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Opiate addiction and depression — cause or effect?
Drug and Alcohol Dependence, Elsevier
Scientific
Publishers
11 (1983) Ireland Ltd.
OPIATE ADDICTION AND DEPRESSION
CHARLES
A. DACKIS
and MARK
105
105-109
- CAUSE OR EFFECT?
S. GOLD
Research Facilities, Fair Oaks Hospital, Summit, NJ 07901
(U.S.A.)
The treatment of opiate addiction is a complex and often frustrating task. Opiate addiction is an illness which is subject to great prejudice and misunderstanding and opiate addicts are generally viewed by society with disdain and ostracism. It is necessary to understand the psychological and physiological forces that form the underpinnings of opiate addiction before the provider of care can transcend societal prejudices and develop an objective strategy of treatment. Such an understanding also provides the empathy necessary to relate to these patients, and coincidentally leads to some surprising speculations regarding possible roles of natural opiate systems in the brain. The purpose of this paper will be to review some of our clinical research data which have led to our structured treatment program for opiate addiction. Before proceeding to a framework for understanding opiate addiction, it is useful to examine some of the reasons why addicts are misunderstood. The recreational use of opiates seems difficult to justify in light of the perils of opiate addiction. The injection of street heroin of unknown potency can easily lead to lethal overdose. Drug-related medical illness such as malnutrition, numerous forms of hepatitis, vasculopathies, tetanus, tuberculosis and other infections, can cause morbidity or mortality. The necessity of obtaining drugs disrupts job performance and social ties, and opiates become the addicts’ pre-eminent focus. Procurement of illegal drugs is a dangerous task, exposing the addict to risks of assault, blackmail, death or incarceration at the time when judgment is often impaired by drug intoxication or abstinence symptoms. Psychiatric complications, particularly depression, can lead to prolonged suffering and even suicide. The development of withdrawal symptoms and panic are always hours away, constituting a firm reinforcement of continued addiction. Sociopathic activities, often employed to avoid withdrawal symptoms and obtain drug supplies, cause others to suffer and increase social isolation. These and other hazards associated with opiate addiction contribute to the general lack of understanding of what could motivate individuals to become or stay opiate dependent. Opiate addiction becomes more comprehensible in the light of classical conditioning theory as described by Wikler [ 11. The euphoric effect of opiates, 0376-8716/83/$03.00 o 1983 Elsevier Scientific Publishers Printed and Published in Ireland
Ireland
Ltd.
106
probably mediated through endogenous opiate systems in the human brain, is a ‘positive reinforcer’. This means that the euphoria of opiate intoxication makes repeated use more likely, even before physical addiction develops. The strength of this positive reinforcement is enhanced when individuals have underlying feelings of ‘dysphoria’, such as anxiety or depression. Therefore, certain individuals who have psychiatric symptoms are more susceptible to the positive reinforcement of opiate euphoria, and these individuals may in fact use opiates to self-medicate feeling of dysphoria. Other individuals may use opiates initially as a result of peer pressure, adventurism or curiosity. Once an individual begins to use opiates repeatedly, due to the positive reinforcer of euphoria or other reasons, there develops an insidious negative reinforcer. This takes the form of the abstinence syndrome, as extremely uncomfortable withdrawal symptoms emerge with physical drug addiction. Furthermore, physiological tolerance leads to progressively increased doses of the drug, and even more severe withdrawal symptoms. A cycle is thus begun whereby positive reinforcement (drug euphoria) alternates with negative reinforcement (withdrawal symptoms), providing strong impetus for continued drug use. This cycle is further strengthened if pre-existing psychiatric symptoms are being self-medicated or if opiate-induced neurochemical or neuroendocrinological imbalances emerge and lead to self medication. This latter situation will be discussed further in relation to opiate-induced depression. The power of the psychological and physiological entrapments of opiate addiction is demonstrated by the addict’s decision to remain in the hazardous drug environment even after tolerance develops and opiates no longer produce as much euphoria. In fact, elements of the drug environment can themselves lead to conditioned abstinence symptoms [2]. Just as Pavlov’s dogs began to salivate upon hearing a bell which was conditioned to feeding time, addicts often experience abstinence symptoms and craving upon exposure to elements of the drug environment. Seeing buildings where drugs were bought, smelling matches or meeting drug-using friends can precipitate strong urges and abstinence symptoms even in detoxified patients. This classical conditioning further fortifies the addictive process and has specific treatment ramifications. Since merely the presence of the environment is potent enough to induce drug craving and withdrawal symptomatology, patients attempting to achieve a drug free state must actively limit access to both drugs and conditioned elements of the drug environment. This requires hospitalization initially, on the most concrete level, but later patients are taught to terminate friendships with addicts, move from old neighborhoods, and change jobs if drug exposure is present. Otherwise, the force of conditioned abstinence symptoms will often lead the patient back into addiction. In addition, the use of the long-acting opiate blocker naltrexone, if available, reduces the lure of opiates by elminiating the positive reinforcement of opiate-induced euphoria.
107
As has been previously mentioned, exogenous opiates, such as heroin or methadone, appear to exert their psychological and physiological effects by acting upon the brain’s endogenous opiate system. Specific opiate binding has been known to exist in the brain since 1972 [3--51 and in 1975 two types of natural opioid peptides were discovered. These were P-endorphin [ 61 and the smaller enkephalin peptides [ 7,8]. Although endogenous opioid peptide systems have yet to be characterized with regard to their functional roles, it is likely that they are somehow related to mood regulation. This is suggested by the euphoriant action of administered opiates, which is completely blocked by the opiate receptor antagonist naltrexone. Furthermore, opioid peptides are most concentrated in brain regions traditionally associated with mood regulation, such as the hypothalamus, locus coeruleus, amygdala and certain other limbic system structures. A description of known neuroanatomical and functional characteristics of endogenous opioid pep tides has been reviewed elsewhere [9] and suggests that these opioids have important connections with catecholamine systems of the brain, which in turn are implicated in mood regulation and affective disorders [lo]. The connection between mood regulation and opiate agents is underscored by reports of extremely high prevalence rates for depression in opiate addicts. Rounsaville [ll], using the Schedule for Affective Disorders and Schizophrenia (SADS) [12] as a diagnostic instrument, found that 17% of opiate addicted individuals suffered from major depression by Research Diagnostic Criteria (RDC) [13] and 48% had suffered from RDC major depressive illness in the past. Furthermore, of addicts with past major depression, 5.6% had depressive episodes preceding their drug abuse and 94.5% were secondary depressives [ 111. This supports the notion that the tremendously high prevalence of major depression in addicts is somehow caused by the addiction, rather than preceding initial drug use. It seems unlikely that widespread preexisting depressive illness would give rise to opiate use as a form of self-medication. In fact, given the extremely hazardous task of procuring opiates, and the relative passivity associated with depression, it would be surprising to see initial opiate use occurring in the context‘of a major depression. At Fair Oaks Hospital, 50 consecutive patients were interviewed three weeks after opiate detoxification with a SADS interview. We found a 32% point prevalence of RDC major depression and a 10% point prevalence of RDC minor depression. Interestingly, shortly after the potent psychoactive opiates are discontinued, and after withdrawal symptoms have abated, the prevalence for major depression nearly doubled as compared to the 17% point prevalence for major depression in addicts taking opiates [ 111. This raises the possibility that opiates can ameliorate the very depressive symptoms that they appear to precipitate, thereby further reinforcing their continued use and bolstering the entrapment of addiction. We have found that the use of antidepressants in the post-detoxification period is often indicated by the severity of depressive symptoms and serves as a deterrant to recidivism. Careful attention to
108
post-detoxification depression, and appropriate treatment when present, is a crucial treatment strategy. Generalized lack of appreciation of this critical complication of opiate use may partially explain the high recidivism rates seen in opiate addiction. Given the high prevalence of depression in post-detoxified opiate addicts, the euphoria caused by opiate intoxification, and the presence of endogenous opiate systems in limbic structures of the brain, it is tempting to speculate that endogenous opioid peptides are involved in mood regulation and perhaps in the pathophysiology of affective disorders. Gold has presented diverse evidence that is consistent with a depletion of endogenous opioids in individuals chronically addicted to opiates [ 14,151. This depletion of naturally occuring opiates with heroin or methadone use has been hypothesized to result from chronic stimulation of a feedback system by the exogenous opiates, resulting in the endogenous opiate system being ‘turned off’. It has been suggested that a compromised endogenous opiate system gives rise to withdrawal symptoms once exogenous opiate use is abruptly terminated [ 161. It appears possible, in addition, that a compromised endogenous opioid system may give rise to depressive symptoms. The addict may use daily exogenous opiates to prevent both abstinence symptoms and depression, leading to further depletion of endogenous opiates, and the perpetuation of addiction. Just as exogenous opiate agonists deplete endogenous systems, it is theoretically possible that exogenous opiate antagonists might reverse this process. Naltrexone is a long acting opiate antagonist which has been used in post-detoxified opiate addicts to maintain the drug-free state [lo]. By blocking the brain’s opiate receptor, naltrexone prevents subjective and physiological effects of exogenous opiates. Patients taking naltrexone will not experience the opiate high, and cannot become readdicted. This prevents the conditioned process of addiction previously described. Naltrexone has been reported to cause dysphoria in normals, but not in post-addicts, suggesting that in the post-addicts the effects of opiate receptor antagonists are different [ 171. In addition, the opiate antagonist naloxone causes a release of or displaces beta-endorphin in humans [ 141. This naloxoneinduced surge in endogenous opiate release is consistent with the notion that naltrexone administration to addicts might release ACI’H and endorphins and may reverse the endogenous opiate depletion caused by chronic opiate addiction. Alternatively, naltrexone may increase opiate receptor sensitivity or receptor numbers. Further research is required to determine whether there are beneficial effects of naltrexone. However, in light of its proven efficacy in blocking the opiate high, and the possibility that it may aid in reversing chronic endogenous opiate depletion in opiate addicts, the use of naltrexone appears to be an important adjunct in the treatment of these patients. We have reviewed some of the aspects of opiate addiction which may not be widely appreciated. The high prevalence of depression in these individuals,
109
particularly when they attempt to be opiate free, serves to impede their sobriety and may lead to actual self-medication with opiates. This cycle of opiate induced depression, followed by self-medication with more opiates, is similar to the pattern seen with opiate induced abstinence symptoms. Careful attention to depressive symptoms and treatment with antidepressants when indicated, can serve to neutralize this particular entrapment of opiate addiction. Furthermore, naltrexone treatment, aside from eliminating the positive reinforcer of drug induced euphoria, may reverse the endogenous opiate depletion hypothesized to cause depressive and abstinence symptoms [lo]. This possibility can be addressed as we develop more precise methods of measuring endogenous opioids and understanding their physiological roles. A more sophisticated understanding of endogenous opioid pathways can only serve to improve our treatment of opiate addiction, and may even cast light on the physiology of mood regulation. REFERENCES 1 A. Wikler, Opioid Dependence: Mechanisms and Treatment, Plenum Press, New York, 1980, pp. 167-218. 2 T. Thompson and W. Ostlund, J. Comp. Physiol. Psychol., 59 (1965) 388. 3 L. Terenius, Acta Pharmacol. Toxicol., 33 (1973) 377. 4 C.B. Pert and S.H. Snyder, Science, 179 (1973) 1011. 5 E.J. Simon, J.M. Hiller and I. Edelman, Proc. Natl. Acad. Sci. U.S.A., 70 (1973) 1947. 6 J. Hughes et al., Nature, 258 (1975) 577. 7 A.F. Bradbury et al., Nature, 260 (1976) 793. 8 C.H. Li and D. Chung, Proc. Natl. Acad. Sci. U.S.A., 73 (1976) 1145. 9 S.H. Snyder, Am. J. Psychiat., 135 (1978) 645. 10 M.S. Gold et al., Med. Res. Rev., (2) 3 (1982) 211. 11 B.J. Rounsaville et al., Arch. Gen. Psychiat., 39 (1982) 151. 12 J. Endicott and R.L. Spitzer, Arch. Gen. Psychiat., 35 (1978) 837. 13 R.L. Spitzer, J. Endicott and E. Robins, Arch. Gen. Psychiat., 35 (1978) 773. 14 M.S. Gold et al., Drug Alcohol Depend., 8 (1981) 257. 15 MS. Gold et al., Lancet, II (1980) 972. 16 MS. Gold et al., Drug Alcohol Depend., 6 (1980) 201. 17 L.E. Hollister et al., Drug Alcohol Depend., 8 (1981) 37.
Scientific
Publishers
11 (1983) Ireland Ltd.
OPIATE ADDICTION AND DEPRESSION
CHARLES
A. DACKIS
and MARK
105
105-109
- CAUSE OR EFFECT?
S. GOLD
Research Facilities, Fair Oaks Hospital, Summit, NJ 07901
(U.S.A.)
The treatment of opiate addiction is a complex and often frustrating task. Opiate addiction is an illness which is subject to great prejudice and misunderstanding and opiate addicts are generally viewed by society with disdain and ostracism. It is necessary to understand the psychological and physiological forces that form the underpinnings of opiate addiction before the provider of care can transcend societal prejudices and develop an objective strategy of treatment. Such an understanding also provides the empathy necessary to relate to these patients, and coincidentally leads to some surprising speculations regarding possible roles of natural opiate systems in the brain. The purpose of this paper will be to review some of our clinical research data which have led to our structured treatment program for opiate addiction. Before proceeding to a framework for understanding opiate addiction, it is useful to examine some of the reasons why addicts are misunderstood. The recreational use of opiates seems difficult to justify in light of the perils of opiate addiction. The injection of street heroin of unknown potency can easily lead to lethal overdose. Drug-related medical illness such as malnutrition, numerous forms of hepatitis, vasculopathies, tetanus, tuberculosis and other infections, can cause morbidity or mortality. The necessity of obtaining drugs disrupts job performance and social ties, and opiates become the addicts’ pre-eminent focus. Procurement of illegal drugs is a dangerous task, exposing the addict to risks of assault, blackmail, death or incarceration at the time when judgment is often impaired by drug intoxication or abstinence symptoms. Psychiatric complications, particularly depression, can lead to prolonged suffering and even suicide. The development of withdrawal symptoms and panic are always hours away, constituting a firm reinforcement of continued addiction. Sociopathic activities, often employed to avoid withdrawal symptoms and obtain drug supplies, cause others to suffer and increase social isolation. These and other hazards associated with opiate addiction contribute to the general lack of understanding of what could motivate individuals to become or stay opiate dependent. Opiate addiction becomes more comprehensible in the light of classical conditioning theory as described by Wikler [ 11. The euphoric effect of opiates, 0376-8716/83/$03.00 o 1983 Elsevier Scientific Publishers Printed and Published in Ireland
Ireland
Ltd.
106
probably mediated through endogenous opiate systems in the human brain, is a ‘positive reinforcer’. This means that the euphoria of opiate intoxication makes repeated use more likely, even before physical addiction develops. The strength of this positive reinforcement is enhanced when individuals have underlying feelings of ‘dysphoria’, such as anxiety or depression. Therefore, certain individuals who have psychiatric symptoms are more susceptible to the positive reinforcement of opiate euphoria, and these individuals may in fact use opiates to self-medicate feeling of dysphoria. Other individuals may use opiates initially as a result of peer pressure, adventurism or curiosity. Once an individual begins to use opiates repeatedly, due to the positive reinforcer of euphoria or other reasons, there develops an insidious negative reinforcer. This takes the form of the abstinence syndrome, as extremely uncomfortable withdrawal symptoms emerge with physical drug addiction. Furthermore, physiological tolerance leads to progressively increased doses of the drug, and even more severe withdrawal symptoms. A cycle is thus begun whereby positive reinforcement (drug euphoria) alternates with negative reinforcement (withdrawal symptoms), providing strong impetus for continued drug use. This cycle is further strengthened if pre-existing psychiatric symptoms are being self-medicated or if opiate-induced neurochemical or neuroendocrinological imbalances emerge and lead to self medication. This latter situation will be discussed further in relation to opiate-induced depression. The power of the psychological and physiological entrapments of opiate addiction is demonstrated by the addict’s decision to remain in the hazardous drug environment even after tolerance develops and opiates no longer produce as much euphoria. In fact, elements of the drug environment can themselves lead to conditioned abstinence symptoms [2]. Just as Pavlov’s dogs began to salivate upon hearing a bell which was conditioned to feeding time, addicts often experience abstinence symptoms and craving upon exposure to elements of the drug environment. Seeing buildings where drugs were bought, smelling matches or meeting drug-using friends can precipitate strong urges and abstinence symptoms even in detoxified patients. This classical conditioning further fortifies the addictive process and has specific treatment ramifications. Since merely the presence of the environment is potent enough to induce drug craving and withdrawal symptomatology, patients attempting to achieve a drug free state must actively limit access to both drugs and conditioned elements of the drug environment. This requires hospitalization initially, on the most concrete level, but later patients are taught to terminate friendships with addicts, move from old neighborhoods, and change jobs if drug exposure is present. Otherwise, the force of conditioned abstinence symptoms will often lead the patient back into addiction. In addition, the use of the long-acting opiate blocker naltrexone, if available, reduces the lure of opiates by elminiating the positive reinforcement of opiate-induced euphoria.
107
As has been previously mentioned, exogenous opiates, such as heroin or methadone, appear to exert their psychological and physiological effects by acting upon the brain’s endogenous opiate system. Specific opiate binding has been known to exist in the brain since 1972 [3--51 and in 1975 two types of natural opioid peptides were discovered. These were P-endorphin [ 61 and the smaller enkephalin peptides [ 7,8]. Although endogenous opioid peptide systems have yet to be characterized with regard to their functional roles, it is likely that they are somehow related to mood regulation. This is suggested by the euphoriant action of administered opiates, which is completely blocked by the opiate receptor antagonist naltrexone. Furthermore, opioid peptides are most concentrated in brain regions traditionally associated with mood regulation, such as the hypothalamus, locus coeruleus, amygdala and certain other limbic system structures. A description of known neuroanatomical and functional characteristics of endogenous opioid pep tides has been reviewed elsewhere [9] and suggests that these opioids have important connections with catecholamine systems of the brain, which in turn are implicated in mood regulation and affective disorders [lo]. The connection between mood regulation and opiate agents is underscored by reports of extremely high prevalence rates for depression in opiate addicts. Rounsaville [ll], using the Schedule for Affective Disorders and Schizophrenia (SADS) [12] as a diagnostic instrument, found that 17% of opiate addicted individuals suffered from major depression by Research Diagnostic Criteria (RDC) [13] and 48% had suffered from RDC major depressive illness in the past. Furthermore, of addicts with past major depression, 5.6% had depressive episodes preceding their drug abuse and 94.5% were secondary depressives [ 111. This supports the notion that the tremendously high prevalence of major depression in addicts is somehow caused by the addiction, rather than preceding initial drug use. It seems unlikely that widespread preexisting depressive illness would give rise to opiate use as a form of self-medication. In fact, given the extremely hazardous task of procuring opiates, and the relative passivity associated with depression, it would be surprising to see initial opiate use occurring in the context‘of a major depression. At Fair Oaks Hospital, 50 consecutive patients were interviewed three weeks after opiate detoxification with a SADS interview. We found a 32% point prevalence of RDC major depression and a 10% point prevalence of RDC minor depression. Interestingly, shortly after the potent psychoactive opiates are discontinued, and after withdrawal symptoms have abated, the prevalence for major depression nearly doubled as compared to the 17% point prevalence for major depression in addicts taking opiates [ 111. This raises the possibility that opiates can ameliorate the very depressive symptoms that they appear to precipitate, thereby further reinforcing their continued use and bolstering the entrapment of addiction. We have found that the use of antidepressants in the post-detoxification period is often indicated by the severity of depressive symptoms and serves as a deterrant to recidivism. Careful attention to
108
post-detoxification depression, and appropriate treatment when present, is a crucial treatment strategy. Generalized lack of appreciation of this critical complication of opiate use may partially explain the high recidivism rates seen in opiate addiction. Given the high prevalence of depression in post-detoxified opiate addicts, the euphoria caused by opiate intoxification, and the presence of endogenous opiate systems in limbic structures of the brain, it is tempting to speculate that endogenous opioid peptides are involved in mood regulation and perhaps in the pathophysiology of affective disorders. Gold has presented diverse evidence that is consistent with a depletion of endogenous opioids in individuals chronically addicted to opiates [ 14,151. This depletion of naturally occuring opiates with heroin or methadone use has been hypothesized to result from chronic stimulation of a feedback system by the exogenous opiates, resulting in the endogenous opiate system being ‘turned off’. It has been suggested that a compromised endogenous opiate system gives rise to withdrawal symptoms once exogenous opiate use is abruptly terminated [ 161. It appears possible, in addition, that a compromised endogenous opioid system may give rise to depressive symptoms. The addict may use daily exogenous opiates to prevent both abstinence symptoms and depression, leading to further depletion of endogenous opiates, and the perpetuation of addiction. Just as exogenous opiate agonists deplete endogenous systems, it is theoretically possible that exogenous opiate antagonists might reverse this process. Naltrexone is a long acting opiate antagonist which has been used in post-detoxified opiate addicts to maintain the drug-free state [lo]. By blocking the brain’s opiate receptor, naltrexone prevents subjective and physiological effects of exogenous opiates. Patients taking naltrexone will not experience the opiate high, and cannot become readdicted. This prevents the conditioned process of addiction previously described. Naltrexone has been reported to cause dysphoria in normals, but not in post-addicts, suggesting that in the post-addicts the effects of opiate receptor antagonists are different [ 171. In addition, the opiate antagonist naloxone causes a release of or displaces beta-endorphin in humans [ 141. This naloxoneinduced surge in endogenous opiate release is consistent with the notion that naltrexone administration to addicts might release ACI’H and endorphins and may reverse the endogenous opiate depletion caused by chronic opiate addiction. Alternatively, naltrexone may increase opiate receptor sensitivity or receptor numbers. Further research is required to determine whether there are beneficial effects of naltrexone. However, in light of its proven efficacy in blocking the opiate high, and the possibility that it may aid in reversing chronic endogenous opiate depletion in opiate addicts, the use of naltrexone appears to be an important adjunct in the treatment of these patients. We have reviewed some of the aspects of opiate addiction which may not be widely appreciated. The high prevalence of depression in these individuals,
109
particularly when they attempt to be opiate free, serves to impede their sobriety and may lead to actual self-medication with opiates. This cycle of opiate induced depression, followed by self-medication with more opiates, is similar to the pattern seen with opiate induced abstinence symptoms. Careful attention to depressive symptoms and treatment with antidepressants when indicated, can serve to neutralize this particular entrapment of opiate addiction. Furthermore, naltrexone treatment, aside from eliminating the positive reinforcer of drug induced euphoria, may reverse the endogenous opiate depletion hypothesized to cause depressive and abstinence symptoms [lo]. This possibility can be addressed as we develop more precise methods of measuring endogenous opioids and understanding their physiological roles. A more sophisticated understanding of endogenous opioid pathways can only serve to improve our treatment of opiate addiction, and may even cast light on the physiology of mood regulation. REFERENCES 1 A. Wikler, Opioid Dependence: Mechanisms and Treatment, Plenum Press, New York, 1980, pp. 167-218. 2 T. Thompson and W. Ostlund, J. Comp. Physiol. Psychol., 59 (1965) 388. 3 L. Terenius, Acta Pharmacol. Toxicol., 33 (1973) 377. 4 C.B. Pert and S.H. Snyder, Science, 179 (1973) 1011. 5 E.J. Simon, J.M. Hiller and I. Edelman, Proc. Natl. Acad. Sci. U.S.A., 70 (1973) 1947. 6 J. Hughes et al., Nature, 258 (1975) 577. 7 A.F. Bradbury et al., Nature, 260 (1976) 793. 8 C.H. Li and D. Chung, Proc. Natl. Acad. Sci. U.S.A., 73 (1976) 1145. 9 S.H. Snyder, Am. J. Psychiat., 135 (1978) 645. 10 M.S. Gold et al., Med. Res. Rev., (2) 3 (1982) 211. 11 B.J. Rounsaville et al., Arch. Gen. Psychiat., 39 (1982) 151. 12 J. Endicott and R.L. Spitzer, Arch. Gen. Psychiat., 35 (1978) 837. 13 R.L. Spitzer, J. Endicott and E. Robins, Arch. Gen. Psychiat., 35 (1978) 773. 14 M.S. Gold et al., Drug Alcohol Depend., 8 (1981) 257. 15 MS. Gold et al., Lancet, II (1980) 972. 16 MS. Gold et al., Drug Alcohol Depend., 6 (1980) 201. 17 L.E. Hollister et al., Drug Alcohol Depend., 8 (1981) 37.