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Recognition of a dopamine replacement therapy dependence syndrome in Parkinson's disease: a pilot study☆
Drug and Alcohol Dependence 76 (2004) 305–310
Recognition of a dopamine replacement therapy dependence syndrome in Parkinson’s disease: a pilot study夽 Jennifer Bearna,∗ , Andrew Evansb , Michael Kellehera , Kirsten Turnerb , Andrew Leesb a b
National Addiction Centre, Institute of Psychiatry, 4 Windsor Walk, London SE58AF, UK Reta Lila Weston Institute of Neurological Studies, Windeyer Medical Institute, UCL 46, Cleveland Street, London W1P 6DB, UK Received 23 June 2004; received in revised form 25 June 2004; accepted 30 June 2004
Abstract Patients with Parkinson’s disease may use Dopamine Replacement Therapy (DRT) in excess of therapeutic need. We investigate whether a group of 10 patients with Parkinson’s disease, provisionally diagnosed with “Hedonistic Homeostatic Dysregulation” because of their excessive use of DRT, met established operational psychiatric criteria for substance dependence, compared with 10 patients with Parkinson’s disease compliant with prescribed DRT. Using a semi-structured questionnaire designed to distinguish between adaptive therapeutic dependence on DRT and a maladaptive pathological pattern of DRT use, in conjunction with the SCID-1, we found that seven of the patients deemed by their treating physicians to be misusing DRT fulfilled operational criteria for maladaptive dependence in contrast to none of the compliant group. The majority experienced dysphoric “withdrawal” symptoms in the “off” state and increased their dose of DRT in an effort to control their mood. They also continued to use high doses of DRT despite disabling dyskinesias and social difficulties. This study provides preliminary evidence that some patients with Parkinson’s disease may become maladaptively dependent on DRT. This finding has both clinical relevance for the treatment of PD and further implicates dopaminergic pathways in the genesis of substance dependence. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Parkinson’s disease; Levodopa; Drug dependence; Cocaine
1. Introduction Dopamine replacement therapy (DRT) is an established treatment for patients with Parkinson’s disease (PD). Recently, a group of 15 predominantly early onset patients who take DRT in excess of their therapeutic requirements with a pattern of maladaptive, escalating DRT use is described (Giovannoni et al., 2000). From an early stage of the disease, these patients took extra medication, from stockpiles accrued through multiple sources, resisted attempts to reduce the prescribed dose and tolerated adverse effects which 夽 Supplementary data may be obtained in the online version of the paper at http://doi.org by entering doi:10.1016/j.drugalcdep.2004.06.005. ∗ Corresponding author. Tel.: +44 20 8776 4114; fax: +44 20 8776 2026. E-mail address: [email protected] (J. Bearn).
0376-8716/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.drugalcdep.2004.06.005
were unacceptable to their treating neurologists. Prominent amongst these were disabling dyskinesias, neuropsychiatric disturbances including mood disorder, complex stereotypies, and social difficulties. The authors applied the term “hedonistic homeostatic dysregulation” (HHD) after a model of substance dependence proposed by (Koob and Le Moal, 1997) that interprets the motivation to take addictive drugs in terms of escape from withdrawal. In PD there is progressive neuronal degeneration in selected neuronal groups, particularly the dopamine neurones of the substantia nigra pars compacta (causing characteristic motor signs and symptoms), and also to a lesser extent in the mesocorticolimbic system (German et al., 1989). DRT with the pro-drug l-DOPA and the prototype dopamine agonist, apomorphine alleviates motor deficits by enhancing DA
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J. Bearn et al. / Drug and Alcohol Dependence 76 (2004) 305–310
neurotransmission within the nigro-striatal pathway and at the post-synaptic DA receptors. Dose-dependent adverse effects of DRT include chorea and dystonia, mood swings and psychosis (Lang and Lozano, 1998). Cocaine induces motor stereotypies and reversible chorea (Cardoso and Jankovic, 1993) through its effects on dorsal basal ganglia dopaminergic systems. Depression, mood swings, paranoia, panic attacks and psychosis are common complications of habitual cocaine use (Williamson et al., 1997; Harris and Batki, 2000). Thus, both the clinical and neurochemical effects of cocaine and amphetamine on dopaminergic neurotransmission are similar to those of DRT. Indeed, amphetamine has been shown to have weak anti-Parkinsonian properties (Elsworth et al., 1982). It is hypothesised that chronic DRT may be complicated by a maladaptive pattern of dependent use in some patients with Parkinson’s disease, the symptoms of which are analogous to those of cocaine dependence. In the present study we test the hypothesis that patients who have been given a diagnosis of “hedonistic homeostatic dysregulation” due to their excessive use of DRT fulfil DSMIV clinical criteria for maladaptive substance dependence (American Psychiatric Association, 2000), compared to patients matched for disease severity who are compliant with the prescribed DRT, using structured and semi-structured clinical measures. We also explore whether excessive DRT use is associated with any specific clinical risk factors that may reflect a vulnerability to maladaptive dependence on DRT.
2. Methodology 2.1. Patients We studied 10 patients who fulfilled provisional clinical criteria for “hedonistic homeostatic dysregulation” as proposed by (Giovannoni et al., 2000) and 10 patients with PD from the same tertiary referral clinic, with similar disease duration and severity, who were compliant with DRT treatment regimes. The HHD patients were a sub group of the original series of patients reported by Giovannoni, patients being excluded if they scored less than 26 on the Mini Mental State Examination for Parkinson’s disease (Mahieux et al., 1995). The core criterion of HHD is a pattern of pathological use whereby patients ingest DRT in excess of that required for alleviating motor impairment and in excess of that recommended by their neurologist which results in europhoriant effects, disabling dyskinesias and behavioural disturbances. The diagnostic criteria (which are at present provisional) comprise: (a) Clinical diagnosis of Parkinson’s disease with documented l-DOPA responsiveness. (b) A need for increasing dose of DRT far in excess of that required to relieve Parkinsonian motor symptoms and signs.
(c) A pattern of pathological use in which patients continue to ingest large quantities of DRT despite the development of severe behavioural disturbances and druginduced dyskinesias. (d) Impairment in social or occupation functioning. (e) Development of a DRT withdrawal state characterised by dysphoria and anxiety on reducing DRT. All patients provided written informed consent to participate in the study, which was approved by the ethics committee of both South London and Maudsley NHS Trust and the National Hospital for Neurology and Neurosurgery, Queen Square. 2.2. Study design The following structured and semi-structured clinical research questionnaires were applied: (a) The Maudsley Addiction Profile, a validated, semistructured questionnaire which detects the nature and pattern of drug use and its psychological, medical and social consequences (Marsden et al., 1998). (b) The structured clinical interview for DSM-IV axis 1 disorders (SCID-1), a validated tool recording current and lifetime axis 1 psychiatric disorders including substance abuse/dependence (First et al., 1997). (c) A semi-structured questionnaire exploring motives for taking DRT including positive mood effects, relief of withdrawal, loss of control and increased salience. These questions was devised to identify the key features of substance dependence according to DSM-IV (Table 1). A diagnosis of dependence requires at least three positive responses occurring at any time in the same 12-month period. The framing of these questions were designed to distinguish between ‘therapeutic’ need to alleviate clinical symptoms (or physiological dependence), and maladaptive, pathological, dependent patterns of use complicated by clinical impairment and/or social harm. (d) The United Kingdom Parkinson’s Disease Rating Scale (UPDRS) part IV to assess disability related to dyskinesia. Patients were considered to have significantly disabling dyskinesia if they scored >1 on item 33 of the UPDRS. (e) Calculation of a daily levodopa equivalent unit (LEU) dose for each patient was based on theoretical equivalence to levodopa as follows; levodopa dose + (levodopa dose × 1/3 if on entacarpone) + (bromocriptine (mg) × 10) + (cabergoline or pramipixole (mg) × 67) + (ropinerole (mg) × 20) = (pergolide (mg) × 100) + (apomorphine (mg) × 8). 2.3. Statistical analysis Data were analysed with SPSS Version 11, SPSS Inc., Chicago, IL. Means were compared using Mann–Whitney U
J. Bearn et al. / Drug and Alcohol Dependence 76 (2004) 305–310
307
Table 1 Semi-structured questionnaire designed to elicit DSM-IV features of dependence Questions on DRT use
DSM-IV feature of dependence
Do you ever use more DRT than is prescribed for you? If so why? What happens when you are unmedicated? Does your mood change following DRT? Do you think that you have taken DRT in larger amounts or over a longer period than you intended? Have you tried to control your DRT intake? Do you spend a great deal of time obtaining, using or recovering from DRT? Has your life been affected in any negative sense by DRT use?
Tolerance Withdrawal Tolerance and withdrawal Taking larger amounts than intended Desire or unsuccessful effort to cut down Time consuming activities to obtain and use substance Negative physical, psychological or social consequences
Table 2 Sociodemographic variables in HHD patients and control PD patients
Age mean (range) Disease duration mean (range) (year) Gender Mean daily LEU* dose (range) (mg) Mean number daily rescue doses Mean dyskinesia rating
HHD patients
Controls
61 (46–76) 15.8 (11–21) 6 M, 4 F 1916 (600–3200) 6.5 (0–20) 3.2 (2–4)
59 (39–74) 9.1 (3–15) 6 M, 4 F 617 (200–1200) 0.02 (0–0.2) 0.6 (0–2)
test. Fisher’s exact test was used for proportions in a two-bytwo contingency table. 3. Results 3.1. Demographic characteristics There were no significant differences between the groups in terms of age and sex (Table 2). The HHD group had significantly longer duration of disease, higher dyskinetic ratings and took larger amounts of medication as indicated by levodopa equivalent unit consumption additional details are shown in the Supplementary Material.1 The difference in disease duration, however, would not account for the very large difference in medication dosing between the two groups. 3.2. Clinical features At one level, all 10 patients in both groups fulfilled the minimum number of clinical criteria for substance dependence. Some of these criteria however reflect patterns of use of medication in a chronic and progressive disease. All patients reported increasing DRT intake over time and needing to persist with their drug use to maintain therapeutic benefit. Therapeutic increase of DRT could be construed as a response to “tolerance” and physical symptoms of PD occurring in the “off” state as “withdrawal”. Since these patients are treated with DRT for PD, it is implicit that exogenous DRT is taken for longer and in far greater amounts than occurs physiologically. Furthermore, exogenous administration is pulsatile and non-physiological. Patients are often obliged to pay great attention to the frequency and timing of their medication to remain mobile, and therefore spend large amounts of time obtaining and using DRT. 1
Supplementary data may be obtained in the online version of the paper at http://doi.org by entering doi:10.1016/j.drugalcdep.2004.06.005.
NS Z = −2.91, P = 0.002 NS Z = −3.19, P = 0.001 Z = −3.6, P = 0.001 Z = −3.78, P < 0.001
When we applied the supplementary questions to probe maladaptive use, we found that seven of the 10 patients in the HHD group met strict DSMIV diagnostic criteria for substance dependence because their DRT use had negative effects on their life compared to none of the control group. HHD patients commonly identified restriction of social activities due to embarrassment about dyskinesia as their most disabling problem. Physical and psychological problems reported by two patients included repeated injury because of dyskinesias and relationship breakdown because of sexual disinhibition. Two other HHD patients also experienced relationship breakdown, whilst only one patient in the control group reported relationship difficulties. An increase in appetitive behaviours was restricted to the HHD group (Table 3). The most common unifying feature was a withdrawal dysphoria (“mental non-motor off”) relieved by DRT. Significantly more patients in the HHD group reported anxiety when they were un-medicated, which they attributed to a fear that they would “freeze” and be unable to obtain more medication (Table 3). 9/10 of the HHD group said that their mood improved after taking DRT compared with none of the control group. Three HHD patients reported euphoriant effects as a reason for excess use. Almost twice as many HHD patients than controls acknowledged that they took more medication than prescribed, most commonly to alleviate distressing physical symptoms in the “off” state. Significantly more HHD patients expressed a desire to avoid the un-medicated state because of the negative effect it had on their mood. 3.3. Concurrent psychiatric disorders There was a trend for a history of alcohol dependence to be more common in the HHD patients (Table 4). Nicotine dependence was equally distributed between the two
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Table 3 Responses to semi-structured questionnaire HHD patients
Controls
P-value
1. Negative effects of DRT (a) Social withdrawal (b) Physical injury (c) Compulsive appetites (sex, shopping, eating) (d) Aggression (e) Marital disharmony
7 5 1 7 4 3
0 0 0 0 0 1
0.003 0.03 1.00 0.003 0.09 0.21
2. Ever taken more DRT than prescribed? (a) To alleviate physical symptoms (b) For pleasure (c) To avoid unmedicated state
7 7 3 7
3 2 0 1
0.18 0.07 0.21 0.02
10 8
10 1
1.00 0.005
4. Improved mood following DRT
9
0
0.00
5. Attempts to reduce
7
6
1.00
3. Effects of being unmedicated? (a) Physical symptoms worse (b) Dysphoric mood/anxiety (fear of inability to get medicated)
Table 4 Lifetime co-morbid 1 psychiatric diagnoses HHD patients
Controls
P-value
Substance dependence Alcohol dependence Nicotine dependence
5 5
1 4
0.14 1.00
Substance misuse Cannabis misuse Cocaine misuse Opiate misuse
2 1 1
0 0 0
0.47 1.00 1.00
Major depressive disorder
4
4
1.00
Substance-induced psychosis
2
3
1.00
Anxiety disorder
3
0
0.21
Current substance-induced psychosis
7
1
0.02
groups, although all were currently abstinent. One HHD patient had a history of non-dependent use of cannabis and another, cannabis, stimulants and opiates, whilst none of the controls had ever used illicit drugs. Six patients with HHD and five controls had a history of other co-morbid psychiatric disorders. The most common diagnosis was major depression. There was no significant difference in psychiatric morbidity between the two groups although there was a trend for more HHD patients to have a history of anxiety disorder (Table 3). It was notable that significantly more patients in the HHD group were currently experiencing substance-induced paranoid delusions and/or hallucinations.
4. Discussion We have described a group of patients with Parkinson’s disease who have developed clinical characteristics of mal-
adaptive dependence on DRT. We have particularly sought to distinguish between a “physiological” adaptive dependence and a “pathological” or maladaptive dependence. “Physiological” dependence reflects a necessity for therapeutic DRT use to alleviate the cardinal motor symptoms of the malady, whilst pathological or maladaptive dependence indicates non-therapeutic motives for DRT use, in the face of collateral harm. There are difficulties in applying the DSM-IV criteria for dependence to the use of medication in a chronic medical condition, for example insulin for diabetes mellitus. Insulindependent diabetics are required to take insulin, occasionally in escalating doses as the disease progresses, in order to prevent hyperglycaemic coma and to stay alive. Diabetics, therefore, fulfil core operational criteria for substance dependence, and so according to DSM-IV terminology could be construed to be “substance” dependent in that they manifest tolerance, “withdrawal” and escalating long-term use. This form of dependence however, reflects a therapeutic need for a substance, the ingestion of which corrects a disease deficit state, and improves symptoms and quality of life. In the present study we determined to distinguish adaptive dependence from maladaptive dependence or addiction. Since the standard DSMIV criteria proved to be inadequate for this purpose, we also supplemented our investigation with a semi-structured interview to explore reasons for, and consequences of DRT use. A major distinguishing feature of the DRT misusing group was an increased sensitivity to the well-recognised euphoriant affect of DRT (Maricle et al., 1995; Nissenbaum et al., 1987). As a corollary to this, they also reported more severe dysphoria as medication wore off, attributed to a fear of being unable to get more medication. Whilst we took care to control for disease severity, we cannot totally exclude that “withdrawal” dysphoria could simply be a response to greater illness severity.
J. Bearn et al. / Drug and Alcohol Dependence 76 (2004) 305–310
Current theories of cocaine addiction attribute euphoriant and motivational effects to progressive dopaminergically mediated sensitisation of the nucleus accumbens and related reward circuitry (Robinson and Berridge, 2001). DRTs induce conditioned place preference and increase dopamine turnover in the nucleus accumbens, thus sharing critical properties of addictive drugs (Woolverton et al., 1984; Wise et al., 1990). It is possible that certain dopamine receptor ge notypes enhance motivational sensitivity to DRT and increase vulnerability for DRT dependence. Alcohol dependence tended to be more frequent in the DRT misusing group. Both alcohol misuse and dependence may in general be less common in Parkinson’s disease (Benedetti et al., 2000) and so this may be a pre-disposing risk factor. The DRD2 receptor has been implicated in alcohol dependence (Noble, 2000) and it may be fruitful to investigate this candidate gene in future studies to identify vulnerable patients. There are previous reports of DRT misuse in patients with Parkinson’s disease (Lawrence et al., 2003) and also in primary recreational users (Manoharan et al., 2002; Ross and Ward, 1992). According to incentive sensitisation theory, in the course of iterative drug use, there is habituation to the rewarding actions of drugs at the same time that their incentive—reward neural systems are sensitised. It is not surprising then that many of the HHD group displayed other compulsive behaviours. Moreover, the development and expression of sensitisation may be influenced by sex and age as well as pharmacological, genetic, temperamental and social factors, such that men with early onset disease and a past history of alcohol or illegal drug use and social stress appear to be particularly at risk (Lawrence et al., 2003). The role and relative importance of these various factors deserves further exploration. DRT dependence appears to be a relatively rare but underrecognised phenomenon, affecting at least 4% of patients in a specialised PD clinic at a national tertiary referral centre. The specialised source from which our patients were recruited limits the extent to which our findings can be generalised to the wider population of patients with PD. The small sample size increases the risk of types one and two statistical errors. The questionnaire was devised specifically for this study and has not been validated or had its reliability ascertained. The interviewers were not blind to patient status and so observer bias could not be eliminated. The term HHD is potentially less stigmatising (Crisp et al., 2000) than the diagnostic label of DRT dependence. Application of the label HHD may alleviate patient and carer distress and reduce any fears that professionals may negatively evaluate them. However, recognition of a dependence syndrome will be more likely to facilitate accurately targeted treatment interventions and guide further research.
Acknowledgements This research was supported by internal funds only.
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Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version of this paper at http://dx.doi.org by entering doi:10.1016/j.drugalcdep.2004.06.005.
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Recognition of a dopamine replacement therapy dependence syndrome in Parkinson’s disease: a pilot study夽 Jennifer Bearna,∗ , Andrew Evansb , Michael Kellehera , Kirsten Turnerb , Andrew Leesb a b
National Addiction Centre, Institute of Psychiatry, 4 Windsor Walk, London SE58AF, UK Reta Lila Weston Institute of Neurological Studies, Windeyer Medical Institute, UCL 46, Cleveland Street, London W1P 6DB, UK Received 23 June 2004; received in revised form 25 June 2004; accepted 30 June 2004
Abstract Patients with Parkinson’s disease may use Dopamine Replacement Therapy (DRT) in excess of therapeutic need. We investigate whether a group of 10 patients with Parkinson’s disease, provisionally diagnosed with “Hedonistic Homeostatic Dysregulation” because of their excessive use of DRT, met established operational psychiatric criteria for substance dependence, compared with 10 patients with Parkinson’s disease compliant with prescribed DRT. Using a semi-structured questionnaire designed to distinguish between adaptive therapeutic dependence on DRT and a maladaptive pathological pattern of DRT use, in conjunction with the SCID-1, we found that seven of the patients deemed by their treating physicians to be misusing DRT fulfilled operational criteria for maladaptive dependence in contrast to none of the compliant group. The majority experienced dysphoric “withdrawal” symptoms in the “off” state and increased their dose of DRT in an effort to control their mood. They also continued to use high doses of DRT despite disabling dyskinesias and social difficulties. This study provides preliminary evidence that some patients with Parkinson’s disease may become maladaptively dependent on DRT. This finding has both clinical relevance for the treatment of PD and further implicates dopaminergic pathways in the genesis of substance dependence. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Parkinson’s disease; Levodopa; Drug dependence; Cocaine
1. Introduction Dopamine replacement therapy (DRT) is an established treatment for patients with Parkinson’s disease (PD). Recently, a group of 15 predominantly early onset patients who take DRT in excess of their therapeutic requirements with a pattern of maladaptive, escalating DRT use is described (Giovannoni et al., 2000). From an early stage of the disease, these patients took extra medication, from stockpiles accrued through multiple sources, resisted attempts to reduce the prescribed dose and tolerated adverse effects which 夽 Supplementary data may be obtained in the online version of the paper at http://doi.org by entering doi:10.1016/j.drugalcdep.2004.06.005. ∗ Corresponding author. Tel.: +44 20 8776 4114; fax: +44 20 8776 2026. E-mail address: [email protected] (J. Bearn).
0376-8716/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.drugalcdep.2004.06.005
were unacceptable to their treating neurologists. Prominent amongst these were disabling dyskinesias, neuropsychiatric disturbances including mood disorder, complex stereotypies, and social difficulties. The authors applied the term “hedonistic homeostatic dysregulation” (HHD) after a model of substance dependence proposed by (Koob and Le Moal, 1997) that interprets the motivation to take addictive drugs in terms of escape from withdrawal. In PD there is progressive neuronal degeneration in selected neuronal groups, particularly the dopamine neurones of the substantia nigra pars compacta (causing characteristic motor signs and symptoms), and also to a lesser extent in the mesocorticolimbic system (German et al., 1989). DRT with the pro-drug l-DOPA and the prototype dopamine agonist, apomorphine alleviates motor deficits by enhancing DA
306
J. Bearn et al. / Drug and Alcohol Dependence 76 (2004) 305–310
neurotransmission within the nigro-striatal pathway and at the post-synaptic DA receptors. Dose-dependent adverse effects of DRT include chorea and dystonia, mood swings and psychosis (Lang and Lozano, 1998). Cocaine induces motor stereotypies and reversible chorea (Cardoso and Jankovic, 1993) through its effects on dorsal basal ganglia dopaminergic systems. Depression, mood swings, paranoia, panic attacks and psychosis are common complications of habitual cocaine use (Williamson et al., 1997; Harris and Batki, 2000). Thus, both the clinical and neurochemical effects of cocaine and amphetamine on dopaminergic neurotransmission are similar to those of DRT. Indeed, amphetamine has been shown to have weak anti-Parkinsonian properties (Elsworth et al., 1982). It is hypothesised that chronic DRT may be complicated by a maladaptive pattern of dependent use in some patients with Parkinson’s disease, the symptoms of which are analogous to those of cocaine dependence. In the present study we test the hypothesis that patients who have been given a diagnosis of “hedonistic homeostatic dysregulation” due to their excessive use of DRT fulfil DSMIV clinical criteria for maladaptive substance dependence (American Psychiatric Association, 2000), compared to patients matched for disease severity who are compliant with the prescribed DRT, using structured and semi-structured clinical measures. We also explore whether excessive DRT use is associated with any specific clinical risk factors that may reflect a vulnerability to maladaptive dependence on DRT.
2. Methodology 2.1. Patients We studied 10 patients who fulfilled provisional clinical criteria for “hedonistic homeostatic dysregulation” as proposed by (Giovannoni et al., 2000) and 10 patients with PD from the same tertiary referral clinic, with similar disease duration and severity, who were compliant with DRT treatment regimes. The HHD patients were a sub group of the original series of patients reported by Giovannoni, patients being excluded if they scored less than 26 on the Mini Mental State Examination for Parkinson’s disease (Mahieux et al., 1995). The core criterion of HHD is a pattern of pathological use whereby patients ingest DRT in excess of that required for alleviating motor impairment and in excess of that recommended by their neurologist which results in europhoriant effects, disabling dyskinesias and behavioural disturbances. The diagnostic criteria (which are at present provisional) comprise: (a) Clinical diagnosis of Parkinson’s disease with documented l-DOPA responsiveness. (b) A need for increasing dose of DRT far in excess of that required to relieve Parkinsonian motor symptoms and signs.
(c) A pattern of pathological use in which patients continue to ingest large quantities of DRT despite the development of severe behavioural disturbances and druginduced dyskinesias. (d) Impairment in social or occupation functioning. (e) Development of a DRT withdrawal state characterised by dysphoria and anxiety on reducing DRT. All patients provided written informed consent to participate in the study, which was approved by the ethics committee of both South London and Maudsley NHS Trust and the National Hospital for Neurology and Neurosurgery, Queen Square. 2.2. Study design The following structured and semi-structured clinical research questionnaires were applied: (a) The Maudsley Addiction Profile, a validated, semistructured questionnaire which detects the nature and pattern of drug use and its psychological, medical and social consequences (Marsden et al., 1998). (b) The structured clinical interview for DSM-IV axis 1 disorders (SCID-1), a validated tool recording current and lifetime axis 1 psychiatric disorders including substance abuse/dependence (First et al., 1997). (c) A semi-structured questionnaire exploring motives for taking DRT including positive mood effects, relief of withdrawal, loss of control and increased salience. These questions was devised to identify the key features of substance dependence according to DSM-IV (Table 1). A diagnosis of dependence requires at least three positive responses occurring at any time in the same 12-month period. The framing of these questions were designed to distinguish between ‘therapeutic’ need to alleviate clinical symptoms (or physiological dependence), and maladaptive, pathological, dependent patterns of use complicated by clinical impairment and/or social harm. (d) The United Kingdom Parkinson’s Disease Rating Scale (UPDRS) part IV to assess disability related to dyskinesia. Patients were considered to have significantly disabling dyskinesia if they scored >1 on item 33 of the UPDRS. (e) Calculation of a daily levodopa equivalent unit (LEU) dose for each patient was based on theoretical equivalence to levodopa as follows; levodopa dose + (levodopa dose × 1/3 if on entacarpone) + (bromocriptine (mg) × 10) + (cabergoline or pramipixole (mg) × 67) + (ropinerole (mg) × 20) = (pergolide (mg) × 100) + (apomorphine (mg) × 8). 2.3. Statistical analysis Data were analysed with SPSS Version 11, SPSS Inc., Chicago, IL. Means were compared using Mann–Whitney U
J. Bearn et al. / Drug and Alcohol Dependence 76 (2004) 305–310
307
Table 1 Semi-structured questionnaire designed to elicit DSM-IV features of dependence Questions on DRT use
DSM-IV feature of dependence
Do you ever use more DRT than is prescribed for you? If so why? What happens when you are unmedicated? Does your mood change following DRT? Do you think that you have taken DRT in larger amounts or over a longer period than you intended? Have you tried to control your DRT intake? Do you spend a great deal of time obtaining, using or recovering from DRT? Has your life been affected in any negative sense by DRT use?
Tolerance Withdrawal Tolerance and withdrawal Taking larger amounts than intended Desire or unsuccessful effort to cut down Time consuming activities to obtain and use substance Negative physical, psychological or social consequences
Table 2 Sociodemographic variables in HHD patients and control PD patients
Age mean (range) Disease duration mean (range) (year) Gender Mean daily LEU* dose (range) (mg) Mean number daily rescue doses Mean dyskinesia rating
HHD patients
Controls
61 (46–76) 15.8 (11–21) 6 M, 4 F 1916 (600–3200) 6.5 (0–20) 3.2 (2–4)
59 (39–74) 9.1 (3–15) 6 M, 4 F 617 (200–1200) 0.02 (0–0.2) 0.6 (0–2)
test. Fisher’s exact test was used for proportions in a two-bytwo contingency table. 3. Results 3.1. Demographic characteristics There were no significant differences between the groups in terms of age and sex (Table 2). The HHD group had significantly longer duration of disease, higher dyskinetic ratings and took larger amounts of medication as indicated by levodopa equivalent unit consumption additional details are shown in the Supplementary Material.1 The difference in disease duration, however, would not account for the very large difference in medication dosing between the two groups. 3.2. Clinical features At one level, all 10 patients in both groups fulfilled the minimum number of clinical criteria for substance dependence. Some of these criteria however reflect patterns of use of medication in a chronic and progressive disease. All patients reported increasing DRT intake over time and needing to persist with their drug use to maintain therapeutic benefit. Therapeutic increase of DRT could be construed as a response to “tolerance” and physical symptoms of PD occurring in the “off” state as “withdrawal”. Since these patients are treated with DRT for PD, it is implicit that exogenous DRT is taken for longer and in far greater amounts than occurs physiologically. Furthermore, exogenous administration is pulsatile and non-physiological. Patients are often obliged to pay great attention to the frequency and timing of their medication to remain mobile, and therefore spend large amounts of time obtaining and using DRT. 1
Supplementary data may be obtained in the online version of the paper at http://doi.org by entering doi:10.1016/j.drugalcdep.2004.06.005.
NS Z = −2.91, P = 0.002 NS Z = −3.19, P = 0.001 Z = −3.6, P = 0.001 Z = −3.78, P < 0.001
When we applied the supplementary questions to probe maladaptive use, we found that seven of the 10 patients in the HHD group met strict DSMIV diagnostic criteria for substance dependence because their DRT use had negative effects on their life compared to none of the control group. HHD patients commonly identified restriction of social activities due to embarrassment about dyskinesia as their most disabling problem. Physical and psychological problems reported by two patients included repeated injury because of dyskinesias and relationship breakdown because of sexual disinhibition. Two other HHD patients also experienced relationship breakdown, whilst only one patient in the control group reported relationship difficulties. An increase in appetitive behaviours was restricted to the HHD group (Table 3). The most common unifying feature was a withdrawal dysphoria (“mental non-motor off”) relieved by DRT. Significantly more patients in the HHD group reported anxiety when they were un-medicated, which they attributed to a fear that they would “freeze” and be unable to obtain more medication (Table 3). 9/10 of the HHD group said that their mood improved after taking DRT compared with none of the control group. Three HHD patients reported euphoriant effects as a reason for excess use. Almost twice as many HHD patients than controls acknowledged that they took more medication than prescribed, most commonly to alleviate distressing physical symptoms in the “off” state. Significantly more HHD patients expressed a desire to avoid the un-medicated state because of the negative effect it had on their mood. 3.3. Concurrent psychiatric disorders There was a trend for a history of alcohol dependence to be more common in the HHD patients (Table 4). Nicotine dependence was equally distributed between the two
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Table 3 Responses to semi-structured questionnaire HHD patients
Controls
P-value
1. Negative effects of DRT (a) Social withdrawal (b) Physical injury (c) Compulsive appetites (sex, shopping, eating) (d) Aggression (e) Marital disharmony
7 5 1 7 4 3
0 0 0 0 0 1
0.003 0.03 1.00 0.003 0.09 0.21
2. Ever taken more DRT than prescribed? (a) To alleviate physical symptoms (b) For pleasure (c) To avoid unmedicated state
7 7 3 7
3 2 0 1
0.18 0.07 0.21 0.02
10 8
10 1
1.00 0.005
4. Improved mood following DRT
9
0
0.00
5. Attempts to reduce
7
6
1.00
3. Effects of being unmedicated? (a) Physical symptoms worse (b) Dysphoric mood/anxiety (fear of inability to get medicated)
Table 4 Lifetime co-morbid 1 psychiatric diagnoses HHD patients
Controls
P-value
Substance dependence Alcohol dependence Nicotine dependence
5 5
1 4
0.14 1.00
Substance misuse Cannabis misuse Cocaine misuse Opiate misuse
2 1 1
0 0 0
0.47 1.00 1.00
Major depressive disorder
4
4
1.00
Substance-induced psychosis
2
3
1.00
Anxiety disorder
3
0
0.21
Current substance-induced psychosis
7
1
0.02
groups, although all were currently abstinent. One HHD patient had a history of non-dependent use of cannabis and another, cannabis, stimulants and opiates, whilst none of the controls had ever used illicit drugs. Six patients with HHD and five controls had a history of other co-morbid psychiatric disorders. The most common diagnosis was major depression. There was no significant difference in psychiatric morbidity between the two groups although there was a trend for more HHD patients to have a history of anxiety disorder (Table 3). It was notable that significantly more patients in the HHD group were currently experiencing substance-induced paranoid delusions and/or hallucinations.
4. Discussion We have described a group of patients with Parkinson’s disease who have developed clinical characteristics of mal-
adaptive dependence on DRT. We have particularly sought to distinguish between a “physiological” adaptive dependence and a “pathological” or maladaptive dependence. “Physiological” dependence reflects a necessity for therapeutic DRT use to alleviate the cardinal motor symptoms of the malady, whilst pathological or maladaptive dependence indicates non-therapeutic motives for DRT use, in the face of collateral harm. There are difficulties in applying the DSM-IV criteria for dependence to the use of medication in a chronic medical condition, for example insulin for diabetes mellitus. Insulindependent diabetics are required to take insulin, occasionally in escalating doses as the disease progresses, in order to prevent hyperglycaemic coma and to stay alive. Diabetics, therefore, fulfil core operational criteria for substance dependence, and so according to DSM-IV terminology could be construed to be “substance” dependent in that they manifest tolerance, “withdrawal” and escalating long-term use. This form of dependence however, reflects a therapeutic need for a substance, the ingestion of which corrects a disease deficit state, and improves symptoms and quality of life. In the present study we determined to distinguish adaptive dependence from maladaptive dependence or addiction. Since the standard DSMIV criteria proved to be inadequate for this purpose, we also supplemented our investigation with a semi-structured interview to explore reasons for, and consequences of DRT use. A major distinguishing feature of the DRT misusing group was an increased sensitivity to the well-recognised euphoriant affect of DRT (Maricle et al., 1995; Nissenbaum et al., 1987). As a corollary to this, they also reported more severe dysphoria as medication wore off, attributed to a fear of being unable to get more medication. Whilst we took care to control for disease severity, we cannot totally exclude that “withdrawal” dysphoria could simply be a response to greater illness severity.
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Current theories of cocaine addiction attribute euphoriant and motivational effects to progressive dopaminergically mediated sensitisation of the nucleus accumbens and related reward circuitry (Robinson and Berridge, 2001). DRTs induce conditioned place preference and increase dopamine turnover in the nucleus accumbens, thus sharing critical properties of addictive drugs (Woolverton et al., 1984; Wise et al., 1990). It is possible that certain dopamine receptor ge notypes enhance motivational sensitivity to DRT and increase vulnerability for DRT dependence. Alcohol dependence tended to be more frequent in the DRT misusing group. Both alcohol misuse and dependence may in general be less common in Parkinson’s disease (Benedetti et al., 2000) and so this may be a pre-disposing risk factor. The DRD2 receptor has been implicated in alcohol dependence (Noble, 2000) and it may be fruitful to investigate this candidate gene in future studies to identify vulnerable patients. There are previous reports of DRT misuse in patients with Parkinson’s disease (Lawrence et al., 2003) and also in primary recreational users (Manoharan et al., 2002; Ross and Ward, 1992). According to incentive sensitisation theory, in the course of iterative drug use, there is habituation to the rewarding actions of drugs at the same time that their incentive—reward neural systems are sensitised. It is not surprising then that many of the HHD group displayed other compulsive behaviours. Moreover, the development and expression of sensitisation may be influenced by sex and age as well as pharmacological, genetic, temperamental and social factors, such that men with early onset disease and a past history of alcohol or illegal drug use and social stress appear to be particularly at risk (Lawrence et al., 2003). The role and relative importance of these various factors deserves further exploration. DRT dependence appears to be a relatively rare but underrecognised phenomenon, affecting at least 4% of patients in a specialised PD clinic at a national tertiary referral centre. The specialised source from which our patients were recruited limits the extent to which our findings can be generalised to the wider population of patients with PD. The small sample size increases the risk of types one and two statistical errors. The questionnaire was devised specifically for this study and has not been validated or had its reliability ascertained. The interviewers were not blind to patient status and so observer bias could not be eliminated. The term HHD is potentially less stigmatising (Crisp et al., 2000) than the diagnostic label of DRT dependence. Application of the label HHD may alleviate patient and carer distress and reduce any fears that professionals may negatively evaluate them. However, recognition of a dependence syndrome will be more likely to facilitate accurately targeted treatment interventions and guide further research.
Acknowledgements This research was supported by internal funds only.
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Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version of this paper at http://dx.doi.org by entering doi:10.1016/j.drugalcdep.2004.06.005.
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