- Email: [email protected]
Benzodiazepine dependence potential: Current studies and trends
JournalojSubstanceAbu
0740-5472/84 $3.00 + .OO
Treatment, Vol. 1, pp. 163-167.1984
Copyright o 1985 Pergatnon Press Ltd
Printed in the USA. All tights reserved.
ORIGINAL
CONTRIBUTION
Benzodiazepine Dependence Potential: Current Studies and Trends DAVID E. SMITH, MD Haight Ashbury Free Medical Clinic and University of California, San Francisco
Abstract- The appearance of newer, short-acting benzodiazepines has produced misconceptions regarding the potential addictive quality of these drugs. Following a review of the Smith ,and Wesson (1983) barbiturate withdrawal technique, application of this procedure to the withdrawal of individual addicted to short-acting benzodiazepines ir reviewed. Attention I&also given to the emergence of ‘look-alike” drugs, and the resultant implications for substance abuse treatment personnel. Key words-
Benzodiazepine,
drug dependence,
detoxification,
addiction
have been identified and followed. Our findings indicate that dependence within the therapeutic range occurs in individuals usually with a past or family history of alcoholism, although they may not currently be using alcohol or any other sedativehypnotic. The classic sedative-hypnotic withdrawal sequelae can occur upon abrupt cessation of benzodiazepine usage. A phenobarbital substitution/withdrawal technique has been developed for use in the detoxification of patients with a general sedativehypnotic dependence, as well as those with a specific benzodiazepine dependence (Smith & Wesson, 1983). It is an effective technique that can block the major sedative-hypnotic withdrawal sequelae of seizure and psychosis. The amount of phenobarbital required for substitution during withdrawal was recently reported (Smith & Wesson, 1983) (see Table 1). The most important factor to be emphasized from this work and the experience of others in this field is that there appears to be no qualitative assessment in the dependence-producing potential of any of the benzodiazepines. However, an increasing number of people are being seen who are dependent on the newer benzodiazepines, particularly those with a shorter half-life. This trend is occurring in individuals who were taking an older benzodiazepine, such as diazepam, and became aware of the dependence potential of that drug. These patients switched to Xanax@, Serax@, or HalciorP, believing that these newer benzodiazepines were not addicting. Actually the dependence characteristics are essentially the same for all
20 YEARS the benzodiazepines have been widely used for a variety of important medical indications and have proven to have great therapeutic efficacy (Smith & Wesson, 1983). Since the work of Hollister in 1963, it has been known that the benzodiazepines can produce physical dependence under certain circumstances (Hollister, 1983). During the intervening period, the characteristics of this physical dependence have been studied in greater depth (Marks & Smith, in press). The involvement of the HaightAshbury Free Clinic in the study of sedative-hypnotic dependence began in 1967; more than 2,000 cases have been treated, primarily at the clinic’s outpatient drug detoxification program and in the inpatient chemical dependency program where clinic staff consulted on patients hospitalized for drug dependence (Smith, 1976; Smith & Wesson, 1983; Wesson & Smith, 1970). When the benzodiazepines have been involved in sedative-hypnotic dependence, it has been at doses several times the accepted level or in combination with other psychoactive drugs, including alcohol. Efforts recently have concentrated on studying the characteristics of benzodiazepine dependence occurring when these drugs are taken at the therapeutic level. Although this is a rare phenomenon, 70 cases FOR
Requests for reprints should be sent to David E. Smith, Haight Ashbury Free Medical Clinic, 409 Clayton Street, San Francisco, CA 94117.
163
_
D. Smith
164
TABLE 1 Phenobarbital Conversion for Withdrawal of Bentodiazeplnes and Other Sedative-Hypnotics
Generic Name Benzodiazepines Alprazolam (Xanax) Chlordiazepoxide (Librium) Clonazepam (Clonopin) Clorazepate (Tranxene) Diazepam (Valium) Flurazepam (Daimane) Halazepam (Paxipam) Lorazepam (Ativan) Oxazepam (Serax) Prazepam (Centrax) Temazepam (Restoril) Barbiturates Amobarbital (Tuinal) Butabarbital Butalbital Pentobarbital Secobarbital (Seconal) Glycerols Meprobamate (Miltown) Piperidinediones Glutethimide (Doriden) Quinazolines Methaqualone (Quaalude)
Dose (mq)
Phenobarbital Withdrawal Conversion (ms)
2; 2 15 10 15 40 1 10 10 15 100 100 50 100 100
30 30
400
30
250
30
300
30
: 30
these agents from a qualitative point of view, and the same phenobarbital substitution/withdrawal technique is effective for all agents in this class. It is important to emphasize the danger of this trend of individuals switching to the newer benzodiazepines under the mistaken belief that they are nonaddicting. Also dangerous is starting patients on these newer agents with the clear message to the patient that they are non-addicting. This problem was recently studied from a clinical point of view in one patient. Case History An individual, prominent in a religious order that is quite conservative about the ingestion of any psychoactive substance, started taking Halcion bought over-the-counter (OTC) in another country because he found that it helped him sleep. Fifteen years prior to entering the religious order, while he was in the military, he had an alcohol abuse problem. Both his father and his grandfather had died of consequences of alcoholism. As a result, he was very concerned about developing a dependence problem. Because of his strict moral position, he wanted to abstain from any mind-altering drugs. Because of its OTC availability, he thought Halcion would deal safely with his particular problem- insomnia associ-
ated with travel. When he returned to the United States, he consulted with a licensed general practitioner in the San Francisco bay area about Halcion and went into detail regarding his views towards medication, stressing his wish to avoid any substance that could produce addiction. The physician indicated that he was aware that the older benzodiazepines, such as diazepam (Valium@), were addicting, but thought this new benzodiazepine was non-addicting. The individual took Halcion within therapeutic dosage and achieved relief for insomnia, but found that he was developing daytime anxiety. Initially he attributed it to situational anxiety and began to selfadminister Halcion as an anti-anxiety medication during the day. When he attempted to stop, the anxiety and insomnia escalated. He still perceived this as situational distress, not drug-dependence withdrawal. As he noticed his dosage increasing, he attempted to stop taking the medication completely. When he came to our clinic, his dosage of Halcion was 1.5 mg per day taken in divided doses. He presented symptoms of anxiety and insomnia plus some depersonalization and visual alteration that were certainly part of the sedative-hypnotic withdrawal sequelae. Patient Withdrawal and Follow-up The above patient was detoxified using the Smith and Wesson (1983) phenobarbital substitution/withdrawal technique. Prolonged follow-up showed that although he does have some situational stress, there is no major underlying psychopathology. A conference with the prescribing physician was held to determine why the patient had been on Halcion, particularly in light of his many questions and concerns regarding dependence. The physician’s position was “It was my understanding that only Valium is addicting; none of the newer benzodiazepines are addicting.” When questioned regarding where he obtained this information or how he had arrived at this opinion, he indicated it was something he had heard- namely, that the new, short half-life benzodiazepines were nonaddicting. Inaccurate information, not scientifically substantiated or supported by the FDA, given to physicians or others working in the chemical dependency field is an added health hazard and contributes to the problem of drug dependence. Although the benzodiazepine hypnotics are the drugs of choice for insomnia, Kales’ sleep lab research (in press) emphasizes that different compounds in the benzodiazepine drug group have considerable differences in their pharmacokinetic properties, many of which directly affect the drug’s clinical profiles, as is the case with the benzodiazepine anxiolytics (Breimer & Jochemsen, 1981; Greenblatt, Divoll, Abernethy, & Shader, 1982). Some of the most important phar-
Benzodiazepine Dependence
Withdrawal
macokinetic properties of the benzodiazepine hypnotics involve their rates of absorption and elimination half-lives. Kales’ sleep lab research suggests that short half-life benzodiazepines may in fact have higher abuse potential (as demonstrated by the above case), although many physicians are prescribing these compounds with the idea that short half-life drugs have lower abuse potential. Benzodiazepine hyp notics with rapid elimination rates may produce early morning insomnia (Kales, Caldwell, Soldatos, Bixler, & Kales, 1983) and daytime anxiety (Morgan & Oswald, 1982). The syndrome of rebound anxiety : and insomnia, consisting of a worsening of sleep and increasing daytime anxiety, appears after one or two weeks of nightly administration when tolerance of the benzodiazepine begins to develop (Kales et al., 1983; Kales, Scharf & Kales, 1978; Kales, Soldatos, & Kales, 1979). Withdrawal from benzodiazepines with short to intermediate half-lives may produce both rei bound anxiety and insomnia (Kales et al., 1979). As with the above case, the individual who takes a shorter half-life benzodiazepine hypnotic to induce sleep may begin administering the drug during the daytime to block rebound anxiety. As a consequence of this continuous administration, the individual may develop dependence on the benzodiazepine and experience tolerance, requiring greater amounts of the drug to achieve the desired effect. Cessation of the benzodiazepine following such long-term administration and dosage escalation can then produce serious withdrawal sequelae. In light of the current perception by many physicians that the newer benzodiazepines with shorter half-lives have less toxic side effects, work such as Kales’ sleep lab research and our own clinical experience with dependence on the newer benzodiazepines must be taken into consideration. BENZODIAZEPINE WITHDRAWAL TECHNIQUES The development of this phenobarbital substitution technique evolved from detoxifying individuals with virtually every type of sedative-hypnotic dependence with short-acting barbiturates. Several different techniques are available. One is simply graded reduction of benzodiazepine dosage. For example, if one is dependent on diazepam, then diazepam is gradually reduced over a specific time period, usually 21 days. However, the phenobarbital substitution/withdrawal technique is preferred since many of the patients seen in treatment have multiple sedative-hypnotic dependencies. This has also proved preferable because most cases are treated on an outpatient basis and phenobarbital has a minimal street reputation, i.e., no one sells phenobarbital. We do not want to detoxify a person on either the same drug that they have
165
abused, or any drug that would be appealing in the drug culture, a drug that would be considered high in abuse potential. Phenobarbital has proven to be therapeutically effective, not well known on the street and rarely encountered by a large-scale drug dependence program such as ours. Finally, it has been found that the phenobarbital substitution technique also works more effectively on an inpatient basis and is generally used by other inpatient chemical dependency treatment programs throughout the United States. In the Haight-Ashbury studies, we have interpreted the effects of some of the newer benzodiazepines which are suppressed by phenobarbital. For example, in the Halcion case described above, the individual followed the classic pattern: Cessation of dosage resulted in anxiety, insomnia and some depersonalization and visual alterations. Administration of phenobarbital suppressed the symptoms. The patient was detoxified and reevaluated after detoxification and none of the withdrawal symptoms was present. Kales (in press) has suggested that the symptom may in fact be intoxication or adverse effects of Halcion. Our clinical experience would cause us to question this hypothesis since if these are indeed intoxication effects, why can they be suppressed with phenobarbital? Kales feels that this could be the result of some special action of phenobarbital. However, when patients on these newer compounds experience anxiety, insomnia and the like, it is recommended that the symptoms be interpreted as withdrawal effects, and that the rapid suppression of these effects by phenobarbital (as a clinical test for intoxication) be utilized. If a withdrawal reaction can be suppressed by administering phenobarbital and an intoxicant effect can also be supressed in the same manner, there must be another mechanism of action in the brain with which we are not familiar. Additional research is needed to understand the interaction of the benzodiazepines and other sedative-hypnotics in the brain. TYPES OF BENZODIAZEPINE WITHDRAWAL AND THE CONTROLLED SUBSTANCE ACT Two types of benzodiazepine or sedative-hypnotic withdrawal syndromes have been identified; with the first type the peak liability depends on the metabolic characteristics of the benzodiazepine. For example, abrupt cessation from diazepam dependence can produce a peak liability for withdrawal seizure with psychosis on the fifth to eighth day. If it is a shortacting benzodiazepine (like Ativan@), the curve shifts to the left, and the peak liability for withdrawal seizure is the third or second day. If it is a mixture, for instance, of diazepam and alcohol, this delays the
D. Smith
166
peak liability for withdrawal and the curve shifts to the right. Clinical studies have indicated that the peak liability for withdrawal seizure may be as late as the tenth day (see Figure 1). These facts are extremely important to know if one is treating a drug dependency problem. All benzodiazepines that are marketed in the United States fit qualitatively into this curve. The second type of curve is a more delayed withdrawal, characterized by low intensity symptoms of anxiety and insomnia, different from symptom reemergence associated with psychopathology predating the long-term benzodiazepine administration. Propranolol can be administered symptomatically to deal with the episodic anxiety of delayed withdrawal associated with delayed withdrawal. The symptoms of delayed withdrawal can be suppressed by readministering the benzodiazepine, but the patient is at risk to become re-addicted. Prolonged use of the benzodiazepines to deal with delayed withdrawal is not recommended. L-Tryptophan can deal with the sleep dysfunction. A very small number of patients will fit into the first curve after taking benzodiazepines within therapeutic range. And, as indicated, the characteristics of benzodiazepine dependence are similar to
FIGURE
1. Comparison
those of other sedative-hypnotics. Unfortunately, it appears that current information given to physicians is not accurate. There is no evidence of a difference in abuse potential among benzodiazepines, and selective scheduling could transmit an inaccurate and false message to both physician and patient. In the drug dependence field, this would be equivalent to saying that heroin is addicting, but methadone is not, as both drugs are in the opiate category with heroin being short-acting and methadone being long-acting. Since all benzodiazepines interact with the benzodiazepine receptor in the brain, it can be predicted reliably that all benzodiazepine agents used worldwide have qualitatively similar dependence-producing characteristics. Therefore, the rescheduling of the drug by class, relative to abuse potential, is more valid than selective scheduling, both clinically and scientifically. Furthermore, selective scheduling could constitute a health hazard. It could be predicted that when and if other benzodiazepines become widely available in the United States, the same characteristics of dependence will appear. The variation in pharmacological properties of the benzodiazepines are most important relative to the therapeutic applications rather than the dependency-producing potential.
of relative intensity and time course of benzodiarepine
withdrawal
syndromes.
Benzodiazepine
Dependence
167
Withdrawal
THE PROBLEM OF LOOK-ALIKE
DRUGS
The Haight-Ashbury Free Clinic’s research on street drug use also includes a Look-Alike Drug Research and Training Project that has studied a wide variety of look-alike drugs in the stimulant, sedative/ hypnotic and opiate areas. “Look-alike? are pills that resemble a controlled substance in appearance, but in fact, contain non-controlled substances. The Look-Alike Project has also studied drugs of deception-drugs which look like one controlled substance, but in fact contain another controlled substance. Research data on street quaaludes show that about 35% contain diazepam instead. In interviews with users of these drugs of deception, it is quite clear that the drug-seeking behavior is directed at methaqualone, a short-acting potent sedative rather than diazepam, a longer-acting, less potent agent. For example, if users have had experience with what they call a pharmaceutical quaalude containing methaqualone versus a street quaalude containing diazepam, they will clearly indicate that the pharmaceutical quaalude is far superior. Toxicological verification will also distinguish between methaqualone and diazepam. It is our belief that in the street drug scene, this is methaqualone drug-seeking behavior (Smith, in press) Such informatioi is very important in clinical treatment. For example, in one of the cases studied, an individual was taking 5-10 street quaaludes a day containing approximately 25 mg of diazepam per each street quaalude. She stopped abruptly, tried to titrate her withdrawal with alcohol and had delayed withdrawal seizures on about the tenth day. The toxicological verification indicated that she had in fact self-administered very high doses of diazepam. According to the drug treatment literature, methaqualone withdrawal seizure peak occurs about the second day. Therefore it is very important that education regarding look-alike drugs or drugs of deception be given to physicians as well as to the general public. The Little Black Pill Book (Smith, Seymour, & Morgan, 1983) includes a comprehensive section of these non-prescription substances. Finally, our studies have also included the street drug scene and its interface with benzodiazepine dependence in the area of methadone maintenance. Findings show that individuals on methadone maintenance who self-administer a benzodiazepine usually do so not for euphoria, but to suppress anxiety. Although these individuals have a problem with opiate addiction, they also have a very high degree of underlying psychological distress, and will tend to titrate their dosages of methadone with a benzodiazepine in order to suppress this underlying distress. The most widely used drug in this setting is diaze-
pam, but other benzodiazepines will also be used for the same purpose. In the street drug scene, the benzodiazepines play a secondary role. They are used as self-medication to “come down” from something else, e.g., a stimulant run. Often they are look-alike drugs or drugs of deception, but they do not play a primary role in drug-seeking behavior. The dependence that may occur from therapeutic administration of a benzodiazepine must always be viewed from the perspective of the majority of physicians who safely and effectively prescribe these medications. However, physicians have a relatively limited understanding of drug dependence and may fall into the trap of believing that one benzodiazepine is addicting while another is not. As a consequence, it is our belief that the class scheduling of the benzodiazepines is scientifically and clinically justified and will, hopefully, decrease the health hazard of benzodiazepine dependency. REFERENCES Breimer, D.D., & Jochemsen, R. (1981). Phannacokinetics of hypnotic drugs. In D. Wheatley (Ed.), Psychopharmacology of sleep. New York: Raven Press. Greenblatt, D.J., Divoll, M., Abernethy, D.R., & Shader, RI. (1982).Benzodiazepine hypnotics: Kinetic and therapeutic options. Sleep, 5, Si8427. Hollister, L.E. (1983). The pre-benzodiazepine era. Journal of Psychoactive Drugs, 15, 9-17. Kales, A., Caldwell, A.B., Soldatos, C.R., Bixler, E.O., & Kales, J.D. (1983). Biopsychobehavioral correlates of insomnia. II. Pattern specificity and consistency with the Minnesota Multiphasic Personality Inventory. Psychosomatic Medicine, 45, 341-356. Kales, A., Scharf, M.B., & Kales, J.D. (1978). Rebound insomnia: A new clinical syndrome. Science, 201, 194-200. Kales, A., Scharf, M.B., Kales, J.D., & Soldatos, C.R. (1979). Rebound insomnia: A potential hazard following withdrawal of certain benxodiazepines. Journal of the American Medical Association, 241, 1692-1695. Kales, A., Soldatos, C.R., & Kales, J.D. (1979). Sleep disorders: Evaluation and management in the office setting. In S. Arieti, & H.K.H. Brodie (Eds.), American Handbook on Psychiatry, Vol. 7, 2nd ad. New York: Basic Books. Kales, A., Soldatos, C.R., & Vela-Bueno, A. (in press). CIinical comparison of benzodiaxepine hypnotics with short and long elimination half-Iives. Marks, J., & Smith, D.E. (in press). Benxodiaxepine abuse and dependence: An international perspective. In The benzodiazepines: Current use and medical practice, London: MTP Press. Morgan, K., & Oswald, I. (1982). Anxiety caused by a short-life hypnotic. British Medical Journal, 2.84, 942. Smith, D.E., & Wesson, D.R. (eds.) (1983). The benzodiazepines: Two decades of research and clinical experience. Journal of Psychoactive Drugs, 15, 00-00. Smith, D.E., & Wesson, D.R. (1983). Benzodiazepine dependency syndromes. Journal of Psychoactive Drugs, 15,85-96. Smith, D.E., Seymour, R.B., & Morgan, J.P. (1983). The little black pi/t book. New York: Bantam Books. Smith, D.E. (in press) Look-alike drugs and drugs of deception: Epidemiological, toxicological and clinical considerations.
0740-5472/84 $3.00 + .OO
Treatment, Vol. 1, pp. 163-167.1984
Copyright o 1985 Pergatnon Press Ltd
Printed in the USA. All tights reserved.
ORIGINAL
CONTRIBUTION
Benzodiazepine Dependence Potential: Current Studies and Trends DAVID E. SMITH, MD Haight Ashbury Free Medical Clinic and University of California, San Francisco
Abstract- The appearance of newer, short-acting benzodiazepines has produced misconceptions regarding the potential addictive quality of these drugs. Following a review of the Smith ,and Wesson (1983) barbiturate withdrawal technique, application of this procedure to the withdrawal of individual addicted to short-acting benzodiazepines ir reviewed. Attention I&also given to the emergence of ‘look-alike” drugs, and the resultant implications for substance abuse treatment personnel. Key words-
Benzodiazepine,
drug dependence,
detoxification,
addiction
have been identified and followed. Our findings indicate that dependence within the therapeutic range occurs in individuals usually with a past or family history of alcoholism, although they may not currently be using alcohol or any other sedativehypnotic. The classic sedative-hypnotic withdrawal sequelae can occur upon abrupt cessation of benzodiazepine usage. A phenobarbital substitution/withdrawal technique has been developed for use in the detoxification of patients with a general sedativehypnotic dependence, as well as those with a specific benzodiazepine dependence (Smith & Wesson, 1983). It is an effective technique that can block the major sedative-hypnotic withdrawal sequelae of seizure and psychosis. The amount of phenobarbital required for substitution during withdrawal was recently reported (Smith & Wesson, 1983) (see Table 1). The most important factor to be emphasized from this work and the experience of others in this field is that there appears to be no qualitative assessment in the dependence-producing potential of any of the benzodiazepines. However, an increasing number of people are being seen who are dependent on the newer benzodiazepines, particularly those with a shorter half-life. This trend is occurring in individuals who were taking an older benzodiazepine, such as diazepam, and became aware of the dependence potential of that drug. These patients switched to Xanax@, Serax@, or HalciorP, believing that these newer benzodiazepines were not addicting. Actually the dependence characteristics are essentially the same for all
20 YEARS the benzodiazepines have been widely used for a variety of important medical indications and have proven to have great therapeutic efficacy (Smith & Wesson, 1983). Since the work of Hollister in 1963, it has been known that the benzodiazepines can produce physical dependence under certain circumstances (Hollister, 1983). During the intervening period, the characteristics of this physical dependence have been studied in greater depth (Marks & Smith, in press). The involvement of the HaightAshbury Free Clinic in the study of sedative-hypnotic dependence began in 1967; more than 2,000 cases have been treated, primarily at the clinic’s outpatient drug detoxification program and in the inpatient chemical dependency program where clinic staff consulted on patients hospitalized for drug dependence (Smith, 1976; Smith & Wesson, 1983; Wesson & Smith, 1970). When the benzodiazepines have been involved in sedative-hypnotic dependence, it has been at doses several times the accepted level or in combination with other psychoactive drugs, including alcohol. Efforts recently have concentrated on studying the characteristics of benzodiazepine dependence occurring when these drugs are taken at the therapeutic level. Although this is a rare phenomenon, 70 cases FOR
Requests for reprints should be sent to David E. Smith, Haight Ashbury Free Medical Clinic, 409 Clayton Street, San Francisco, CA 94117.
163
_
D. Smith
164
TABLE 1 Phenobarbital Conversion for Withdrawal of Bentodiazeplnes and Other Sedative-Hypnotics
Generic Name Benzodiazepines Alprazolam (Xanax) Chlordiazepoxide (Librium) Clonazepam (Clonopin) Clorazepate (Tranxene) Diazepam (Valium) Flurazepam (Daimane) Halazepam (Paxipam) Lorazepam (Ativan) Oxazepam (Serax) Prazepam (Centrax) Temazepam (Restoril) Barbiturates Amobarbital (Tuinal) Butabarbital Butalbital Pentobarbital Secobarbital (Seconal) Glycerols Meprobamate (Miltown) Piperidinediones Glutethimide (Doriden) Quinazolines Methaqualone (Quaalude)
Dose (mq)
Phenobarbital Withdrawal Conversion (ms)
2; 2 15 10 15 40 1 10 10 15 100 100 50 100 100
30 30
400
30
250
30
300
30
: 30
these agents from a qualitative point of view, and the same phenobarbital substitution/withdrawal technique is effective for all agents in this class. It is important to emphasize the danger of this trend of individuals switching to the newer benzodiazepines under the mistaken belief that they are nonaddicting. Also dangerous is starting patients on these newer agents with the clear message to the patient that they are non-addicting. This problem was recently studied from a clinical point of view in one patient. Case History An individual, prominent in a religious order that is quite conservative about the ingestion of any psychoactive substance, started taking Halcion bought over-the-counter (OTC) in another country because he found that it helped him sleep. Fifteen years prior to entering the religious order, while he was in the military, he had an alcohol abuse problem. Both his father and his grandfather had died of consequences of alcoholism. As a result, he was very concerned about developing a dependence problem. Because of his strict moral position, he wanted to abstain from any mind-altering drugs. Because of its OTC availability, he thought Halcion would deal safely with his particular problem- insomnia associ-
ated with travel. When he returned to the United States, he consulted with a licensed general practitioner in the San Francisco bay area about Halcion and went into detail regarding his views towards medication, stressing his wish to avoid any substance that could produce addiction. The physician indicated that he was aware that the older benzodiazepines, such as diazepam (Valium@), were addicting, but thought this new benzodiazepine was non-addicting. The individual took Halcion within therapeutic dosage and achieved relief for insomnia, but found that he was developing daytime anxiety. Initially he attributed it to situational anxiety and began to selfadminister Halcion as an anti-anxiety medication during the day. When he attempted to stop, the anxiety and insomnia escalated. He still perceived this as situational distress, not drug-dependence withdrawal. As he noticed his dosage increasing, he attempted to stop taking the medication completely. When he came to our clinic, his dosage of Halcion was 1.5 mg per day taken in divided doses. He presented symptoms of anxiety and insomnia plus some depersonalization and visual alteration that were certainly part of the sedative-hypnotic withdrawal sequelae. Patient Withdrawal and Follow-up The above patient was detoxified using the Smith and Wesson (1983) phenobarbital substitution/withdrawal technique. Prolonged follow-up showed that although he does have some situational stress, there is no major underlying psychopathology. A conference with the prescribing physician was held to determine why the patient had been on Halcion, particularly in light of his many questions and concerns regarding dependence. The physician’s position was “It was my understanding that only Valium is addicting; none of the newer benzodiazepines are addicting.” When questioned regarding where he obtained this information or how he had arrived at this opinion, he indicated it was something he had heard- namely, that the new, short half-life benzodiazepines were nonaddicting. Inaccurate information, not scientifically substantiated or supported by the FDA, given to physicians or others working in the chemical dependency field is an added health hazard and contributes to the problem of drug dependence. Although the benzodiazepine hypnotics are the drugs of choice for insomnia, Kales’ sleep lab research (in press) emphasizes that different compounds in the benzodiazepine drug group have considerable differences in their pharmacokinetic properties, many of which directly affect the drug’s clinical profiles, as is the case with the benzodiazepine anxiolytics (Breimer & Jochemsen, 1981; Greenblatt, Divoll, Abernethy, & Shader, 1982). Some of the most important phar-
Benzodiazepine Dependence
Withdrawal
macokinetic properties of the benzodiazepine hypnotics involve their rates of absorption and elimination half-lives. Kales’ sleep lab research suggests that short half-life benzodiazepines may in fact have higher abuse potential (as demonstrated by the above case), although many physicians are prescribing these compounds with the idea that short half-life drugs have lower abuse potential. Benzodiazepine hyp notics with rapid elimination rates may produce early morning insomnia (Kales, Caldwell, Soldatos, Bixler, & Kales, 1983) and daytime anxiety (Morgan & Oswald, 1982). The syndrome of rebound anxiety : and insomnia, consisting of a worsening of sleep and increasing daytime anxiety, appears after one or two weeks of nightly administration when tolerance of the benzodiazepine begins to develop (Kales et al., 1983; Kales, Scharf & Kales, 1978; Kales, Soldatos, & Kales, 1979). Withdrawal from benzodiazepines with short to intermediate half-lives may produce both rei bound anxiety and insomnia (Kales et al., 1979). As with the above case, the individual who takes a shorter half-life benzodiazepine hypnotic to induce sleep may begin administering the drug during the daytime to block rebound anxiety. As a consequence of this continuous administration, the individual may develop dependence on the benzodiazepine and experience tolerance, requiring greater amounts of the drug to achieve the desired effect. Cessation of the benzodiazepine following such long-term administration and dosage escalation can then produce serious withdrawal sequelae. In light of the current perception by many physicians that the newer benzodiazepines with shorter half-lives have less toxic side effects, work such as Kales’ sleep lab research and our own clinical experience with dependence on the newer benzodiazepines must be taken into consideration. BENZODIAZEPINE WITHDRAWAL TECHNIQUES The development of this phenobarbital substitution technique evolved from detoxifying individuals with virtually every type of sedative-hypnotic dependence with short-acting barbiturates. Several different techniques are available. One is simply graded reduction of benzodiazepine dosage. For example, if one is dependent on diazepam, then diazepam is gradually reduced over a specific time period, usually 21 days. However, the phenobarbital substitution/withdrawal technique is preferred since many of the patients seen in treatment have multiple sedative-hypnotic dependencies. This has also proved preferable because most cases are treated on an outpatient basis and phenobarbital has a minimal street reputation, i.e., no one sells phenobarbital. We do not want to detoxify a person on either the same drug that they have
165
abused, or any drug that would be appealing in the drug culture, a drug that would be considered high in abuse potential. Phenobarbital has proven to be therapeutically effective, not well known on the street and rarely encountered by a large-scale drug dependence program such as ours. Finally, it has been found that the phenobarbital substitution technique also works more effectively on an inpatient basis and is generally used by other inpatient chemical dependency treatment programs throughout the United States. In the Haight-Ashbury studies, we have interpreted the effects of some of the newer benzodiazepines which are suppressed by phenobarbital. For example, in the Halcion case described above, the individual followed the classic pattern: Cessation of dosage resulted in anxiety, insomnia and some depersonalization and visual alterations. Administration of phenobarbital suppressed the symptoms. The patient was detoxified and reevaluated after detoxification and none of the withdrawal symptoms was present. Kales (in press) has suggested that the symptom may in fact be intoxication or adverse effects of Halcion. Our clinical experience would cause us to question this hypothesis since if these are indeed intoxication effects, why can they be suppressed with phenobarbital? Kales feels that this could be the result of some special action of phenobarbital. However, when patients on these newer compounds experience anxiety, insomnia and the like, it is recommended that the symptoms be interpreted as withdrawal effects, and that the rapid suppression of these effects by phenobarbital (as a clinical test for intoxication) be utilized. If a withdrawal reaction can be suppressed by administering phenobarbital and an intoxicant effect can also be supressed in the same manner, there must be another mechanism of action in the brain with which we are not familiar. Additional research is needed to understand the interaction of the benzodiazepines and other sedative-hypnotics in the brain. TYPES OF BENZODIAZEPINE WITHDRAWAL AND THE CONTROLLED SUBSTANCE ACT Two types of benzodiazepine or sedative-hypnotic withdrawal syndromes have been identified; with the first type the peak liability depends on the metabolic characteristics of the benzodiazepine. For example, abrupt cessation from diazepam dependence can produce a peak liability for withdrawal seizure with psychosis on the fifth to eighth day. If it is a shortacting benzodiazepine (like Ativan@), the curve shifts to the left, and the peak liability for withdrawal seizure is the third or second day. If it is a mixture, for instance, of diazepam and alcohol, this delays the
D. Smith
166
peak liability for withdrawal and the curve shifts to the right. Clinical studies have indicated that the peak liability for withdrawal seizure may be as late as the tenth day (see Figure 1). These facts are extremely important to know if one is treating a drug dependency problem. All benzodiazepines that are marketed in the United States fit qualitatively into this curve. The second type of curve is a more delayed withdrawal, characterized by low intensity symptoms of anxiety and insomnia, different from symptom reemergence associated with psychopathology predating the long-term benzodiazepine administration. Propranolol can be administered symptomatically to deal with the episodic anxiety of delayed withdrawal associated with delayed withdrawal. The symptoms of delayed withdrawal can be suppressed by readministering the benzodiazepine, but the patient is at risk to become re-addicted. Prolonged use of the benzodiazepines to deal with delayed withdrawal is not recommended. L-Tryptophan can deal with the sleep dysfunction. A very small number of patients will fit into the first curve after taking benzodiazepines within therapeutic range. And, as indicated, the characteristics of benzodiazepine dependence are similar to
FIGURE
1. Comparison
those of other sedative-hypnotics. Unfortunately, it appears that current information given to physicians is not accurate. There is no evidence of a difference in abuse potential among benzodiazepines, and selective scheduling could transmit an inaccurate and false message to both physician and patient. In the drug dependence field, this would be equivalent to saying that heroin is addicting, but methadone is not, as both drugs are in the opiate category with heroin being short-acting and methadone being long-acting. Since all benzodiazepines interact with the benzodiazepine receptor in the brain, it can be predicted reliably that all benzodiazepine agents used worldwide have qualitatively similar dependence-producing characteristics. Therefore, the rescheduling of the drug by class, relative to abuse potential, is more valid than selective scheduling, both clinically and scientifically. Furthermore, selective scheduling could constitute a health hazard. It could be predicted that when and if other benzodiazepines become widely available in the United States, the same characteristics of dependence will appear. The variation in pharmacological properties of the benzodiazepines are most important relative to the therapeutic applications rather than the dependency-producing potential.
of relative intensity and time course of benzodiarepine
withdrawal
syndromes.
Benzodiazepine
Dependence
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Withdrawal
THE PROBLEM OF LOOK-ALIKE
DRUGS
The Haight-Ashbury Free Clinic’s research on street drug use also includes a Look-Alike Drug Research and Training Project that has studied a wide variety of look-alike drugs in the stimulant, sedative/ hypnotic and opiate areas. “Look-alike? are pills that resemble a controlled substance in appearance, but in fact, contain non-controlled substances. The Look-Alike Project has also studied drugs of deception-drugs which look like one controlled substance, but in fact contain another controlled substance. Research data on street quaaludes show that about 35% contain diazepam instead. In interviews with users of these drugs of deception, it is quite clear that the drug-seeking behavior is directed at methaqualone, a short-acting potent sedative rather than diazepam, a longer-acting, less potent agent. For example, if users have had experience with what they call a pharmaceutical quaalude containing methaqualone versus a street quaalude containing diazepam, they will clearly indicate that the pharmaceutical quaalude is far superior. Toxicological verification will also distinguish between methaqualone and diazepam. It is our belief that in the street drug scene, this is methaqualone drug-seeking behavior (Smith, in press) Such informatioi is very important in clinical treatment. For example, in one of the cases studied, an individual was taking 5-10 street quaaludes a day containing approximately 25 mg of diazepam per each street quaalude. She stopped abruptly, tried to titrate her withdrawal with alcohol and had delayed withdrawal seizures on about the tenth day. The toxicological verification indicated that she had in fact self-administered very high doses of diazepam. According to the drug treatment literature, methaqualone withdrawal seizure peak occurs about the second day. Therefore it is very important that education regarding look-alike drugs or drugs of deception be given to physicians as well as to the general public. The Little Black Pill Book (Smith, Seymour, & Morgan, 1983) includes a comprehensive section of these non-prescription substances. Finally, our studies have also included the street drug scene and its interface with benzodiazepine dependence in the area of methadone maintenance. Findings show that individuals on methadone maintenance who self-administer a benzodiazepine usually do so not for euphoria, but to suppress anxiety. Although these individuals have a problem with opiate addiction, they also have a very high degree of underlying psychological distress, and will tend to titrate their dosages of methadone with a benzodiazepine in order to suppress this underlying distress. The most widely used drug in this setting is diaze-
pam, but other benzodiazepines will also be used for the same purpose. In the street drug scene, the benzodiazepines play a secondary role. They are used as self-medication to “come down” from something else, e.g., a stimulant run. Often they are look-alike drugs or drugs of deception, but they do not play a primary role in drug-seeking behavior. The dependence that may occur from therapeutic administration of a benzodiazepine must always be viewed from the perspective of the majority of physicians who safely and effectively prescribe these medications. However, physicians have a relatively limited understanding of drug dependence and may fall into the trap of believing that one benzodiazepine is addicting while another is not. As a consequence, it is our belief that the class scheduling of the benzodiazepines is scientifically and clinically justified and will, hopefully, decrease the health hazard of benzodiazepine dependency. REFERENCES Breimer, D.D., & Jochemsen, R. (1981). Phannacokinetics of hypnotic drugs. In D. Wheatley (Ed.), Psychopharmacology of sleep. New York: Raven Press. Greenblatt, D.J., Divoll, M., Abernethy, D.R., & Shader, RI. (1982).Benzodiazepine hypnotics: Kinetic and therapeutic options. Sleep, 5, Si8427. Hollister, L.E. (1983). The pre-benzodiazepine era. Journal of Psychoactive Drugs, 15, 9-17. Kales, A., Caldwell, A.B., Soldatos, C.R., Bixler, E.O., & Kales, J.D. (1983). Biopsychobehavioral correlates of insomnia. II. Pattern specificity and consistency with the Minnesota Multiphasic Personality Inventory. Psychosomatic Medicine, 45, 341-356. Kales, A., Scharf, M.B., & Kales, J.D. (1978). Rebound insomnia: A new clinical syndrome. Science, 201, 194-200. Kales, A., Scharf, M.B., Kales, J.D., & Soldatos, C.R. (1979). Rebound insomnia: A potential hazard following withdrawal of certain benxodiazepines. Journal of the American Medical Association, 241, 1692-1695. Kales, A., Soldatos, C.R., & Kales, J.D. (1979). Sleep disorders: Evaluation and management in the office setting. In S. Arieti, & H.K.H. Brodie (Eds.), American Handbook on Psychiatry, Vol. 7, 2nd ad. New York: Basic Books. Kales, A., Soldatos, C.R., & Vela-Bueno, A. (in press). CIinical comparison of benzodiaxepine hypnotics with short and long elimination half-Iives. Marks, J., & Smith, D.E. (in press). Benxodiaxepine abuse and dependence: An international perspective. In The benzodiazepines: Current use and medical practice, London: MTP Press. Morgan, K., & Oswald, I. (1982). Anxiety caused by a short-life hypnotic. British Medical Journal, 2.84, 942. Smith, D.E., & Wesson, D.R. (eds.) (1983). The benzodiazepines: Two decades of research and clinical experience. Journal of Psychoactive Drugs, 15, 00-00. Smith, D.E., & Wesson, D.R. (1983). Benzodiazepine dependency syndromes. Journal of Psychoactive Drugs, 15,85-96. Smith, D.E., Seymour, R.B., & Morgan, J.P. (1983). The little black pi/t book. New York: Bantam Books. Smith, D.E. (in press) Look-alike drugs and drugs of deception: Epidemiological, toxicological and clinical considerations.