ADVERSE EFFECTS

eNS Drugs 1996 Mar: 5 (3): 190-199 1172-7047/96/0003-0190/$05.00/0 © Adis International Limited. All rights reserved.

Anticholinergic Drug Abuse and Misuse

Epidemiology and Therapeutic Implications

Patricia A. Marken,1,2,3 Steven C. Stoner1,3 and Mark T. Bunker1,3 1 Department of Pharmacy Practice, University of Missouri-Kansas City, Kansas City, Kansas, USA 2 Department of Psychiatry, University of Missouri-Kansas City, Kansas City, Kansas, USA 3 Schools of Pharmacy and Medicine, Western Missouri Mental Health Center, Kansas City, Missouri, USA

Contents Summary ................. . 1. History of Anticholinergic Drug Abuse . . 2. Pharmacology of Anticholinergic Drugs 2.1 Medicallndlcations . 2.2 Receptor Effects . . . 2.3 Dose-Related Effects. 2.4 Drug Interactions . . . 3. Characterising Use Patterns of Anticholinergic Drugs . 3.1 DSM-IV Diagnostic Criteria for Abuse and Dependence 3.2 Analysis of 110 Case Reports . . . . . . . . . . . . . . . 3.3 Subgrouplngs of Patterns of Anticholinergic Drug Use . 3.3.1 True Abusers . . . . . . . . . . . . . . . . . . . . . 3.3.2 Abusers with Valid Medical Indications . . . . . . 3.3.3 Patients who Potentially Benefit from Anticholinergic Drugs. 3.3.4 Role of Acetylcholine in Depression and Schizophrenia 4. Application to Practice . . . 4.1 When to Suspect Abuse . . . . . . . . . . . 4.2 Management of Abuse . . . . . . . . . . . 4.3 Risk-Benefit Assessment for Long Term Use. 4.4 Withdrawal and Discontinuation 5. Conclusion . . . . . . . . . . . . . . . . . . . . .

Summary

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Abuse of the centrally acting anticholinergic agents is a phenomenon occasionally reported in the medical literature. Anticholinergics, most often used in psychiatry to treat antipsychotic-induced extrapyramidal symptoms, are also used by some patients for their mood altering and psychedelic effects. The changes in sensorium can range from mild euphoria and increased sociability to hallucinations and toxic psychosis. In this article, we have reviewed 110 cases of reported anticholinergic abuse and identified 3 distinct groups of abusers: (i) those individuals who have no valid medical need for the medication and consume it only for its mind-altering effects;

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(ii) those with a valid indication for the use of anticholinergics who also abuse the agents for their mind-altering effects; and (iii) those who have an appropriate medical indication for the agents and appear to be using anticholinergics to relieve chronic or subclinical extrapyramidal symptoms, depression or negative schizophrenic symptoms. True abusers (i.e. those individuals in the first 2 groups) can be recognised because they feign extrapyramidal symptoms, repeatedly 'lose' their medications or request unnecessary dose increases. In order to reduce the risk of abuse, exposure to anticholinergics should be minimised in patients at risk. Patients who are reluctant to have their anticholinergics discontinued should be carefully evaluated to identify potential risks and benefits of continued use before prolonged therapy is instituted. Anticholinergics should not be abruptly discontinued, but instead tapered over a 2-week period in patients receiving high doses or long term treatment.

1. History of Anticholinergic Drug Abuse Belladonna alkaloids are natural occurring compounds that have been used as both medicinal and hallucinogenic agents for centuries. Ancient Romans and Egyptians used these substances to dilate the pupils of young girls and enhance their beauty, hence the name 'belladonna' . Belladonna alkaloids were also used as poisons during the Roman Empire and in the Middle Ages.[ll Bolin[2l reported the first case of anticholinergic drug abuse in 1960. A young woman with severe torticollis was prescribed 2mg tablets of trihexyphenidyl (benzhexol), to be taken up to a maximum of 6 per day. She escalated the dosage up to 30 mg/day in order to experience euphoria and a sense of well-being. She subsequently developed toxic psychosis and paranoia. The patient was not on concurrent antipsychoticsPl Few reports of anticholinergic abuse were found in the literature until the mid-1970s. Subsequently, there have been numerous published case reports and small studies describing anticholinergic abuse. Estimates of abuse vary from infrequent to 17.5% of inpatientsJ3l The wide range in the incidence is probably due to inconsistencies in the identification methods and definitions of abuse. The intent of this paper is to review the published reports of anticholinergic abuse to describe the demographics of abuse, characterise the different types of misuse and abuse, describe potential mechanisms of mis© Adis International Umited, All rights reserved,

use and abuse, and offer treatment recommendations.

2. Pharmacology of Anticholinergic Drugs 2.1 Medical Indications

Although atropine was isolated from the Atropa belladonna (deadly nightshade) plant in 1831, its pharmacology was not described until 1867. Anticholinergics are widely used in medicine for such varied indications as: • ophthalmological examinations • irritable bowel syndrome • emesis prevention • bradycardia • antipsychotic-induced extrapyramidal symptoms (EPS) • Parkinson's disease. Synthetic anticholinergics have replaced atropine as the most commonly used agents. 2.2 Receptor Effects

The mechanism of action of both synthetic anticholinergics and natural belladonna alkaloids is competitive inhibition of acetylcholine at muscarinic receptors. Very high doses will also partially block nicotinic receptors, including those at the neuromuscular junction. All anticholinergics have similar pharmacological profiles and, because of their indiscriminate eNS Drugs 1996 Mar; 5 (3)

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Table I. Anticholinergic drugs Drug

Daily oral dose (mg/day)

Dose for acute dystonia IMIIV (mg/dose)

Benzatropine (benztropine)

2-12

1-2

Biperiden

4-16

2

Diphenhydramine

50-200

25-50

Procyclidine

5-20

Trihexyphenidyl (benzhexol)

4-15

Abbreviations: 1M = intramuscular; IV = intravenous.

muscarinic blockade, cause a wide range of therapeutic and toxic effects. Attempts to increase the receptor site and organ system specificity of anticholinergics has been largely unsuccessful. Apart from potency at muscarinic receptors, dosage form availability and pharmacokinetics,[ll only small differences exist between anticholinergics (table 1))41 Clinically, benzatropine (benztropine) is reported to be more sedating, while trihexyphenidyl is more stimulating.[51 2.3 Dose-Related Effects

Anticholinergic medications have both peripheral and central dose-related effects. Small doses of atropine (O.5mg or less) cause mild cardiac slowing due to transient vagal nerve stimulation, and dry mouth and decreased sweating. Larger doses (between 1 and lOmg) exaggerate the dry mouth and decreased sweating, and additionally causes pupil dilation, tachycardia, decreased visual accommodation, difficulty in micturition and slowed gastrointestinal motility. Toxic doses (> lOmg) result in more marked presentation of previously described symptoms along with excitation, irritability, disorientation, hallucinations and delirium. Ultimately, respiratory failure, cardiovascular collapse, coma and death can occur with massive dosesPI 2.4 Drug Interactions

Drug interactions are primarily limited to additive anticholinergic and hyperthermic effects with concurrent use of other agents that have antimuscarinic activity, such as tricyclic antidepressants, © Adis International Umited. All rights reserved.

and additive CNS depression with concurrent depressants such as alcohol (ethanol))61

3. Characterising Use Patterns of Anticholinergic Drugs Despite the potential for misuse and abuse, physicians must prescribe anticholinergics and clinicians should be able to assess the difference between abuse, misuse and benefit. 3.1 DSM-IV Diagnostic Criteria for Abuse and Dependence

Dependence, misuse and abuse are terms used in the literature to describe inappropriate patterns of anticholinergic consumption. The DSM-IV[71 lists diagnostic criteria for substance dependence and abuse, but not for misuse (tables II and III). Substance dependence has both the physiological consequences of long term, heavy drug use (such as tolerance, compulsive consumption and withdrawal), along with the psychosocial consequences of loss of role functioning and continued use despite harm. Abuse is more focused on the recurrent and significant adverse life consequences due to the drug use and not the physiological manifestations. DSM-IV lists dependence and abuse with anti parkinsonian-anticholinergic and antihistaminic agents under 'other substance-related disorders' . Table II. Adapted DSM-IV[7] diagnostic criteria for substance dependence

A pattern of substance use, leading to clinical significant impairment or distress, as manifested by at least 3 of the following occurring at any time in the same 12-month period: Tolerance Withdrawal Taking larger amounts or over a longer period Persistent. yet unsuccessful. desire to cut down or control use Significant time is spent in activities to obtain the substance or recover from its effects Important activities/commitments are curtailed because of substance use Continued use despite persistent or recurrent physical or psychological problems caused or exacerbated by the substance

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Table III. Adapted DSM·IVI7) diagnostic criteria for substance abuse A pattern of substance use, leading to clinical significant impairment or distress as manifested by 1 (or more) of the following, occurring within a 12-month period: Recurrent use resulting in a failure to meet major obligations Use in situations in which it is physically hazardous Recurrent substance-related legal problems Continued use despite persistent or recurrent social or interpersonal problems caused or exacerbated by the substance Never met criteria for substance dependence

3.2 Analysis of 110 Case Reports

Tables IV and V detail the diagnostic characteristics from an analysis of 110 published cases of anticholinergic abusep,3,8-22] These cases were identified from a search of MEDLINE. Additional previous reports were then identified from the bibliographies of these articles. The cases were selected because demographic data such as age, drugs of abuse and diagnosis were available for analysis. As can be seen from table IV, all patients were taking anticholinergics for the treatment of psychiatric disorders. Abuse of anticholinergic agents that are usually prescribed for other conditions has been rarely reported. Sato et alP3) reported 2 cases of women abusing cyclopentolate eye drops for central cholinergic blocking effects. Buckley et aU24) reported a case of anticholinergic psychosis following abuse of prescription antidiarrhoeal medication containing morphine and belladonna extract. Finally, Delisle[25) reported a case of amitriptyline abuse in a 24-year-old woman. She consumed up to 2g of amitriptyline a day and experienced withdrawal symptoms, nausea and vivid dreams upon discontinuation. These cases were not included in the analysis of 110 cases of anticholinergic abuse. Of the 110 cases reviewed, 8 individuals (7%) were described as having abuse, addiction or dependence to 1 or more substances, with no other Axis I diagnosis (table IV). 67 patients (61 %) concurrently used or abused at least 1 mind-altering substance and also had another Axis I diagnosis, usually schizophrenia (table V). In fact, 60% of the analysed patients had schizophrenia. These pa© Adls International Limited. All rights reserved.

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tients could rarely be given the specific DSM diagnosis of substance abuse or dependence. Instead, the terms were used in a more descriptive manner rather than being reflective of a patient meeting the actual criteria for a diagnosis. Most patients used more than 1 substance (polysubstance abuse) [table V]. The individuals overall were young, with an average age of 29 years (age range 17 to 56 years), and predominantly male (70%). Data on employment status were available in only 27 individuals. 22 of the 27 (81.5%) were unemployed at the time of the study. Trihexyphenidyl was used in 69% of cases (table VI). However, there was no way of determining whether the preference for trihexyphenidyl was because it was the most commonly prescribed anticholinergic or because of a true preference for the agent.[18) The dosages of trihexyphenidyl consumed by patients ranged from 15 to 60 mg/day. Most reports did not state why anticholinergics were originally prescribed or whether patients were regularly reassessed for ongoing extrapyramidal symptoms, which would necessitate long term treatment. 3.3 Subgroupings of Patterns of Anticholinergic Drug Use

Even though the bulk of the literature on anticholinergic abuse is descriptive and uncontrolled, Table IV. Psychiatric diagnoses from an analysis of 110 published cases of anticholinergic drug abuse[2.3.8-22) Psychiatric disorder No. of patients Schizophrenia 65 Personality disorder 15 Mood disorder 11 Schizoaffective disorder 5 Polysubstance abuse/dependence 4 Diamorphine (heroin)/opioid addiction 3 Adjustment disorder 2 Psychosis not otherwise specified 2 Schizophreniform disorder Alcohol (ethanol) dependence 1 Total 109" a One patient had no Axis I diagnosis and was not included.

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Table V. Patients from an analysis of 110 published cases of anticholinergic drug abuse who also used/abused other drugs[2.3.8.22j Drug class

No. of patients

Polysubstance use"

62 3 2

Benzodiazepines Hallucinogens (general use) a

Polysubstance use included alcohol (ethanol), marijuana, opioids, amphetamines, cocaine, hallucinogens, benzodiazepines, cough mixtures, solvents, antipsychotics and diamorphine (heroin).

cases can be subdivided into 3 groups, based on diagnoses and reasons for use. 3.3. 1 True Abusers

The first group is composed of patients with substance dependence or abuse as their sole Axis I diagnosis. Members of this group have no valid medical indication for anticholinergics, but take them for the toxic effects of euphoria or psychosis.l Il ,14,17,22,26] Only 7% of the analysed cases fit into this group. 3.3.2 Abusers with Valid Medical Indications

Another subgroup comprised patients who appeared to have been started on anticholinergics for valid medical reasons, most likely for the management of antipsychotic-induced EPS, and now consume them in an abusive or dependent manner. These patients sometimes stop or reduce the dose of their concurrent antipsychotics, while continuing their anticholinergics in order to experience toxic effects.[3,17] Reasons for abuse in this group are varied, however many schizophrenic patients seek an euphoric or energising 'buzz', while patients with personality disorder report a psychedelic experience.[3,1l,12,14,16,19] Patients can become habituated to the energising effects of anticholinergics, leading to tolerance and dose escalation.[2,3] People who take anticholinergics in an abusive manner (these initial 2 groups) will obtain their drugs in a variety of ways. Some may purchase them illegally. Others obtain them from physicians by feigning EPS, requesting dose increases even though their antipsychotic dose is unchanged, or repeatedly 'losing' their prescriptionsJl4,19,27] © Adis International Limited. All rights reserved.

These patients describe a variety of psychedelic experiences after taking anticholinergics. The high was described by one patient as 'a weird combination of LSD and amphetamines' .1 19] Others said that benzatropine produced realistic and intense visual hallucinations that could not be separated from reality. Some had extended conversations with their hallucinations, losing total insight into the substance-induced experience)}] Anticholinergics are not usually a hallucinogen of choice, but instead are used when the preferred substance is unavailable, or to enhance the psychoactive effects of other substances.[28] 3.3.3 Patients who Potentially Benefit from Anticholinergic Drugs

A third group of patients are sometimes described in the literature as abusers based on their reluctance to discontinue anticholinergics. The lack of information given in some reports often made it difficult to separate this group from the patients described in section 3.3.2; nevertheless, real differences exist. These patients also have an appropriate medical indication for anticholinergics, but they use their medication as prescribed. They are labelled as 'abusers' because they voice opposition to stopping their anticholinergics, a behaviour viewed as a 'red flag' for abuse. However, further evaluation often uncovers valid reasons for their lack of cooperation.[17,29] Often these patients have a history of EPS and fear its return. Others have chronic EPS, especially akinesia and akathisia, which require ongoing anticholinergic therapy. Akinesia, a Table VI. Anticholinergic drugs abused from an analysis of 110 published cases[2.3,8-22j Drug Trihexyphenidyl (benzhexol) Benzatropine (benztropine) Biperiden Diphenhydramine Orphenadrine

No. of patients 76

16 8 8 6

Procyclidine 2 Total 1168 a Some patients abused more than one anticholinergic agent.

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loss of spontaneous movement or speech, can present without muscle rigidity and may be missed during an EPS assessment. Akinesia can also be confused with depression or negative symptoms of schizophrenia. Akathisia (characterised by subjective and/or objective restlessness) is especially disturbing to patients, as many are unable to verbalise their feelings of unrest. Both the patient and clinician may have difficulty distinguishing akathisia from the psychomotor agitation found with psychosis. Many, but not all patients, develop tolerance to EPS after several weeks of continuous antipsychotic treatment. A study by Saran[30] evaluated 108 outpatients with schizophrenia to identify differences between patients with a real ongoing need for anticholinergics from those who were abusing themPO] Patients were included if they took anticholinergics and anti psychotics concurrently for at least a year. 32 had moderate-to-severe EPS at baseline and remained on their anticholinergics. 76 had mild-tono EPS and were further subdivided based on their willingness to discontinue their anticholinergics while continuing their antipsychotics. 27 were reluctant to have their anticholinergics discontinued and all were found to have mild EPS. They were afraid to stop the medication because without it they felt nervous or slowed down. Six of the 27 (22%) had a history of drug abuse, and none appeared to be taking anticholinergics for toxic effects. The remaining 49 had their anticholinergic dose cut in half or stopped abruptly. 33 of the 49 patients (67%) developed moderate-to-severe EPS, and 9 stopped anti psychotics on their own. Saran's study demonstrates that long term use of anticholinergics and reluctance at the time of discontinuation alone are not reasons enough to label a patient an anticholinergic abuser. In fact, some patients require long term anticholinergics to manage chronic EPSpO.31] Patients in this third group also describe a socialising and antidepressant effect from their anticholinergics, and may be self-medicating underlying depression or negative symptoms of schizophrenia.[l8.21.32] The relationship between depres© Adis Intematlonal Limited, All rights reserved,

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sion, antipsychotic-induced akinesia and negative symptoms is a confusing and controversial one. All 3 diagnoses share common symptoms such as anhedonia, blunted affect, poor grooming and hygiene, poverty of speech and poor social skills. All 3 disorders have been reported to improve with anticholinergic treatmentP3.34] 3.3.4 Role of Acetylcholine in Depression and Schizophrenia

The role of acetylcholine in the regulation of schizophrenia and mood disorders may explain why anticholinergics produce beneficial effects in patients, even though they do not have obvious EPS. The adrenergic-cholinergic hypothesis of affective disorders states that mania is caused by a relative predominance of the central adrenergic system, whereas depression is secondary to an increase in central cholinergic activityP5.36] The dopaminergic-cholinergic theory of schizophrenia finds that positive symptoms, such as hallucinations and delusions, are caused by an increased dopaminergic activity in the mesolimbic and mesocortical systems. Cholinergic system hyperactivity causes negative symptoms and may be protective against emergent positive symptoms. Negative symptoms are masked by positive symptoms during an acute psychotic episode, but once the psychosis remits, negative symptoms dominate because the cholinergic system takes longer to normalise. Emergent or persistent negative symptoms after resolution of an acute psychotic episode has been called 'postpsychotic depression', and may be found in up to 25% of patientsP4.37] Anticholinergics could thereby reduce depression and negative symptoms by reestablishing the balance between the adrenergic and cholinergic system and the dopaminergic and cholinergic system.[33.35.38.39] Only a few studies have been published that specifically assess the efficacy of anticholinergics in postpsychotic depression and the negative symptoms of schizophrenia. A study by Siris[33] found that anticholinergics only partially resolved postpsychotic depression and that antidepressants were needed to completely relieve the symptoms. Anticholinergics were very effective in resolving antieNS Drugs 1996 Mar; 5 (3)

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psychotic-induced akinesia, which was almost indistinguishable clinically from postpsychotic depression. Tandon et aI.l34] gave trihexyphenidyl Smg twice a day for 8 weeks to 5 patients with chronic residual schizophrenia.[34] The patients had no evidence of EPS, as measured by the Simpson Angus Scale; however, depression was not specifically assessed. An improvement in affective blunting, anhedonia, anxiety, sleep, emotional withdrawal and depressed mood was noted. Trihexyphenidyl was well tolerated and did not exacerbate positive schizophrenic symptoms, a concern expressed by others.l40] The authors suggested that patient improvement may be secondary to a direct antidepressant action of trihexyphenidyl, or from an improvement of unrecognised antipsychotic-induced akinesia.[39] However, the results of another trial[41] did not support the findings of Tandon et al.[34] Trihexyphenidyl was administered to lO unmedicated patients with schizophrenia to assess its impact on negative symptoms, depression and psychosis and to determine the abuse potential of the drug. The patients were given trihexyphenidyl Smg twice a day or placebo for 4 weeks. Subsequently, they were crossed over to the other arm of the trial for an additional 4 weeks of treatment. There was no significant change in psychotic, negative or depressive symptoms in the placebo or trihexyphenidyl group. The authors concluded that schizophrenic patients do not abuse anticholinergic agents to improve their negative or depressive symptoms.l 41 ] The lack of benefit in this latter trial may be because the patients were in a stable phase of their illness. The ability of anticholinergics to modulate positive and negative symptoms of schizophrenia is thought by some to be most significant during the acute phase, before the dopaminergic and cholinergic systems return to a resting state.[39.42]

4. Application to Practice 4.1 When to Suspect Abuse

Anticholinergics clearly have the potential to be agents of abuse. In order to reduce the confusion © Adis International Limited. All rights reserved.

surrounding issues of inappropriate use, a practitioner should develop a clear definition of anticholinergic abuse and dependence. DSM-IV diagnostic criteria are the most consistent way to characterise anticholinergic consumption. Most real abusers are young, single, polysubstance abusers with poor psychosocial functioning.l27] A clinician should suspect abuse and/or dependence when new or unusual psychotic or mood symptoms develop along with any physical signs and symptoms of anticholinergic consumption. Additionally, patients taking prescribed anticholinergics who ask for a dose increase without an obvious reason, complain of EPS despite none being found on physical examination, or frequent emergency rooms complaining of dystonia should be assessed for abuse. 4.2 Management of Abuse

The best way to manage anticholinergic abuse is by prevention. This can be achieved by minimising exposure to the drugs in high risk patients. However, anticholinergic treatment may be needed in patients at risk of real abuse. Anticholinergic prophylaxis should be avoided in high risk patients, such as those with a significant history of substance abuse. Whenever possible, avoid placing high risk patients on high potency antipsychotics, especially large doses, thereby decreasing the risk of EPS)27] High risk patients who require treatment for EPS should be managed initially with antipsychotic dose reduction whenever possible, or with alternative agents such as ~-adrenoceptor blockers for akathisia and amantadine for pseudoparkinsonism. If anticholinergics are used, the presentation and severity of the EPS should be charted, along with a specific plan for duration of use. Instead of automatic refills, the clinician must complete regular evaluations to assess whether anticholinergics are still indicated. For example, a patient treated for acute dystonia may only need anticholinergics for a few weeks. Pseudoparkinsonism usually needs treatment for more than a few weeks, but should be reevaluated every 3 months because tolerance may eNS Drugs 1996 Mar; 5 (3)

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develop to EPS over timePll Careful attention to refill patterns and unusual psychiatric symptoms should also be made.

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larly at risk for anticholinergic-induced memory impairment.[451 4,4 Withdrawal and Discontinuation

4.3 Risk-Benefit Assessment for Long Term Use

The group of patients who are compliant with their anticholinergics, but report improvement in depression, negative symptoms of schizophrenia and EPS may be confused with true abusers. The use of anticholinergics for these reasons may be more common than real abuse and dependence, and more difficult to detect.[3 21 These patients become labelled as abusers because of their opposition to changes in their anticholinergic regimens. Opposition to dose reduction or discontinuation is a warning sign, but alone does not constitute abuse. Reluctance may be well founded and based on a fear of reemergent EPS. These patients warrant careful evaluation to identify the real risks and benefits of their anticholinergic treatment before prolonged therapy is prescribed. Currently, there are no data to suggest that appropriate long term anticholinergic treatment increases the risk for true abuse. Before a long term course of anticholinergic treatment can be advocated, consideration of other risks should be undertaken. Anticholinergics can acutely worsen tardive dyskinesia; however, worsening appears to be short-lived and symptoms diminish on discontinuation of the anticholinergic. Of greater concern was the fear that long term anticholinergics increased the risk for tardive dyskinesia.l43 ,441 Reanalysis of the relationship between long term anticholinergic use and the risk of this disorder, indicates that pseudoparkinsonism itself may be the risk factor, independent of treatment with anticholinergics. Another potential problem with long term anticholinergic use is a worsening of memory in already cognitively impaired patients. There is an inverse relationship between anticholinergic drug concentration and performance on recent memory tests such as verbal recall. The elderly are particu© Adls International Umited, All rights reserved.

If a patient is to be discontinued from long term or high-dose anticholinergics, then tapering is recommended in order to avoid withdrawal. Abrupt withdrawal can result in a variety of symptoms (see table VII). Anticholinergic withdrawal has been evaluated primarily in the antidepressant literature. Krammer et aU461 found that patients taking imipramine, a highly anticholinergic antidepressant, for more than 2 months had a greater risk of withdrawal than patients taking it for less than 2 months. Of the 45 patients evaluated during imipramine discontinuation, 85% of those treated for more than 2 months had withdrawal symptoms versus only 16% treated for less than 2 months. Although, no specific protocols have been studied for antiparkinsonian-anticholinergic withdrawal, tapering the medication over 2 to 3 weeks is likely to minimise any significant distress)27,28, 361 The antidepressant literature recommends tapering over 2 to 4 weeks. Krammer et al.l 461 evaluated methods of imipramine withdrawal in patients treated for longer than 2 months. They found that only 2 of 12 patients (17%) who were tapered over a 2-week period or longer had withdrawal symptoms. In contrast, 8 of 13 patients (62%) who were tapered over less than 2 weeks experienced withdrawal. Patient support during the tapering phase, Table VII. Symptoms induced by rapid withdrawal of antichOlinergic drugs CholinergiC rebound Myalgias Depression Anxiety Insomnia Headaches Gastrointestinal distress Vomiting Nightmares Rebound pseudoparkinsonism Malaise

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along with frequent assessment and, if needed, intervention for reemergent EPS, depression or declining psychosocial functioning will improve the likelihood of success. Tricyclic antidepressantinduced withdrawal symptoms usually resolve within a week.l47 ] A similar time course would be expected for antiparkinsonian-anticholinergics, therefore long t~rm problems are unlikely. Once the medication is stopped in a true abuser, clear documentation of the abuse should be made in the records, so that anticholinergics are avoided in the future. 5. Conclusion

Anticholinergic medications make important contributions to the management of many medical conditions. When one considers how often anticholinergics are prescribed, it appears that only a minority of patients truly abuse them. Careful identification of the patient's perceived benefits from the anticholinergic medication and implementation of alternative strategies to achieve such benefits, is needed to successfully minimise the use of these drugs. Real abusers should not receive anticholinergics, unless there are no other options available. Additional long term studies are needed to better identify patients who benefit from long term therapeutic doses of anticholinergics. Acknowledgements The authors would like to acknowledge Susan Khan and Rene Home for their technical support during the preparation of this manuscript.

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7. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994 8. Buckley P, Larkin C, O'Callaghan E. Psychosis following use of proprietary antidiarrhoeal medicines. Br J Psychiatry 1990; 157: 758-9 9. Craig DH, Rosen P. Abuse of antiparkinsonian drugs. Ann Emerg Med 1981; 10: 98-100 10. Deutsch A, Eyma J. Massive ingestion of trihexyphenidyl [letter]. Am J Psychiatry 1992; 149: 574-5 II. Fisch RZ. Trihexyphenidyl abuse: therapeutic implications for negative symptoms of schizophrenia? Acta Psychiatr Scand 1987; 75: 91-4 12. Goggin DA. Trihexyphenidyl abuse for euphorigenic effect. Am J Psychiatry 1979; 136: 459-60 13. Harrison G. The abuse of anticholinergic drugs in adolescents [letter]. Br J Psychiatry 1980; 137: 495 14. JeIlinek T. Mood elevating effect of trihexyphenidyl and biperiden in individuals taking antipsychotic medication. Dis Nerv Syst 1977; 38: 353-5 15. Johnson AL, Hollister LE, Berger PA. The anticholinergic intoxication syndrome: diagnosis and treatment. J Clin Psychiatry 1981;42: 313-7 16. Kaminer Y, Munitz H, Wijsenbeek H. Trihexyphenidyl (Artane) abuse: euphoriant and anxiolytic. Br J Psychiatry 1982; 140: 473-4 17. Macvicar K. Abuse of antiparkinsonian drugs by psychiatric patients. Am J Psychiatry 1977; 134: 809-11 18. Pullen Gp, Best NR, Maguire J. Anticholinergic drug abuse: a common problem? BMJ 1984; 289: 612-3 19. Rubinstein JS. Antiparkinsonian drug abuse: eight case reports. Hosp Community Psychiatry 1979; 30: 34-7 20. Sofair J, Campion J, Angrist B. High dose trihexyphenidyl abuse with psychological dependence [letter]. J Clin Psychopharmacol 1983; 3: 263-4 21. Wells BG, Marken PA, Rickman LA, et al. Characterizing anticholinergic abuse in community mental health. J Clin PsychopharmacoI1989;9:431-5 22. Woody GE, O'Brien CPo Anticholinergic toxic psychosis in drug abusers treated with benztropine. ComprPsychiatry 1974; 15: 439-42 23. Sato EH, Freitas DD, FosterCS. Abuse of cyclopentolate hydrochloride (Cyclogyl) drops [letter]. N Engl J Med 1992; 326: 1363-4 24. Buckley P, Larkin C, O'Callaghan E. Psychosis following use of proprietary anti diarrhoeal medicines. Br J Psychiatry 1990; 157: 758-9 25. Delisle J. A case of amitriptyline abuse [letter]. Am J Psychiatry 1990; 147: 1377-8 26. Marriott P. Dependence on antiparkinsonian drugs [letter]. BMJ 1976; 17: 1152 27. Land W, Pinsky D, Salzman C. Abuse and misuse of anticholinergic medications. Hosp Community Psychiatry 1991; 42: 580-1 28. Dilsaver SC. Antimuscarinic agents as substances of abuse: a review. J Clin Psychopharmacol 1988; 8: 14-22 29. Rubinstein JS. Abuse of antiparkinsonism drugs: feigning of extrapyramidal symptoms to obtain trihexyphenidyl. JAMA 1978; 239: 2365-6 30. Saran AS. Use or abuse of antiparkinsonian drugs by psychiatric patients. J Clin Psychiatry 1986; 47: 130-2 31. Casey DE. Neuroleptic-induced acute extrapyramidal syndromes and tardive dyskinesia. Psychiatr Clin North Am 1993; 16: 589-610

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Anticholinergic Drug Abuse and Misuse

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Correspondence and reprints: Prof. Patricia A. Marken, Associate Professor of Pharmacy Practice and Psychiatry; University of Missouri-Kansas City, School of Pharmacy, Division of Pharmacy Practice, 2411 Holmes M3-C19, Kansas City, Missouri, USA.

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