Abstinence Symptoms Research Articles

Opioid-reinforced operant behavior: selective suppression by alpha-methyl-para-tyrosine.

Morphine-addicted rats performed operant responses for opioid or milk rewards. When rats were then denied access to opioids, abstinence symptoms developed. Responding under extinction conditions 2 wk. after opioid withdrawal provided a measure of the "relapse" tendency. Systemic administration of DL-alpha-methyl-para-tyrosine, an inhibitor of catecholamine synthesis, suppressed these responses if they had been reinforced by an opioid but not if they had been established with milk reinforcement. This indicates that the integrity of the catecholamine systems is vital for relapse to occur.

Failure obtain ?cannabis-directed behavior? and abstinence syndrome in rats chronically treated with Cannabis sativa extracts

Experiments were performed to verify whether chronic treatment with Cannabis saliva extracts would induce dependence and/or abstinence symptoms in rats. In Experiment one, rats ingested cannabis extract as the only fluid for 126 days. On days 1, 43, 48, 62, 80, 92 and 119 when the animals were in abstinence from previous administration of marihuana for 0 to 96 h, behavioral measures and choice tests between marihuana suspension and control solution were carried out; the rats preferred to drink the control solution and no behavioral symptoms indicating abstinence were noted. In Experiment two, rats were trained to drink a marihuana suspension or control solution in order to be rewarded with sweetened milk. After 22 sessions water was substituted for the milk. Extinction curves for both groups were similar, and in choice tests among cannabis suspension, water and control solution, the animals refused to drink the marihuana suspension. In Experiment three, rats received i.p. injections of a cannabis extract or control solution during 36 days. From days 37–40 the drugs were withheld and sensitivity to penty-lenetetrazol was assessed. Marihuana chronically treated rats were more resistant to convulsions and fewer died after pentylenetetrazol. In Experiment four, rats were treated with marihuana extract, control solution or sodium barbitone during 73 days. At days 74–76, when undergoing 24, 48 and 72 h of abstinence, the animals were exposed to sound from a bell. Animals in abstinence from barbitone showed a high incidence of convulsions; marihuana treated rats did not differ from control animals. These results suggest that rats do not self administer marihuana (Experiments one and two) and do not present abstinence symptoms after prolonged periods of ingestion of the drug (Experiments 1, 3 and 4).

Azidomorphine and rymazolium an approach to the ideal analgesic

Summary From a series of newly synthetized morphine derivatives 6-deoxy-6-azido-dihydroisomorphine /azido-morphine/ and 6-deoxy-6-azido-dihydroisocodeine /azido-codeine/ were selected for detailed pharmacological study. In the hot plate test in rats, azidomorphine proved to be about 300 times, azidocodeine about 13 times more potent than morphine. Administration of azidomorphine over a period of ten weeks proved it to be significantly less toxic in the rat than morphine. In the jumping test severe withdrawal symptoms could be precipitated in mice who received 40 times the analgesic ED50 dose /200 mg/kg/ of morphine. In contrast, only moderate dependence could be demonstrated with this test in mice who received 2800 times the analgesic ED50 dose of azidomorphine /70 mg/kg/. Treatment with increasing doses of morphine led to the development of high grade tolerance and physical dependence in rats and monkeys /Rhesus macacus/. Severe abstinence syndrome was precipitated following the administration of nalorphine in rats pretreated for 24 days with rapidly increasing doses of morphine. Severe abstinence symptoms were elicited in addicted monkeys on abrupt withdrawal of morphine on the 55th, 176th and 300th days of treatment. In parallel experiments no tolerance or physical dependence developed in rats or monkeys pretreated with increasing, equianalgesic doses of azidomorphine. Rymazolium /1,6-dimethyl1-3-carbethoxy-4-oxo-6,7,8,9, tetra-hydrohomopyrimidazole methylsulphate, Probon, MZ-144/ a new non-narcotic analgesic strongly potentiated the analgesic effect of azidomorphine and azidocodeine. On the basis of the reported animal experiments and preliminary clinical trials it is reasonable to expect that with the combined administration of azidomorphine or azidocodeine with Rymazolium it will be possible to obtain relief of severe, acute or chronic pain without significant risk of the development of addiction and/or tolerance.

Acute physical dependence upon morphine in rats

An investigation was made to determine if physical dependence would develop after a small number of large intravenous injections of morphine. Six rats, given 150 mg/kg injections 8 hr apart for 2 days and then allowed to withdraw, exhibited a mean of 90% of the abstinence symptoms measured. Six control rats injected with saline showed no symptoms. Three rats given a single 50 mg/kg morphine injection 56 hr in withdrawal showed complete cessation of symptoms, and a return to 82% in 16 hr. Similar results were obtained in another experiment in which rats of different age and strain were used. A comparison with rats made tolerant to large doses of morphine over a long time found no significant difference in abstinence scores. In two further experiments, no withdrawal symptoms were observed in rats after a single 150 mg/kg intravenous morphine injection nor after three such injections.

THE DEVELOPMENT OF TOLERANCE TO AND OF PHYSICAL DEPENDENCE ON MORPHINE FOLLOWING INTRAVENTRICULAR INJECTION IN THE RAT

The mechanism of the development of tolerance to and of physical dependence on morphine has been examined from a wide range of aspects. One of the approaches is to investigate the participation of brain biogenic amines in the actions of morphine. In 1954 Vogt (1) found a reduction of the content of hypothalamic norepinephrine after a subcutaneous morphine in the cat. Following her studies, some investigations were made on the change of the level of brain norepinephrine, dopamine and 5-hyroxytryptamine (5-HT) after either single or repeated administration of morphine.Recently it was found that the analgesic action of morphine was abolished when either catecholamine releasers such as reserpine and tetrabenazine (2), or a potent inhibitor of tyrosine hydroxylase, α-methyltyrosine (3), was given several hours before morphine in mice. This fact has suggested an important role played by catecholamines in the analgesic action of morphine. This suggestion has been further supported by the observation that the abstinence symptoms manifested by nalorphine in morphinized rats is deteriorated by a pretreatment with α-methyltyrosine or disulfiram (4).The present study deals with the development of tolerance to analgesic action of morphine and the change of brain norepinephrine content after intraventricular injection of morphine into the rat. The abstinence symptoms induced by levallorphan in the rat that received repeated intraventricular injections of morphine are also reported.

The development of tolerance to and of physical dependence on morphine following intraventricular injection in the rat.

The mechanism of the development of tolerance to and of physical dependence on morphine has been examined from a wide range of aspects. One of the approaches is to investigate the participation of brain biogenic amines in the actions of morphine. In 1954 Vogt (1) found a reduction of the content of hypothalamic norepinephrine after a subcutaneous morphine in the cat. Following her studies, some investigations were made on the change of the level of brain norepinephrine, dopamine and 5-hyroxytryptamine (5-HT) after either single or repeated administration of morphine. Recently it was found that the analgesic action of morphine was abolished when either catecholamine releasers such as reserpine and tetrabenazine (2), or a potent inhibitor of tyrosine hydroxylase, α-methyltyrosine (3), was given several hours before morphine in mice. This fact has suggested an important role played by catecholamines in the analgesic action of morphine. This suggestion has been further supported by the observation that the abstinence symptoms manifested by nalorphine in morphinized rats is deteriorated by a pretreatment with α-methyltyrosine or disulfiram (4). The present study deals with the development of tolerance to analgesic action of morphine and the change of brain norepinephrine content after intraventricular injection of morphine into the rat. The abstinence symptoms induced by levallorphan in the rat that received repeated intraventricular injections of morphine are also reported.

Role of biogenic amines in morphine dependence in the rat

We have studied the effect of depleting the rat brain of serotonin or catecholamines upon the precipitated abstinence symptoms in morphine-dependent rats. Serotonin depletion by prior administration of p-chlorophenylalanine did not modify the symptoms of ptosis, diarrhea, number of “wet dog” shakes or temperature change, whereas depletion of brain norepinephrine by alpha-methyl-p-tyrosine significantly reduced the number of shakes and the hypothermia precipitated by nalorphine. Administration of L-DOPA 3 hours before precipitating the abstinence syndrome prevented the amelioration of symptoms by AMPT. Modification of catecholamine metabolism by diethyldithiocarbamate and imipramine also reduced the shakes, but affected temperature changes variably. The complete expression of the abstinence syndrome in the rat appears to depend upon adequate brain levels of norepinephrine.

Propoxyphene (Darvon) addiction and withdrawal syndrome.

A 31-year-old woman with longstanding psychiatric difficulty was introduced to propoxyphene (Darvon®) by prescription after gynecologic surgery. She gradually developed a primary addiction and took an oral dose that at times reached 2,300 mg daily. She was hospitalized for drug withdrawal and initially maintained on 1,300 mg propoxyphene daily. Laboratory evaluation showed no evidence of chronic liver, kidney, or hematologic toxicity. Placebos were then substituted for the propoxyphene, and definite abstinence symptoms and signs occurred. These consisted of anorexia, rhinitis, and fatigue, followed by irritability and insomnia. Vomiting developed by the end of 48 hr of abstinence. Propoxyphene was then reinstituted, and within 24 hr the patient was asymptomatic. We conclude that tolerance and physical dependence to propoxyphene can occur.

Withdrawal Symptoms after Abrupt Termination of Imipramine

The reports and clinical experience cited illustrate the physiological withdrawal reaction which follows abrupt imipramine withdrawal. Many such reactions have probably gone unreported or have been misinterpreted as incipient exacerbations of the process under treatment. It is suggested that the patient reported here meets the W.H.O. criteria of a true addiction (31). These findings are discussed in terms of life situation and personality predisposition contributing to development of addiction in this patient at this time. He was in a heightened state of anxious oral dependency and wished to make drug therapy almost a way of life. The following conclusions are drawn: 1) A drug's specific psychopharmacologic effect cannot be considered without reference to the emotional significance of drugs to the psychiatric patient, i.e. to each patient's characteristic way of responding to the drug experience. 2) Withdrawal phenomena may interfere with the evaluation of change due to treatment, or may seem to produce a clinically worse patient. This possibility should be considered when a trial without drugs produces symptoms like those which led to treatment. 3) Imipramine and most psychotropic drugs should be withdrawn gradually, especially following prolonged treatment, and in addicted patients. If abstinence symptoms develop, the dosage should be increased and then gradually withdrawn again over a longer period. 4) The imipramine withdrawal syndrome appears to be non-specific and morphine-like. This suggests the speculation that imipramine belongs to the group of physiological C.N.S. ‘depressants’.

Drug dependence as a criterion for differentiation of psychotropic drugs

Summary Investigations in 81 patients—in whom the administration of neuroleptics or neuroleptics and antiparkinson agents, which had been administered for months or years, was abruptly discontinued—showed that such withdrawal can produce an abstinence syndrome comprising a feeling of warmth or cold, sweating, vertigo, tachycardia, a tendency to collapse, headache, insomnia, nausea, or vomiting. Tremor and the mouth-tongue-throat syndrome, exacerbated or occurring for the first time, were also observed. Elderly and female patients are especially predisposed toward the appearance of these symptoms on discontinuation of prolonged treatment with neuroleptics or neuroleptics combined with antiparkinson agents. Comparative trials showed that in contrast to tranquilizers (meprobamate), neuroleptics do not produce tolerance and their withdrawal does not give rise to psychosis, muscle twitching or grand mal, but to the extrapyramidal disturbances mentioned. Both neurolepties and tranquilizers produce the abstinence symptoms referable to the autonomic nervous system. A broadening of the term “drug dependence” is discussed and the suggestion made that a neuroleptic type—physical dependence without tolerance, presenting as autonomic and extrapyramidal symptoms and characterized by the absence of psychic dependence—should be included. An understanding of this type of drug dependence is important in order that the effects of sudden withdrawal of these drugs be known and distinguished from the symptoms of recurrence of the basic disease.

Spontaneous Opiate Addiction in Rhesus Monkeys

Spontaneous drug-seeking behavior was established in 3 out of 4 rhesus monkeys that were given unrestricted access to morphine and placebo solutions. The monkeys were kept in their home cages throughout the experiment and were not subjected to conditions of stress; prior addiction was not established by the usual injection procedures. The animals became physically dependent on the drug and showed abstinence symptoms when injected intramuscularly with nalorphine (N-allyl normorphine hydrochloride). This method may be useful for studying individual differences in susceptibility to drug abuse.

A CLINICAL TRIAL OF A MIXTURE OF LEVORPHANOL AND LEVALLORPHAN AS AN ORAL ANALGESIC

SUMMARY The effects of a mixture of 1 part levallorphan and 10 parts levorphanol taken by mouth were studied in subjects needing symptomatic control of intractable pain. Response varied according to previous treatment with potent analgesics. The effects were similar to those of the same dose of levorphanol alone in patients not already receiving drugs of addiction. The incidence of side effects was high after long-term opiate therapy. These appeared to be levallorphan-induced abstinence symptoms and were also troublesome when the mixture was given for long periods to patients who had not previously received addicting drugs. Side effects became evident after two or three weeks and render this drug combination unsuitable for clinical use.

Catecholamine metabolism in morphine withdrawal in the dog.

I HAVE noted1 a decrease in the catecholamine content of the rat brain after withdrawal of chronic administration of morphine. This finding, however, seemed to be confined to a certain strain of rats with very conspicuous abstinence symptoms, while an increased urinary excretion of adrenaline and nor-adrenaline2 was observed in three different rat strains. For studies of abstinence phenomena of the excitatory type, comparable with those found in man, higher species must be studied. In 1932 Tachikawa3 reported an increased amount of ‘adrenaline’ in the blood of chronically morphine-treated dogs when the drug was withheld. In 1960 and 1961 Maynert and Klingman4,5 reported a decrease of brain and adrenal catecholamines in morphine-tolerant dogs and rabbits when an abstinence syndrome was produced by nalorphine. No numerical data were given for the decrease.

A STUDY OF EXPERIMENTAL INTOXICATION OF ANTIEPILEPTIC DRUGS (PHENOBARBITAL, 5-5-DIPHENYL-HYDANTOIN, TRIDIONE)

Summary Three kinds of anticonvulsant (Phenobarbital, Hydantoin and Tridione), were administered to 12 adult rabbits and 40 adult cats for 630 days at the longest for the purpose of experimenting the acute and chronic intoxication of those drugs. 1 Concerning these three kinds, histopathological findings were almost similar. The vulnerabilities, however, were diverse as is shown in Table 2. 2 The duration factor of medication influenced much more on histopathological findings than the dosage factor. 3 The animals subjected to chronic intoxication of those drugs showed abstinent symptoms (grand ma1 seizure, vomiting, coma etc.) when administrations were abruptly cut off. 4 The changes of nerve cells are classified in following five patterns; 1) Nuclear swelling, 2) Chromatolysis, 3) Vacuolization, 4) Atrophic change and 5) Eosinophilic cell change. Furthermore, binuclear nerve cells were not seldom observed. 5 In truncus cerebri and medulla spinalis, the motor nuclei tend to show tumescent change i.e., vacuolization and chromatolysis, while the sensory nuclei presented tendency for atrophic sclerosis. 6 The author, comparing so-called ischemic cell change with other eosinophilic cell change and transitional type between these two, came to the conclusion that all of them are to be classified to eosinophilic cell changes as a whole, as there is hardly strict category of differentiation. 7 Oligodendroglial change was classified in 3 forms, namely, rosary oligodendrogliosis racemose oligodendrogliosis and so-called acute swelling. 8 Macrogliosis around the blood vessels, ventricle walls and cortical surface were classified in three types according to the arrangement of the glia cells. 9 In this experiment series also, the various histopathological findings described in the human epileptic brain, namely, so-called ischemic cell change and Chaslin's gliosis etc. were observable, however, neither Ammon's horn sclerosis nor “Prellungs Herd” were observed. 10 The author discussed the difference of vulnerability of Ammon's horn between the human and animals, trying to explain it in terms of genetic anatomy.

The History of the Development of Narcotics

Man and animals generally seek escape from discomfort. Man today seems more prone to do so than ever before and, as will be seen, has acquired a considerable variety of means to that end. No one knows when man learned that there were natural agents available, the poppy among them, to ease his pains; but he did acquire that knowledge, and there the history of narcotics begins. Legally and otherwise, narcotic has a broader connotation than opiate. Practically, however, the major part of the narcotics problem centers around the opiates and their synthetic substitutes, and this account of historical development will deal with these only. Chopra suggests that the food value of the seeds of the opium poppy was recognized much earlier than the somniferous property of the capsule or poppy head,' but the capsules were used in the preparation of soporific drugs and soothing beverages from time immemorial. Poppies were grown for the capsules in Asia Minor many centuries ago, and the Arabs carried the dried poppy heads to eastern countries at a very early date. Eventually, someone discovered that at one stage in the development of the poppy plant, Nature seemed to concentrate its soporific properties-that is, the ingredients responsible for them-in the plant juice which would exude from the lanced ripe poppy head. This juice, collected and dried, is crude opium. Opium became a household remedy and the mainstay of the physician in its crude form, in pills, and in various liquid preparations-laudanum, paregoric, etc.whatever the symptomatic need. It also became a medium of social exchange and self indulgence as a confection and, in modified form, for smoking. Even into the latter half of the nineteenth century, there was little recognition of and less attention paid to overindulgence in or abuse of opium. It was the panacea for all ills. When a person became tolerant to its action and dependent upon it so that abstinence symptoms developed if a dose or two were missed, more was taken for the aches and pains and other discomforts of abstinence, just as it was taken for similar symptoms from any other cause. In the first decade of the last century, just about 150 years ago, the curiosity of Sertiirner, a German pharmacist, brought about the separation and recognition of

The effects of maternal narcotic addiction on the newborn

I N RECENT years the increased use of narcotics among teenagers and young adults has been widely publicized. Our attention was further focused on the problems of addiction when a local agency questioned the senior author on the possible effects of maternal morphinism on the newborn. As we searched for such cases and discussed this problem with other obstretricians and pediatricians we were able to find 10 cases of pregnancy complicated by drug addiction. Five of these women were admitted to the obstetrical service of the Morrisania City Hospital during the years 1951 to 1954. Since the effects of narcotic withdrawal were not always characteristic in the cases under our observation, we checked the standard texts in pediatrics and obstet,rics and the current literature, but were unable to gather much information. The United States Public Health Service and the World Health Organizat,ion at Geneva were contacted but they could offer us little help. Because of the paucity of available information we feel that a thorough review of this subject is timely. Table I lists the number of cases reported in the literature of infants delivered of narcotic-addicted mothers, the symptoms reported, and the therapy given. Some of the infants were entirely asymptomatic. Those infants who develop abstinence symptoms, however, show a characteristic syndrome. Most authors have reported that t,he infant appears normal at birth, but within 24 to 72 hours a progrcssivc restlessness ancl irritability begin. Accompanying the restlessness is a protracted shrill cry that may last for hours at a time ancl gives the impression that the infant is in pain. The infants feed poorly and the small amount of nourishment taken by mout,h is usually vomited. Other authors have reported that yawning and intermittent cyanosis are frequently seen. Diarrhea occurs and together with the pool intake causes inanition. The infants undergo severe dystrophy and may die in convulsions. Generally speaking, the symptoms prominent in the newborn arc very similar to those found in the abstinence syndrome of the adult. It is readily understandable how somatic requirements for opiates can be built up in the fetus. It is well known that morphine readily passes the placenta and produces varyin g degrees of asphyxia in utero as indicated by changes in rate and rhythm of the fetal heart. Shute ancl Davis 2o howcvcr, felt that individual susceptibility played an important role in tie effects of

SERUM CHOLINE ESTERASE IN BARBITURATE ADDICTION AND EPILEPSY

1. The previously described decrease of serum choline esterase after prolonged administration of barbiturates in man was studied in epileptics after sudden withdrawal of the drug. The number of seizures then rises sharply to a maximum, while the choline esterase is still at a low level.2. The seizures become less frequent again when the choline esterase starts to rise, and usually disappear completely when the choline esterase has just reached what proves to be, in the particular individual, its highest level.3. When the drug is given, the choline esterase decreases to a minimum in about three weeks, whereas the number of seizures is minimal in a few days.4. A time sequence of the abstinence symptoms was noted, the withdrawal psychosis appearing first and wearing off when the grand mals were at their peak, whereas the latter preceded the maximal frequency of petit mal seizures.5. In an unselected group of cryptogenic (idiopathic) epileptics, when under no treatment for some time, a slightly higher average value of serum choline esterase was found than the normal average, the difference being statistically not significant. In some of the epileptics, however, much higher values were found than were ever found in normals. The possible existence of one group of epileptics, characterised by a high choline esterase, is discussed.6. After the withdrawal of the drug the narcotic effect seems to wear off more rapidly than the choline esterase increases. Thus the cholinergic system, free from narcotic and probably at a high level of activity, is left with an inadequate amount of choline esterase. This discrepancy probably accounts for the abstinence symptoms.7. Because of the relative lack of choline esterase during the period of abstinence symptoms, excessive cholinergic activity is assumed to exist. A number of indications for this are found, and its possible rôle in the production of seizures is discussed. Some diverse features, such as the peak incidence of seizures during the night, the precipitating action of alcohol in epilepsy, and some features in the electro‐encephalograms, become more understandable from this viewpoint.I am greatly indebted to Professor P. C. Cloake for his interest and helpful encouragement in this investigation. I am also very grateful to Dr. J. J. O'Reilly, Medical Superintendent of the Birrningham City Mental Hospital, Winson Green, for providing me with the necessary material from the patients under his care, for altering within limits of safety the treatment given to a number of them as this appeared important for these experiments, and for his kind help. I am also grateful to G. Hoyle and D. Marshall for valuable technical assistance.