AM. J. DRUG ALCOHOL ABUSE, 17(4), pp. 457-468 (1991)
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Snorting Benzodiazepines Michael F. Sheehan, MD David V. Sheehan, MD Department of Psychiatry and Behavioral Medicine University of South Florida College of Medicine Tampa, Florida 336 13
Ana Torres,' MD Psychiatty Department University of Puerto Rico School of Medicine San Juan, Puerto Rico 00936
Anthony Coppola,* MD University of Medicine and Dentistry of New Jersey Camden, New Jersey 08 104
Elie Francis, MD Department of Psychiatry and Behavioral Medicine University of South Florida College of Medicine Tampa, Florida 336 13 ABSTRACT Two cases of intranasal benzodiazepine use are presented. The methods of preparation and administration of the powder and accounts of the pharmacological effects of the drugs used are described. The pattern of development and progress of the habit and its associated features are delineated. Snorting benzodiazepines appears to be more common than is currently appreciated, and the clinical complications and implications of this habit are discussed.
*On psychiatric rotation at Department of Psychiatry and Behavorial Medicine, University of South Florida College of Medicine, Tampa, Florida 33620.
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INTRODUCTION The prevalence of benzodiazepineabuse and dependence in the general population and in medical practice is low. One Swiss study found the prevalence of benzodiazepine abuse was 1 in 10,000 (0.01 %) in a catchment area of 300,000 [where an additional 88 polysubstance users were identified (0.03%)] [l]. The incidence of benzodiazepine dependence in the therapeutic setting (among those for whom it is medically prescribed) is estimated to be one case in 50 million patient months [2]. This is based on the number of published cases of dependence between 1961 and 1977 and must be taken as an underestimate. Ninety-two percent of these cases were associated with alcohol or other drug abuse [2]. In a study of 33,000 consecutive admissions to a German Psychiatric State Hospital between 1974 and 1983, benzodiazepine dependence was diagnosed in only 0.5 % [3]. In contrast, 18.5% of this hospital’s admissions in 1984 were found to be long-term benzodiazepine users (as opposed to abusers) [3]. In a prospective study of 71 outpatients with an anxiety disorder or major depression treated with benzodiazepines, no evidence of benzodiazepine abuse was found. Five patients (7%) misused their benzodiazepine, and all had a major depression [4]. Thirty-nine percent of those on benzodiazepines for chronic anxiety increased their dose over time, but the mean dose change was small-from 6 to 13.3 mglday of diazepam IS]. Another study confirmed this finding, noting that 50% of chronic benzodiazepine users increased their doses over time, but only by a very small amount [6]. Normal subjects and those with low anxiety levels had dysphoria on benzodiazepines [7]. Two studies [8, 91 found normals preferred placebo to Valium. Yet another reported less happy and less pleasant mood among normals after they were given 10 mg diazepam [lo]. In contrast to these findings, other studies suggest that those who abuse alcohol and other drugs are at significantly higher risk to abuse benzodiazepines. Ten to 17% of alcoholics were considered benzodiazepine abusers or misusers [l 1, 121. Among polysubstance abusers, benzodiazepines were the primary drug of abuse in one-third [ 131. Twenty-ninepercent of drug abusers admitted to the street purchase of diazepam in the previous month [14]. Forty percent of methadone maintenance clinic patients used diazepam [15]. The principal reasons for benzodiazepine use among drug addicts were the self-treatment of withdrawal symptoms and potentiation or amelioration of other street drug effects [ 161. The literature on benzodiazepine abuse and dependence is confined to the oral use. This paper reports a new form of benzodiazepine abuseintranasal use.
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Case 1 is of a 25-year-old single White male certified nursing assistant who was admitted to an inpatient alcohol and drug abuse treatment program. A structured clinical interview for DSM-III-R [ 171 revealed an Axis I diagnosis of bipolar disorder-recurrent, panic disorder with limited phobic avoidance and social phobia. He also met criteria for severe dependence on cannabis, sedatives, and amphetamines, and mild cocaine dependence. He used marijuana extensively as his drug of first choice. He met criteria for obsessive compulsive, self-defeating, paranoid, borderline, and antisocial personality disorders on Axis I1 [ 181. He began using marijuana at age 13, added Quaaludes at 16, and hashish at 18. At 20 he used intranasal cocaine for a short period. He resumed cocaine intranasally 3 years later. His drug habit increased significantly over the 2 years prior to admission when he abused Valium, Xanax, Percocet, cannabis, and crank (crystal methamphetamine) in various combinations. His panic disorder began at age 14 and by age 17 was complicated by limited phobic avoidance and social phobia. He was treated with alprazolam at age 22 and had a dramatic improvement in his panic symptoms. After 3 years on alprazolam (4 mg/d by mouth), he found this dose was not as effective as before in controlling his panic disorder. Intermittently, he used up to 6 mg/d when his panic disorder worsened. Several confluent factors influenced the next stage in his drug use. First, in order to blunt the side effects (nausea, abdominal cramps, tachycardia, shakes, and chills) of the “crystal methamphetamine,” he began experimenting with other drugs. He sought a feeling of calm while attempting to retain the benefits he felt from the methamphetamine. He knew from snorting cocaine, methamphetamine, and Percocet that the intranasal route offered a faster onset of drug action and a more powerful drug effect. In addition, he wished a more rapid relief of acute panic attacks than he got through oral benzodiazepine administration. During a manic episode, he conceived the idea of crushing a l-mg Xanax tablet to a fine powder with a pestle and mortar. Two 6-in. lines arranged with a razor blade on a mirror were then snorted through a straw or a rolled up dollar bill. As is common with other users of intranasal drugs, his snorting of Xanax was followed by a ritual of dipping his finger in a bowl of water and insufflating a few drops into each nostril to relieve the dryness of his nasal passages. He then tilted his head backwards, felt the water dripping down the back of his throat, and then would feel the first effects. These first symptoms- a numbness and dryness in his throat-occurred within 10 s. In 20 s he felt a “rush” in his head and a feeling of warmth. By 1 min a calm feeling came over his mind which then intensified gradually to a peak at 3 min, at which time he felt sedated and “calm through the mind,” accompanied
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by a sense of ‘‘stupor.” He did not have any mood change, feel elated or euphoric, or have any motor incoordination or other unpleasant symptoms. He would stare at his shoes and avoid talking in order to concentrate on enjoying the calm. The drug effect plateaued at 3 min for approximately 12 min; then it disappeared gradually by about the 20th minute following administration. See Fig. 1. The onset of the withdrawal would then start with tremor, shaking of his hands and arms, and later his whole body. This was accompanied by hot rushes and cold chills. He felt separate areas of his face (e.g., his ear, cheek) get hot, flushed, and red, and he sweated under his arms and in his hands and feet. These symptoms were followed by nausea, abdominal cramps, and sensations that “his bowels were loosening.” Then he had tachycardia and a feeling he was going to die. This was associated with regrets (“feeling stupid”) about his drug abuse. These withdrawal effects lasted about 10 min and were perceived as highly unpleasant and even “punitive.” He received 4 mg Xanax by prescription for treatment of his panic disorder, and on the street he got an additional 2 mg Xanax, which he ground and snorted in the evenings. He used the Xanax intranasally on its own about 55 times in the first month, 35 times in the second month, and 6 times alone in the third month. However, in this thirtfmonth he began to combine intranasal Xanax with intranasal crank in a 5050 combination in one “line” and continued this combination for the next 7 months. His usual pattern later was to smoke some marijuana to prevent the nausea, gastrointestinal cramps, shakes, and chills associated with the snorting of Xanax and/or crank. The frequency of his monthly rate of Xanax snorting is plotted in Fig. 2. In plotting his mood fluctuations, it was apparent that he had the manic phases of his bipolar illness from May to September each year. Figure 2 plots the relationship between bipolar mood swings, psychosocial events, and Xanax snorting. The frequency of his Xanax snorting increased during the manic phase of his illness and lessened significantly in the depressed phases. In both 1986 and 1987, when he was not using intranasal benzodiazepines or “crank,” he had manic phases from March through July, and depressed phases from September through January, similar in profile to those mood swings of 1988-1989 which are plotted in Fig. 2. This suggests that the biopolarity was not secondary to his intranasal drug use. There appears to be a small delay between the time the manic mood starts subsiding and the time when the frequency of X d c r a n k snorting lessens. Indeed, as the mania begins to subside, there appears to be a further increase in the frequency of Xandcrank snorting. This suggests that the increased frequency of use is a temporary attempt to protect against (or a response to) the drop from mania into depression. There does not seem to be a similar delay
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Fig. 1. Intensity of effect of intranasal benzodiazepines over time: Patient impression.
between the onset of the manic phases and the escalation of use frequency. There were some fluctuations in his Xanax abuse beyond that predicted by his mood swing cycle alone. These fluctuations in Xanax snorting appeared to be related to adverse life events (see Fig. 2 legend). In other words, the Xanax snorting frequency appeared to be driven by two factors: the mood swing cycle and the pychosocial events of the moment. Of these, the mood swing cycle seemed to be the prime driving influence (see Fig. 2). The psychosocial events appeared to be associated with fluctuations around this prime cycle. Before his intranasal Xanax use, he had used intranasal Valium (5 mg) intermittently. He switched to Xanax as it was more available on the street and by his prescription, and also cost about one-quarter the street price of the equivalent dose of Valium (e.g., $2-$3 for 1 mg Xanax, compared to $8 for 10 mg Valium). Following intranasal Valium (5 mg), he reported the initial “rush” being more pleasurable than Xanax. The calm feeling, although much less intense than with Xanax, peaked at 5 min and remained on a plateau for 25-30 min before coming
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down more gently (Fig. 1). V a h m (but not Xanax) caused some slurring of speech during the high, The withdrawal from Valium was easier, being less precipitous, half as intense, and twice the duration (20-25 vs 10 min). By comparison, the Xanax withdrawal was described as “more punitive and nasty” while the withdrawal symptoms themselves were the same for both drugs. Overall, he preferred Valium because of its milder withdrawal (1 mg Xanax is generally accepted as approximately equivalent to 10 mg Valium). Asked if he knew of others who took benzodiazepines intranasally, he reported that most of his friends had tried benzodiazepines intranasally and that he had introduced them to that route of administration. Of those he knew who were using that route of administration, he calculated that 60% were female. He did meet some prostitutes in the Miami area who had been using this route of administration independently. They reported a significant increase in the intranasal use of benzodiazepines in the Miami area in 1989. He also saw some nurses at work in both Ohio and Florida use intranasal benzodiazepines. He even gave up his nursing job at one point to “escape from their negative influence.” He reported that almost all of those who started using Xanax alone intranasally had stopped doing so because they found the withdrawal too “punitive and unpleasant.” The negative effects detracted too much from the benefit of continued use in this manner and, therefore, abuse seemed to be self-limiting in many cases. It is possible that the increasing fear of AIDS has precipitated more exploration of intranasal administration of a variety of psychoactive drugs. The patient never used intravenous drugs at any point because his brother had developed AIDS from IV cocaine and heroin use. He was asked to rate the pleasing effects of each drug when it was taken through the intranasal route on a scale of 0 to + 10 and the negative effects or complications associated with each drug on a 0 to - 10 scale. The results are described on Table 1. Case 2 is a 23-year-old single White unemployed female who was admitted as an inpatient for treatment of her drug problem. A structured clinical interview for DSM-111-R [17] revealed Axis I diagnoses of major chronic depressive episodes, mild alcohol dependence, moderate cannabis and opiate dependence, and severe cocaine and sedative dependence. She used marijuana and alcohol extensively, but cocaine was her drug of choice. On the structured clinical interview for DSM-111-R Axis I1 [I81 diagnoses, she met criteria for avoidant, dependent, obsessive-compulsive,passive-aggressiveself-defeating,paranoid, histrionic, borderline, and antisocial personality disorders. She had a prolonged history of physical and sexual abuse as a child. Her major depression was present (with significant suicidal ideation daily) since the age of 12. She made two suicide
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Table 1. Pleasing and Negative Effects of Drugs by Intranasal Route (Patient 1)
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Drug taken intranasally Xanax Valium Percocet Crank Cocaine “THC c r y s t a l ~ ” ~
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+ 5 8 5 9 10 8
aTHC crystals were described as white crystals similar to rock salt, also called “power T” on the street. He has not seen it for several years on the street, and it is likely to have been PCP.
attempts at ages 15 and 20. Intensification of those suicidal ideas precipitated her current admission. She began using marijuana at age 10, and later added Quaaludes, “speed,” alcohol, intranasal cocaine, LSD, other psychodelics, and, later still, IV heroin and cocaine. At age 17, her alcohol use intensified and she was involved in two treatment programs with remissions of 2 years and 10 months. At 21 she began to use Valium and Xanax orally. She used Xanax 4-6 mg p.o./d for the past 2 years. She increased it to 7 mg p.o./d during the 3 months prior to admission. She also began snorting heroin and cocaine. She particularly enjoyed this combination (‘‘speedball”). At about the same time, she was introduced to snorting a cocaine-benzodiazepine (either Valium or Xanax) combination by a friend. Several factors led to her continued snorting of this cocainebenzodiazepinecombination. Heroin @er preferred drug to combine with cocaine) was not often available. In addition, the benzodiazepine helped to lessen the side effects of snorting cocaine; in particular, she found Xanax to be effective at reducing the palpitations, sweats, and hot and cold flashes. Her preparations for use were less relined than those of the first patient: breaking a 1-mg Xanax tab with spoons or a pen on a table, and then using a razor and a mirror. She mixed cocaine with the benzodiazepine in a 90:10 ratio by volume. A dry mouth and throat numbness were her first symptoms, and they occurred within 20 s of snorting the Xanax-cocaine mix. She got the usual cocaine rush and high, with these effects reaching a plateau, during the 2nd to the 5th minute, with a calming feeling, a normalization of her tachycardia, and disappearance of blurring of vision. She would then slowly come down in the next 25 min. The itching, tingling, and dry mouth tapered after 30 min, and she drank alcohol or water to relieve this latter symptom. She then readministered the drug to avoid withdrawal until her supply was used up.
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The withdrawal would start at about 30 min after the last benzodiazepine administration, with nausea, vomiting, shaking, headache, and hypersensitivity to sound, which intensified to a peak at 60 min after snorting. By her account, the Valium-cocaine mixture produced the same high, but the withdrawal emerged later, at 60 min, and reached its maximum at 90 min and was rated 100 on the intensity scale. She described an ‘‘inner pain” following intranasal Valium-cocaine that was like a severe depression. She felt she “desperately needed to cry out but couldn’t.” Her daily pattern was to start the morning at 6:00 A.M. with one joint of marijuana, some alcohol, and Xanax 2 mg p.0. She would use Valium, marijuana, Percodan, and Xanax orally throughout the day. At 9:00 P.M. she started to snort cocaine and Xanax at 30-45 min intervals until about 3:OO A.M. She then slept for 3 h and repeated the cycle. Her monthly intranasal intake of cocaine and Xanax could not be calculated accurately. She estimated she took approximately 4-5 Xanax-cocaine “hits” per day. She estimated she had about 112-150 hits of cocaine-Xanax per month. There were no monthly fluctuations as with the previous patient. There was no progressive escalation of use, although there was serious psychosocial disruption. Her drug of choice was cocaine, followed by Xanax with marijuana third.
DISCUSSION With the alarming rise in AIDS among drug abusers, we may be witnessing some shift away from intravenous drug use toward experimentation with other routes of administration that can deliver fast and more intense effects. Patients reported to us that they snort almost any drug they buy on the street, including many types of opiates, stimulants, benzodiazepines, and diet pills. We even encountered one case of intranasal Thorazine abuse. The pharmacokinetic profile of the Xanax and Valium appeared to be different when taken intranasally from that reported with oral ingestion. New complications will doubtless emerge from these new routes of administration and pharmacokinetic profile. The physician, particularly in emergency ward and addiction centers, needs to be aware of these. Could intranasal intake of benzodiazepines increase the abuse and dependence liability of these drugs? It is also highly likely that, before long, some patients will try to smoke this powder with tobacco or marijuana or when they freebase cocaine or other psychostimulants, with possible alarming consequences. The sublingual route of administrationmay also increase the dependence liability among abusers, but this has not yet been seen clinically.
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In the two patients reported, and among their acquaintances, they reported minimal, and usually only short-lived, use of benzodiazepine snorting alone. Indeed, the first patient suggested that Xanax snorting alone would be self-limiting for most people and would not be favored in isolation. However, it is clear that those abusing methamphetamine and cocaine have found that benzodiazepines are effective in blunting some of the more unpleasant effects of these drugs and now frequently combine these drugs to produce a more acceptable balance of positive and negative effects. Because benzodiazepines with a shorter duration of action and shorter halflife have more immediate and precipitous withdrawal effects, it is likely that they will be less favored intranasally than those with longer half-lives and durations of action. Long-acting benzodiazepines provide more sustained effect during the full length of a psychostimulant high and will have a more gradual and gentle tapering into withdrawal that patients will experience as less punitive. One complication that could arise from the combination of cocaine or methamphetamine with a benzodiazepine is that, if the benzodiazepine used has a short duration of action, the benzodiazepine withdrawal syndrome may occur while the psychostimulant is still exerting full effects. Or the stimulant could be used again during benzodiazepine withdrawal. In either case, the theoretical risk of a seizure is significant, and the risk of a cardiac arrhythmia might be increased. In using a benzodiazepine to blunt the psychostimulant’s excessive stimulation, patients are likely to use greater doses of the psychostimulant than they might otherwise use, increasing the risk of complications. The data presented here should be interpreted cautiously. Habitual drug abusers are often unreliable in their reporting, and both of these patients met criteria for a number of personality disorders, including antisocial personality disorder. It is also difficult to differentiate the effects of one drug from another in polysubstance-dependentpatients. The first patient was more intelligent, articulate, obsessive in his attention to detail, and reliable as a historian than the second patient, whose life and pattern of drug use can only be described as wildly chaotic. However, much time and effort were spent with these two patients in an attempt to get as accurate a description as possible of their benzodiazepine snorting habits. The relationship between the bipolar mood swings, adverse psychosocial events, and frequency of Xanax snorting is strikingly illustrated in Case 1. It is probably not an accident that he invented the idea of benzodiazepine snorting in the manic phase of his mood swing cycle. The existing literature suggests that, while benzodiazepine abuse and dependence alone is rare with oral administration in those who do not abuse alcohol or other drugs, it is not unusual in the population who abuse psychoactive substances, especially alcohol, cocaine, and amphetamines,
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and who have a history of a mood disorder. Both these cases fall into the latter category. Pharmaceutical companies making benzodiazepines ought to investigate whether an ingredient, otherwise inactive or harmless, could be added to the formulation so that, when these drugs are snorted, they precipitate a sneeze or other response adversive to continued intranasal use. Whether these first reported cases of benzodiazepine snorting are a prelude to more widespread use or to an epidemic is too early to tell. The implications are serious, the pharmacokinetic profde different, the possible complicationshazardous, and the need for physicians and drug enforcement agencies to be forewarned apparent. REFERENCES [l] Ladewig, D., and Grossenbacher, H., Benzodiazepine abuse in patients of doctors in domicilary practice in the Basle area, Phamcopsychiutry 21(2):104-108 (1988). [2] Marks, J., 7he Benzodiazepines, Lancaster (England), M.T.P. Press, 1978. [3] Laux, G . , and Konig, W., Long term use of benzodiazepines in psychiatric inpatients, Actu Psychiutr. S c u d . 76(1):64-70 (1987). [4] Gamey, M. J., and Tollefson, G. D., Prevalence of misuse of prescribed benzodiazepines in patients with primary anxiety disorder or major depression, Am. J. Psychiatry 143(12):1601-1603 (1986). [5] Khan, A., Hornblow, A. R., and Walshe, J. W. B., Benzodiazepine dependence: A general practice survey, N. 2. Med. J . 93:19-21 (1981). [6] Maletzky, B. M.. and Klotter, J., Addiction to diazepam, Int. J . Addict. 11:95-115 (1976). [7] Reed, C. F . , Witt, P. N., and Peakall, D. B., Freehand copying of a geometric pattern as a test for sensory-motor disturbance, Percept. Mot. Skills 20:941-951 (1965). [8] Johanson, C. E., and Uhlenhuth, E. H., Drug preference and mood in humans: Diazepam, PSyChOphn~COlOgy71 1269-273 (1980). [9] Johanson, C. E., and Uhlenhuth, E. H., Drug self administration in humans, Not. Insr. Dncg Abuse Res. Monog. Ser. 20:68-85 (1978). [lo] Svenson, E. M., Persson, L., and Sjoberg, L., Mood effects of diazepam and caffeine, P S y c h o ~ h a ~ C O l O g62173-80 y (1980). [Ill Busco, U., Simpkins, J., Sellers, E. M., et a l . , Objective determination of benzodiazepine use and abuse in alcoholics, Br. J. Addict. 78:429-435 (1983). [I21 Ashley, M. J., LeRiche, W. H., O h , G. S., et al., “Mixed” (drug abusing) and “pure” alcoholics: A socio-medical comparison, Br. J. Addict. 73:19-34 (1978). [13] Busco, U., Sellzrs, E. M., Naranjo, C. A,, et al., Patterns of benzodiazepine abuse and dependence, Br. J. Addict. 81:87-94 (1986). [14] Woody, G. E., O’Brien, C. P., and Greenstein, R., Misuse and abuse of diazepam: An increasingly common medical problem, Inr. J. Addict. 10:843-848 (1975). [15] Woody, G . E., Mintz, G., Ottare, K., et al., Diazepam use by patients in a methadone program: How serious a problem?, J. Psychedelic Drugs 7:373-379 (1975). [16] Petera, K . M. H., Tulley, M., and Jenner. F. A,, The use of benzodiazepines among street drug addicts, Br. J. Addict. 82:511-515 (1987).
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[17] Spitzer, R. L., Williams, J. B. W., and Gibbon, M . , Structured Clinical Interview for DSM Ill-R ( h i s I), Biometrics Research Department, New York State Psychiatric Institute, New York, 1986. [18] Spitzer, R. L., Williams, J. B. W., and Gibbon, M., Srructured Clinical lntem'ewfor DSM III-R ( h i s ll), Biometrics Research Department, New York State Psychiatric Institute, New York, 1986.
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Snorting Benzodiazepines Michael F. Sheehan, MD David V. Sheehan, MD Department of Psychiatry and Behavioral Medicine University of South Florida College of Medicine Tampa, Florida 336 13
Ana Torres,' MD Psychiatty Department University of Puerto Rico School of Medicine San Juan, Puerto Rico 00936
Anthony Coppola,* MD University of Medicine and Dentistry of New Jersey Camden, New Jersey 08 104
Elie Francis, MD Department of Psychiatry and Behavioral Medicine University of South Florida College of Medicine Tampa, Florida 336 13 ABSTRACT Two cases of intranasal benzodiazepine use are presented. The methods of preparation and administration of the powder and accounts of the pharmacological effects of the drugs used are described. The pattern of development and progress of the habit and its associated features are delineated. Snorting benzodiazepines appears to be more common than is currently appreciated, and the clinical complications and implications of this habit are discussed.
*On psychiatric rotation at Department of Psychiatry and Behavorial Medicine, University of South Florida College of Medicine, Tampa, Florida 33620.
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INTRODUCTION The prevalence of benzodiazepineabuse and dependence in the general population and in medical practice is low. One Swiss study found the prevalence of benzodiazepine abuse was 1 in 10,000 (0.01 %) in a catchment area of 300,000 [where an additional 88 polysubstance users were identified (0.03%)] [l]. The incidence of benzodiazepine dependence in the therapeutic setting (among those for whom it is medically prescribed) is estimated to be one case in 50 million patient months [2]. This is based on the number of published cases of dependence between 1961 and 1977 and must be taken as an underestimate. Ninety-two percent of these cases were associated with alcohol or other drug abuse [2]. In a study of 33,000 consecutive admissions to a German Psychiatric State Hospital between 1974 and 1983, benzodiazepine dependence was diagnosed in only 0.5 % [3]. In contrast, 18.5% of this hospital’s admissions in 1984 were found to be long-term benzodiazepine users (as opposed to abusers) [3]. In a prospective study of 71 outpatients with an anxiety disorder or major depression treated with benzodiazepines, no evidence of benzodiazepine abuse was found. Five patients (7%) misused their benzodiazepine, and all had a major depression [4]. Thirty-nine percent of those on benzodiazepines for chronic anxiety increased their dose over time, but the mean dose change was small-from 6 to 13.3 mglday of diazepam IS]. Another study confirmed this finding, noting that 50% of chronic benzodiazepine users increased their doses over time, but only by a very small amount [6]. Normal subjects and those with low anxiety levels had dysphoria on benzodiazepines [7]. Two studies [8, 91 found normals preferred placebo to Valium. Yet another reported less happy and less pleasant mood among normals after they were given 10 mg diazepam [lo]. In contrast to these findings, other studies suggest that those who abuse alcohol and other drugs are at significantly higher risk to abuse benzodiazepines. Ten to 17% of alcoholics were considered benzodiazepine abusers or misusers [l 1, 121. Among polysubstance abusers, benzodiazepines were the primary drug of abuse in one-third [ 131. Twenty-ninepercent of drug abusers admitted to the street purchase of diazepam in the previous month [14]. Forty percent of methadone maintenance clinic patients used diazepam [15]. The principal reasons for benzodiazepine use among drug addicts were the self-treatment of withdrawal symptoms and potentiation or amelioration of other street drug effects [ 161. The literature on benzodiazepine abuse and dependence is confined to the oral use. This paper reports a new form of benzodiazepine abuseintranasal use.
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Case 1 is of a 25-year-old single White male certified nursing assistant who was admitted to an inpatient alcohol and drug abuse treatment program. A structured clinical interview for DSM-III-R [ 171 revealed an Axis I diagnosis of bipolar disorder-recurrent, panic disorder with limited phobic avoidance and social phobia. He also met criteria for severe dependence on cannabis, sedatives, and amphetamines, and mild cocaine dependence. He used marijuana extensively as his drug of first choice. He met criteria for obsessive compulsive, self-defeating, paranoid, borderline, and antisocial personality disorders on Axis I1 [ 181. He began using marijuana at age 13, added Quaaludes at 16, and hashish at 18. At 20 he used intranasal cocaine for a short period. He resumed cocaine intranasally 3 years later. His drug habit increased significantly over the 2 years prior to admission when he abused Valium, Xanax, Percocet, cannabis, and crank (crystal methamphetamine) in various combinations. His panic disorder began at age 14 and by age 17 was complicated by limited phobic avoidance and social phobia. He was treated with alprazolam at age 22 and had a dramatic improvement in his panic symptoms. After 3 years on alprazolam (4 mg/d by mouth), he found this dose was not as effective as before in controlling his panic disorder. Intermittently, he used up to 6 mg/d when his panic disorder worsened. Several confluent factors influenced the next stage in his drug use. First, in order to blunt the side effects (nausea, abdominal cramps, tachycardia, shakes, and chills) of the “crystal methamphetamine,” he began experimenting with other drugs. He sought a feeling of calm while attempting to retain the benefits he felt from the methamphetamine. He knew from snorting cocaine, methamphetamine, and Percocet that the intranasal route offered a faster onset of drug action and a more powerful drug effect. In addition, he wished a more rapid relief of acute panic attacks than he got through oral benzodiazepine administration. During a manic episode, he conceived the idea of crushing a l-mg Xanax tablet to a fine powder with a pestle and mortar. Two 6-in. lines arranged with a razor blade on a mirror were then snorted through a straw or a rolled up dollar bill. As is common with other users of intranasal drugs, his snorting of Xanax was followed by a ritual of dipping his finger in a bowl of water and insufflating a few drops into each nostril to relieve the dryness of his nasal passages. He then tilted his head backwards, felt the water dripping down the back of his throat, and then would feel the first effects. These first symptoms- a numbness and dryness in his throat-occurred within 10 s. In 20 s he felt a “rush” in his head and a feeling of warmth. By 1 min a calm feeling came over his mind which then intensified gradually to a peak at 3 min, at which time he felt sedated and “calm through the mind,” accompanied
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by a sense of ‘‘stupor.” He did not have any mood change, feel elated or euphoric, or have any motor incoordination or other unpleasant symptoms. He would stare at his shoes and avoid talking in order to concentrate on enjoying the calm. The drug effect plateaued at 3 min for approximately 12 min; then it disappeared gradually by about the 20th minute following administration. See Fig. 1. The onset of the withdrawal would then start with tremor, shaking of his hands and arms, and later his whole body. This was accompanied by hot rushes and cold chills. He felt separate areas of his face (e.g., his ear, cheek) get hot, flushed, and red, and he sweated under his arms and in his hands and feet. These symptoms were followed by nausea, abdominal cramps, and sensations that “his bowels were loosening.” Then he had tachycardia and a feeling he was going to die. This was associated with regrets (“feeling stupid”) about his drug abuse. These withdrawal effects lasted about 10 min and were perceived as highly unpleasant and even “punitive.” He received 4 mg Xanax by prescription for treatment of his panic disorder, and on the street he got an additional 2 mg Xanax, which he ground and snorted in the evenings. He used the Xanax intranasally on its own about 55 times in the first month, 35 times in the second month, and 6 times alone in the third month. However, in this thirtfmonth he began to combine intranasal Xanax with intranasal crank in a 5050 combination in one “line” and continued this combination for the next 7 months. His usual pattern later was to smoke some marijuana to prevent the nausea, gastrointestinal cramps, shakes, and chills associated with the snorting of Xanax and/or crank. The frequency of his monthly rate of Xanax snorting is plotted in Fig. 2. In plotting his mood fluctuations, it was apparent that he had the manic phases of his bipolar illness from May to September each year. Figure 2 plots the relationship between bipolar mood swings, psychosocial events, and Xanax snorting. The frequency of his Xanax snorting increased during the manic phase of his illness and lessened significantly in the depressed phases. In both 1986 and 1987, when he was not using intranasal benzodiazepines or “crank,” he had manic phases from March through July, and depressed phases from September through January, similar in profile to those mood swings of 1988-1989 which are plotted in Fig. 2. This suggests that the biopolarity was not secondary to his intranasal drug use. There appears to be a small delay between the time the manic mood starts subsiding and the time when the frequency of X d c r a n k snorting lessens. Indeed, as the mania begins to subside, there appears to be a further increase in the frequency of Xandcrank snorting. This suggests that the increased frequency of use is a temporary attempt to protect against (or a response to) the drop from mania into depression. There does not seem to be a similar delay
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Fig. 1. Intensity of effect of intranasal benzodiazepines over time: Patient impression.
between the onset of the manic phases and the escalation of use frequency. There were some fluctuations in his Xanax abuse beyond that predicted by his mood swing cycle alone. These fluctuations in Xanax snorting appeared to be related to adverse life events (see Fig. 2 legend). In other words, the Xanax snorting frequency appeared to be driven by two factors: the mood swing cycle and the pychosocial events of the moment. Of these, the mood swing cycle seemed to be the prime driving influence (see Fig. 2). The psychosocial events appeared to be associated with fluctuations around this prime cycle. Before his intranasal Xanax use, he had used intranasal Valium (5 mg) intermittently. He switched to Xanax as it was more available on the street and by his prescription, and also cost about one-quarter the street price of the equivalent dose of Valium (e.g., $2-$3 for 1 mg Xanax, compared to $8 for 10 mg Valium). Following intranasal Valium (5 mg), he reported the initial “rush” being more pleasurable than Xanax. The calm feeling, although much less intense than with Xanax, peaked at 5 min and remained on a plateau for 25-30 min before coming
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down more gently (Fig. 1). V a h m (but not Xanax) caused some slurring of speech during the high, The withdrawal from Valium was easier, being less precipitous, half as intense, and twice the duration (20-25 vs 10 min). By comparison, the Xanax withdrawal was described as “more punitive and nasty” while the withdrawal symptoms themselves were the same for both drugs. Overall, he preferred Valium because of its milder withdrawal (1 mg Xanax is generally accepted as approximately equivalent to 10 mg Valium). Asked if he knew of others who took benzodiazepines intranasally, he reported that most of his friends had tried benzodiazepines intranasally and that he had introduced them to that route of administration. Of those he knew who were using that route of administration, he calculated that 60% were female. He did meet some prostitutes in the Miami area who had been using this route of administration independently. They reported a significant increase in the intranasal use of benzodiazepines in the Miami area in 1989. He also saw some nurses at work in both Ohio and Florida use intranasal benzodiazepines. He even gave up his nursing job at one point to “escape from their negative influence.” He reported that almost all of those who started using Xanax alone intranasally had stopped doing so because they found the withdrawal too “punitive and unpleasant.” The negative effects detracted too much from the benefit of continued use in this manner and, therefore, abuse seemed to be self-limiting in many cases. It is possible that the increasing fear of AIDS has precipitated more exploration of intranasal administration of a variety of psychoactive drugs. The patient never used intravenous drugs at any point because his brother had developed AIDS from IV cocaine and heroin use. He was asked to rate the pleasing effects of each drug when it was taken through the intranasal route on a scale of 0 to + 10 and the negative effects or complications associated with each drug on a 0 to - 10 scale. The results are described on Table 1. Case 2 is a 23-year-old single White unemployed female who was admitted as an inpatient for treatment of her drug problem. A structured clinical interview for DSM-111-R [17] revealed Axis I diagnoses of major chronic depressive episodes, mild alcohol dependence, moderate cannabis and opiate dependence, and severe cocaine and sedative dependence. She used marijuana and alcohol extensively, but cocaine was her drug of choice. On the structured clinical interview for DSM-111-R Axis I1 [I81 diagnoses, she met criteria for avoidant, dependent, obsessive-compulsive,passive-aggressiveself-defeating,paranoid, histrionic, borderline, and antisocial personality disorders. She had a prolonged history of physical and sexual abuse as a child. Her major depression was present (with significant suicidal ideation daily) since the age of 12. She made two suicide
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Table 1. Pleasing and Negative Effects of Drugs by Intranasal Route (Patient 1)
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Drug taken intranasally Xanax Valium Percocet Crank Cocaine “THC c r y s t a l ~ ” ~
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+ 5 8 5 9 10 8
aTHC crystals were described as white crystals similar to rock salt, also called “power T” on the street. He has not seen it for several years on the street, and it is likely to have been PCP.
attempts at ages 15 and 20. Intensification of those suicidal ideas precipitated her current admission. She began using marijuana at age 10, and later added Quaaludes, “speed,” alcohol, intranasal cocaine, LSD, other psychodelics, and, later still, IV heroin and cocaine. At age 17, her alcohol use intensified and she was involved in two treatment programs with remissions of 2 years and 10 months. At 21 she began to use Valium and Xanax orally. She used Xanax 4-6 mg p.o./d for the past 2 years. She increased it to 7 mg p.o./d during the 3 months prior to admission. She also began snorting heroin and cocaine. She particularly enjoyed this combination (‘‘speedball”). At about the same time, she was introduced to snorting a cocaine-benzodiazepine (either Valium or Xanax) combination by a friend. Several factors led to her continued snorting of this cocainebenzodiazepinecombination. Heroin @er preferred drug to combine with cocaine) was not often available. In addition, the benzodiazepine helped to lessen the side effects of snorting cocaine; in particular, she found Xanax to be effective at reducing the palpitations, sweats, and hot and cold flashes. Her preparations for use were less relined than those of the first patient: breaking a 1-mg Xanax tab with spoons or a pen on a table, and then using a razor and a mirror. She mixed cocaine with the benzodiazepine in a 90:10 ratio by volume. A dry mouth and throat numbness were her first symptoms, and they occurred within 20 s of snorting the Xanax-cocaine mix. She got the usual cocaine rush and high, with these effects reaching a plateau, during the 2nd to the 5th minute, with a calming feeling, a normalization of her tachycardia, and disappearance of blurring of vision. She would then slowly come down in the next 25 min. The itching, tingling, and dry mouth tapered after 30 min, and she drank alcohol or water to relieve this latter symptom. She then readministered the drug to avoid withdrawal until her supply was used up.
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The withdrawal would start at about 30 min after the last benzodiazepine administration, with nausea, vomiting, shaking, headache, and hypersensitivity to sound, which intensified to a peak at 60 min after snorting. By her account, the Valium-cocaine mixture produced the same high, but the withdrawal emerged later, at 60 min, and reached its maximum at 90 min and was rated 100 on the intensity scale. She described an ‘‘inner pain” following intranasal Valium-cocaine that was like a severe depression. She felt she “desperately needed to cry out but couldn’t.” Her daily pattern was to start the morning at 6:00 A.M. with one joint of marijuana, some alcohol, and Xanax 2 mg p.0. She would use Valium, marijuana, Percodan, and Xanax orally throughout the day. At 9:00 P.M. she started to snort cocaine and Xanax at 30-45 min intervals until about 3:OO A.M. She then slept for 3 h and repeated the cycle. Her monthly intranasal intake of cocaine and Xanax could not be calculated accurately. She estimated she took approximately 4-5 Xanax-cocaine “hits” per day. She estimated she had about 112-150 hits of cocaine-Xanax per month. There were no monthly fluctuations as with the previous patient. There was no progressive escalation of use, although there was serious psychosocial disruption. Her drug of choice was cocaine, followed by Xanax with marijuana third.
DISCUSSION With the alarming rise in AIDS among drug abusers, we may be witnessing some shift away from intravenous drug use toward experimentation with other routes of administration that can deliver fast and more intense effects. Patients reported to us that they snort almost any drug they buy on the street, including many types of opiates, stimulants, benzodiazepines, and diet pills. We even encountered one case of intranasal Thorazine abuse. The pharmacokinetic profile of the Xanax and Valium appeared to be different when taken intranasally from that reported with oral ingestion. New complications will doubtless emerge from these new routes of administration and pharmacokinetic profile. The physician, particularly in emergency ward and addiction centers, needs to be aware of these. Could intranasal intake of benzodiazepines increase the abuse and dependence liability of these drugs? It is also highly likely that, before long, some patients will try to smoke this powder with tobacco or marijuana or when they freebase cocaine or other psychostimulants, with possible alarming consequences. The sublingual route of administrationmay also increase the dependence liability among abusers, but this has not yet been seen clinically.
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In the two patients reported, and among their acquaintances, they reported minimal, and usually only short-lived, use of benzodiazepine snorting alone. Indeed, the first patient suggested that Xanax snorting alone would be self-limiting for most people and would not be favored in isolation. However, it is clear that those abusing methamphetamine and cocaine have found that benzodiazepines are effective in blunting some of the more unpleasant effects of these drugs and now frequently combine these drugs to produce a more acceptable balance of positive and negative effects. Because benzodiazepines with a shorter duration of action and shorter halflife have more immediate and precipitous withdrawal effects, it is likely that they will be less favored intranasally than those with longer half-lives and durations of action. Long-acting benzodiazepines provide more sustained effect during the full length of a psychostimulant high and will have a more gradual and gentle tapering into withdrawal that patients will experience as less punitive. One complication that could arise from the combination of cocaine or methamphetamine with a benzodiazepine is that, if the benzodiazepine used has a short duration of action, the benzodiazepine withdrawal syndrome may occur while the psychostimulant is still exerting full effects. Or the stimulant could be used again during benzodiazepine withdrawal. In either case, the theoretical risk of a seizure is significant, and the risk of a cardiac arrhythmia might be increased. In using a benzodiazepine to blunt the psychostimulant’s excessive stimulation, patients are likely to use greater doses of the psychostimulant than they might otherwise use, increasing the risk of complications. The data presented here should be interpreted cautiously. Habitual drug abusers are often unreliable in their reporting, and both of these patients met criteria for a number of personality disorders, including antisocial personality disorder. It is also difficult to differentiate the effects of one drug from another in polysubstance-dependentpatients. The first patient was more intelligent, articulate, obsessive in his attention to detail, and reliable as a historian than the second patient, whose life and pattern of drug use can only be described as wildly chaotic. However, much time and effort were spent with these two patients in an attempt to get as accurate a description as possible of their benzodiazepine snorting habits. The relationship between the bipolar mood swings, adverse psychosocial events, and frequency of Xanax snorting is strikingly illustrated in Case 1. It is probably not an accident that he invented the idea of benzodiazepine snorting in the manic phase of his mood swing cycle. The existing literature suggests that, while benzodiazepine abuse and dependence alone is rare with oral administration in those who do not abuse alcohol or other drugs, it is not unusual in the population who abuse psychoactive substances, especially alcohol, cocaine, and amphetamines,
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and who have a history of a mood disorder. Both these cases fall into the latter category. Pharmaceutical companies making benzodiazepines ought to investigate whether an ingredient, otherwise inactive or harmless, could be added to the formulation so that, when these drugs are snorted, they precipitate a sneeze or other response adversive to continued intranasal use. Whether these first reported cases of benzodiazepine snorting are a prelude to more widespread use or to an epidemic is too early to tell. The implications are serious, the pharmacokinetic profde different, the possible complicationshazardous, and the need for physicians and drug enforcement agencies to be forewarned apparent. REFERENCES [l] Ladewig, D., and Grossenbacher, H., Benzodiazepine abuse in patients of doctors in domicilary practice in the Basle area, Phamcopsychiutry 21(2):104-108 (1988). [2] Marks, J., 7he Benzodiazepines, Lancaster (England), M.T.P. Press, 1978. [3] Laux, G . , and Konig, W., Long term use of benzodiazepines in psychiatric inpatients, Actu Psychiutr. S c u d . 76(1):64-70 (1987). [4] Gamey, M. J., and Tollefson, G. D., Prevalence of misuse of prescribed benzodiazepines in patients with primary anxiety disorder or major depression, Am. J. Psychiatry 143(12):1601-1603 (1986). [5] Khan, A., Hornblow, A. R., and Walshe, J. W. B., Benzodiazepine dependence: A general practice survey, N. 2. Med. J . 93:19-21 (1981). [6] Maletzky, B. M.. and Klotter, J., Addiction to diazepam, Int. J . Addict. 11:95-115 (1976). [7] Reed, C. F . , Witt, P. N., and Peakall, D. B., Freehand copying of a geometric pattern as a test for sensory-motor disturbance, Percept. Mot. Skills 20:941-951 (1965). [8] Johanson, C. E., and Uhlenhuth, E. H., Drug preference and mood in humans: Diazepam, PSyChOphn~COlOgy71 1269-273 (1980). [9] Johanson, C. E., and Uhlenhuth, E. H., Drug self administration in humans, Not. Insr. Dncg Abuse Res. Monog. Ser. 20:68-85 (1978). [lo] Svenson, E. M., Persson, L., and Sjoberg, L., Mood effects of diazepam and caffeine, P S y c h o ~ h a ~ C O l O g62173-80 y (1980). [Ill Busco, U., Simpkins, J., Sellers, E. M., et a l . , Objective determination of benzodiazepine use and abuse in alcoholics, Br. J. Addict. 78:429-435 (1983). [I21 Ashley, M. J., LeRiche, W. H., O h , G. S., et al., “Mixed” (drug abusing) and “pure” alcoholics: A socio-medical comparison, Br. J. Addict. 73:19-34 (1978). [13] Busco, U., Sellzrs, E. M., Naranjo, C. A,, et al., Patterns of benzodiazepine abuse and dependence, Br. J. Addict. 81:87-94 (1986). [14] Woody, G. E., O’Brien, C. P., and Greenstein, R., Misuse and abuse of diazepam: An increasingly common medical problem, Inr. J. Addict. 10:843-848 (1975). [15] Woody, G . E., Mintz, G., Ottare, K., et al., Diazepam use by patients in a methadone program: How serious a problem?, J. Psychedelic Drugs 7:373-379 (1975). [16] Petera, K . M. H., Tulley, M., and Jenner. F. A,, The use of benzodiazepines among street drug addicts, Br. J. Addict. 82:511-515 (1987).
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[17] Spitzer, R. L., Williams, J. B. W., and Gibbon, M . , Structured Clinical Interview for DSM Ill-R ( h i s I), Biometrics Research Department, New York State Psychiatric Institute, New York, 1986. [18] Spitzer, R. L., Williams, J. B. W., and Gibbon, M., Srructured Clinical lntem'ewfor DSM III-R ( h i s ll), Biometrics Research Department, New York State Psychiatric Institute, New York, 1986.
