable method for administering a drug, is ineffective because of
`rapid hepatic elimination, e.g. first pass effect (Fishman, Roffwarg, & Hellman, 1973;
`Weinstein, Pfeffer, & Schor, 1973). Conjunctival administration of naloxone was
`unsuccessful as a test of opiate dependence (Loimer, Grunberger, Linzmayer, & Schmid,
`1990).
`During a search for another approach, increased bioavailability of naloxone was identified
`a fter buccal administration (Hussain , Aungst, Kearney, & Shefter, 1987). Reviewing the
`earlier literature we have so far been unable to find any alternative route of administering
`naloxone in humans, providing the same benefits as the intravenous route e.g., rapid onset,
`high bioavailability and short duration of action. without any of the risks associated with
`vessel puncture. With the advent of AIDS, it has become very important to identify a
`noninvasive alternative method of drug administration in intravenous drug users which
`can be used routinely for diagnostic and therapeutic purposes. Based on encouraging
`findings in animal studies by Hussain. Kimura. Huang, and Kashihara (1984), we report
`a simple, but effective method of overcoming this problem.
`
`J9
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`40
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`NORBERT LOIM E R C! a l.
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`Patients and Methods
`
`Patients
`At the central hospital of Lahore district jail, 30 consecutive volunteer patients were
`investigated immediately after admission to prison hospital prior (0 routine gradual
`detoxification. The procedure had been explained to them and they had given informed
`consent. Twenty-two male prisoners satisfied DSM-IIl-R opiate-dependence criteria (age
`20-50 years; drug addiction history 3-15 years, bodyweight 48-70 kg, height 160-178 em,
`daily heroin dose 2-5 g (all inhaling). The control group consisted of 8 male prisoners (age
`22-50 years; bodyweight 50-65 kg, height 166-176 em).
`To control drug abuse, urine samples of all subjects were screened for drugs of abuse,
`by means of EMIT_dau™. All patients were free of systemic illness and medication.
`
`Measurement of naloxone effect
`The severity of withdrawal symptoms after nasal naloxene application (the naloxone nasal
`spray, Img/ 400 p.l, was freshly prepared by CURAMEDR in isotonic phosphate buffer,
`pH = 6.5) in each patient was assessed by means of a modified rating scale (Kolb &
`Himmelsbach, 1938). This clinical evaluation scale included: uncontrollable yawning,
`running nose, lacrimation, profuse sweating, shivering, abdominal cramps, piloerection,
`hand tremors, muscular twitches, restlessness, vomiting and diarrhoea. Clinical ratings were
`carried out before nasal naloxone instillation. and 1,5,10,15,30 min thereafter. Hearl
`rate and blood pressure were measured, before naloxene instillation and 10 and 30 min
`thereafter. Clinical ratings were performed by physicians blind to the patient's diagnosis.
`Pupillary response was assessed photographically by means of a Polaroid photo (Type
`Polaroid CU-5land camera, USA-specially equipped with a fixed photocell pupil distance,
`and two-fold enlargement) of the left eye before instillation of naloxone and 10 and 30
`min thereafter. The procedure was carried out under constant conditions of reduced ambient
`lightening in an illuminated room (200 lux; size: 7 x 9 m) after an adaptation period of
`10 min. Changes in pupillary diameter are best detected by comparison of the pupil/iris
`ratios (Creighton & Ghodse, 1989)_ The diameters of iris and pupil were measured and
`the ratio between them calculated.
`Statistical analysis included univariant analysis of variance, the Newman-KeuIs test and
`the Duncan test.
`
`Results
`Comparing group A (addicted patients, n = 22) and group B (control group, n = 8) with
`respect to clinical rating scale, there was no difference in rating score before naloxone was
`instilled (F = 2.196, n.s.; D = 1.48, n.s.). After I min, the difference reached a level of
`statistical significance (Fo:::: 5.021, p < 0.05; D = 2.24, P < 0.05). After 5 min: F = 19.181,
`P < 0.01; D = 4.38, p < 0.01; 10 min rating: F= 22.943, p < 0.01; D = 4.79, P < 0.01. The
`IS min rating showed: F= 27.373, P < 0.01; D = 5.23, p < 0.01. The final rating after 30
`min showed: F = 10.162, P < 0.01; D = 3.19, P < 0.01.
`As shown in Fig. I, clinical rating reveals no changes reaching the level of significance,
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`NASAL NALOXONE IN OPlATE DEPENDENCE
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`4,
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`throughout the observation period. In contrast, the changes in group A between the first
`and subsequent ratings did reach a level of significance.
`
`5
`
`0 •
`~ 3
`
`,
`" 0
`0 , ,
`• 2 ,
`~ " ,
`
`Figure I. Changes in clinical ratings in addicted (- - -) and nonaddicted subjects ( -- ).
`
`time (minutes )
`
`Heart rate and blood pressure (Table I) showed no statistically significant change either
`within groups or comparing the two groups. The measurement of iris-pupil ratio in group
`B (two-way ANOV A. Duncan test) revealed no changes reaching the level of significance
`
`Tablc: I
`Vitol signs. in response to nasal administration of 1 mg naloxone
`
`Time
`
`Heart rate
`group A
`SO
`group B
`SO
`
`Systolic blood presure
`group A
`SO
`group B
`SO
`
`Diastolic blood pressure
`group A
`SO
`group B
`SO
`
`8asdine
`
`10 min
`
`30 min
`
`82.95
`(9.01)
`80.63
`(1l.66)
`
`112.27
`(13.86)
`108.13
`(8.84)
`
`74.55
`(9.5)
`75 .63
`(11.16)
`
`83.91
`{I !.I 7)
`79.63
`(8 .8)
`
`114 .32
`(15.22)
`108 .75
`(9.91)
`
`78.41
`(13.57)
`74 .38
`(11.16)
`
`86.77
`(14.47)
`80.75
`(14.06)
`
`115.68
`(15.30)
`109.38
`(10.16)
`
`79.09
`(10.87)
`76.25
`(5.18)
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`NORBEIlT L OIMEil el al.
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`thrqughout the observation period. In group A, pupillary dilation of statistically significant
`leve'ls 10 min (Newman-Keuls - 3,63, p < 0.01) after naloxone administration. After 30
`min no statistically significant difference could be detected. Comparing the two groups
`before naloxone application, a significant difference was observed (F == 6.558, p < 0.05;
`D = 2.56, p < 0.05). In subsequent observations no statistically significant differencc~
`between the two groups were detected (Fig. 2). Urine analyses revealed recent use of opiates
`only in group A; in both grOups, no other classes of drug could be detected.
`
`2.1 ~
`I
`
`k . ,
`r--i.
`" \
`'71
`
`"
`
`" L
`'1 ---
`
`----
`
`I
`
`----
`
`1
`
`·p <: O.OS
`
`1.6
`
`,
`o
`
`------.-'.-.--..,--- _ . - , - - . - -
`5
`10
`15
`20
`25
`30
`35
`
`Figure 2. Mean iris/ pupil ratio ill addicted (- _ .) and nonaddictcd subjects (- -J.
`
`t im o ( mi nll ttls )
`
`Discussion
`According LO the clinical rating scores, naloxone was found ro be absorbed rapidly from
`the nasal cavity. The onset of withdrawal distress in opiate addicts was nearly as rapid
`as after intravenous administration of naloxone. Withdrawal distress reached a climax aftcr
`10 min and showed a significant decline thereafter (Fig. 1). A.s expected, there was a
`significant difference in diameter of the pupil between the two groups before naloxone
`was administered. This difference disappeared after naloxone-induced pupillary dilation
`in group A. Clinical evaluation of withdrawal distress symptoms was supported by parallel
`pupillary changes induced by naloxone in opiate addicts! The administration of I rng
`naloxone did not lead to any changes in vital signs, and this approach appears to offer
`a substantial safety margin. The clinical response to naloxone was paralleled by findings
`in the urine samples. Mydriasis and withdrawal distress in response to intranasal naloxone
`administration indicates chronic exposure to opiate agonisls and therefore physical
`dependence (Creighton & Ghodsc, 1989). However, naloxone has already been used
`successfully as a tool for predicting treatment outcome (Jacobsen & Kosten, 1989). As
`sniffing is commonly used for heroin self administration, it is interesting that naloxone
`
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`NASAL NALOXONE IN OPIATE DIlJ>ENDEN C E
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`43
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`has never been employed in this manner until now. These data suggest that nasal
`administration of naloxone is as effective as intravenous administration, Thus, the use of
`a nasal naloxone spray is proposed for the detection of physical dependency, not only for
`methadone programs but also for forensic problems, for the prevention of acute relapse
`avoiding long term naltrexone treatment, for noninvasive detoxification treatment
`procedures, for treating emergency cases, for neonatal intensive care and for other
`indications.
`
`Acknowledgements-We thank Polaroid, CuraMed for assislance and Prof. J. Griinberger for statistical analysis.
`Thanks 10 the IG-prison of Punjab Hafiz M. Qasim, the superintendent of Lahore prison, S. Kahn. and Prof.
`M. R. Chaudhry and Prof. P. Berner, who supported our study.
`
`References
`Creighton, to. J .• &. Ghodse, A. H. (1989). Naloxone applied 10 conjunctiva as a lest for physical opiate dependence.
`Lancet, i, 748-750.
`Fishman, J., Roffwarg, H., & Hellman, L. (1973). Disposition of naloxone 7, 8-H in normal and narcotic dependent
`men. Journal 0/ Pharmacology and Experimental Therapeutics. 187,575-580.
`Hussain, A., Kimura, R., Huang, C . H., & Kashihara, T. (1984). Nasal absorption of naloxone and buprenorphine
`in rats. International Journal 0/ Pharmaceutics, 21, 233-237.
`Hussain, M. A., Aungst, B. 1., Kearney , A., & Shefler, E. (1987). Buccal and oral bioavailabilily of naloxone
`and naltrexone in rats. Internafional Journal 0/ Pharmaceutics, 36, 127-130.
`Jacobsen, L. K., & Kosten. T. R. (1989). Naloxone challenge as a biological predictor of treatment-outcome
`in opiate addicts. American Journal oj Drug and Alcohol Abuse, 15, 355-366.
`Kolb, L., & Himmelsbach, C. K. (1938). A critical review of the withdrawal treatments with method of evalualing
`abstinence 5yndromes. American Journal 0/ Psychiatry, 94,759-799.
`Loimer, N., Gri.inberger. J., Linzmayer, L., & Schmid, R. (1990). Conjunct ival naloxone is no decision aid in
`opioid addiction. Lancet, 335, 1107-1108.
`Martin, W . R. (1976). Naloxone. Annals 0/ Infernal Medicine, 85. 765-768 .
`Peachey, J. E., & Lei, H. (198g). Assessment of opioid dependence with naloxone. British Journal oj Addiction,
`83, 193-201.
`Wang, R. I. H., Wiesen, R. L., Lamid, S., & Roth, B. l. (1974). Rating the presence of opiate dependence.
`Clinical Pharmacology and Therapeutics, 16, 653- 658.
`Weinstein, S. H .• Pfeffer, M .. & Schor. J. M. (1973). Metabolism and pharmacokinetic~ of naloxone. Advances
`in Biochemical Psychopharmacology. 8, 525-535 .
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