Editorial Manager(tm) for NeuroEthics Manuscript Draft Manuscript Number: NERO110R2 Title: Ethical Issues Raised by Proposals to Treat Addiction Using Deep Brain Stimulation Article Type: S. I. Deep Brain Stimulation Keywords: addiction, deep brain stimulation, treatment, neurosurgery, neuroethics, consent, coercion Corresponding Author: Dr Adrian Carter, Ph.D Corresponding Author's Institution: First Author: Adrian Carter, Ph.D Order of Authors: Adrian Carter, Ph.D; Emily Bell, PhD; Eric Racine, PhD; Wayne Hall, PhD Abstract: Deep brain stimulation (DBS) has been proposed as a potential treatment of drug addiction on the basis of its effects on drug self-administration in animals and on addictive behaviours in some humans treated with DBS for other psychiatric or neurological conditions. DBS is seen as a more reversible intervention than ablative neurosurgery but it is nonetheless a treatment that carries significant risks. A review of preclinical and clinical evidence for the use of DBS to treat addiction suggests that more animal research is required to establish the safety and efficacy of the technology and to identify optimal treatment parameters before investigating its use in addicted persons. Severely addicted persons who try and fail to achieve abstinence may, however, be desperate enough to undergo such an invasive treatment if they believe that it will cure their addiction. History shows that the desperation for a "cure" of addiction can lead to the use of risky medical procedures before they have been rigorously tested. In the event that DBS is used in the treatment of addiction, we provide minimum ethical requirements for clinical trials of its use in the treatment of addiction. These include: restrictions of trials to severely intractable cases of addiction; independent oversight to ensure that patients have the capacity to consent and give that consent on the basis of a realistic appreciation of the potential benefits and risks of DBS; and rigorous assessments of the effectiveness and safety of this treatment compared to the best available treatments for addiction.

Ethical Issues Raised by Proposals to Treat Addiction Using Deep Brain Stimulation

A. Carter, E. Bell, E. Racine and W. Hall

* Dr Adrian Carter UQ Centre for Clinical Research The University of Queensland Herston QLD 4029 Australia adrian.carter@uq.edu.au Phone: +617-3346 5474 Fax: +617-3346-5598 Dr Emily Bell Neuroethics Research Unit Institut de recherches cliniques de Montréal Montréal QC H2W 1R7 Canada Assistant Professor Eric Racine Neuroethics Research Unit Institut de recherches cliniques de Montréal and Department of Medicine and Department of Social and Preventive Medicine, Université de Montréal Departments of Neurology and Neurosurgery, Medicine, and Biomedical Ethics Unit, McGill University Montréal QC H2W 1R7 Canada Professor Wayne Hall UQ Centre for Clinical Research and Queensland Brain Institute The University of Queensland Herston QLD 4029 Australia * Corresponding Author

author(s) details

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Ethical Issues Raised by Proposals to Treat Addiction Using Deep Brain Stimulation

A. Carter, E. Bell, E. Racine and W. Hall

* Dr Adrian Carter School of Psychological Sciences The University of Melbourne Carlton VIC 3010 and UQ Centre for Clinical Research The University of Queensland Herston QLD 4029 Australia adrian.carter@uq.edu.au Phone: +617-3346 5474 Fax: +617-3346-5598 Dr Emily Bell Neuroethics Research Unit Institut de recherches cliniques de Montréal Montréal QC H2W 1R7 Canada Assistant Professor Eric Racine Neuroethics Research Unit Institut de recherches cliniques de Montréal and Department of Medicine and Department of Social and Preventive Medicine, Université de Montréal Departments of Neurology and Neurosurgery, Medicine, and Biomedical Ethics Unit, McGill University Montréal QC H2W 1R7 Canada Professor Wayne Hall UQ Centre for Clinical Research and Queensland Brain Institute The University of Queensland Herston QLD 4029 Australia * Corresponding Author Word count: 6,214 (excl. references and tables)

*ManuscriptClick here to download Manuscript: DBS for Addiction_Final.docx

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Abstract

Deep brain stimulation (DBS) has been proposed as a potential treatment of drug addiction on the

basis of its effects on drug self-administration in animals and on addictive behaviours in some

humans treated with DBS for other psychiatric or neurological conditions. DBS is seen as a more

reversible intervention than ablative neurosurgery but it is nonetheless a treatment that carries

significant risks. A review of preclinical and clinical evidence for the use of DBS to treat addiction

suggests that more animal research is required to establish the safety and efficacy of the technology

and to identify optimal treatment parameters before investigating its use in addicted persons.

Severely addicted persons who try and fail to achieve abstinence may, however, be desperate

enough to undergo such an invasive treatment if they believe that it will cure their addiction. History

shows that the desperation for a “cure” of addiction can lead to the use of risky medical procedures

before they have been rigorously tested. In the event that DBS is used in the treatment of addiction,

we provide minimum ethical requirements for clinical trials of its use in the treatment of addiction.

These include: restrictions of trials to severely intractable cases of addiction; independent oversight

to ensure that patients have the capacity to consent and give that consent on the basis of a realistic

appreciation of the potential benefits and risks of DBS; and rigorous assessments of the

effectiveness and safety of this treatment compared to the best available treatments for addiction.

Keywords

addiction, deep brain stimulation, treatment, neurosurgery, neuroethics, consent, coercion

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Introduction

Addiction can be a chronic relapsing disorder in severely addicted persons who try and fail to

achieve abstinence with the assistance of various psychosocial and pharmacological interventions.

Some of these patients may be prepared to consider more invasive treatments that promise to

“cure” their addiction. The promotion of “cures” in the media or direct to patients has prompted

some families to pay large sums of money for treatment and to demand that these treatments be

provided by governments [1-3]. History shows that the desperation for a “cure” of addiction can lead

to the use of risky medical procedures before they have been rigorously tested for safety or efficacy

[4, 5].

Deep brain stimulation (DBS) is an invasive neurosurgical intervention that was originally developed

to treat Parkinson’s disease and is now being trialled to treat intractable obsessive compulsive

disorder (OCD) and depression [6]. It has also been suggested that DBS should be trialled as a

treatment of addiction [7-9]. In this paper we consider the ethical issues raised by proposals to

conduct clinical trials of DBS for the treatment of addiction and discuss the ethical issues raised by its

possible use (if it proves to be safe and effective in some addicted persons). We consider this

proposal within the history of other putative neurobiological cures of addiction, such as ultra-rapid

opioid detoxification and functional neurosurgery. These provide cautionary tales for the uncritical

acceptance of claims made in favour of deep brain stimulation. We argue that it is currently

premature to be trialling DBS as a treatment for addiction until further preclinical research is

conducted. We specify some minimum ethical requirements for conducting future trials of DBS in

the treatment of addiction.

What is Deep Brain Stimulation?

DBS involves the insertion of microelectrodes into particular regions of the brain in order to

modulate neural activity via the passage of an external electrical current. The hypothesis is that DBS

resolves an electrical imbalance at the level of the cortico-basal ganglia-thalamocortical loop by

inactivating the target area [8].

DBS has primarily been used to treat intractable cases of neurological movement disorders, such as

Parkinson’s disease (PD), that is, persons with PD who have failed to respond, or who no longer

respond, to pharmacological treatments such as levodopa and dopamine agonists. In the recent

literature there has been a move to use DBS earlier in the treatment of PD [10, 11]. The treatment

involves inserting electrodes into subthalamic nuclei (STN) and attaching these to a battery-

controlled stimulator that the physician, and sometimes the patient, can use to control the motor

symptoms of their disorder. It was first trialled 20 years ago by French neurosurgeons and has since

been extensively used in the USA, Canada and Australia.

New indications for DBS

DBS was originally approved by the US Food and Drug Administration (FDA) for the treatment of PD

and other movement disorders such as essential tremor. More recently it was approved under the

provision of a Humanitarian Use Device (HUD) for OCD [12]. Researchers are now investigating the

use of DBS in treatment resistant forms of psychiatric disorders, such as Tourette’s syndrome [13,

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14], obsessive compulsive disorder [15, 16], and depression [17, 18]. The use of DBS for psychiatric

disorders is still in an experimental phase with most studies limited to case reports and small clinical

series. Much more research is required to determine if DBS is an effective treatment for these

disorders, and if so, which patients respond best to it [19].

Researchers have argued that DBS may be used to treat other behavioural disorders, such as obesity

[20, 21], impulsive and violent behaviour [22], and addiction [7-9]. The use of electrical stimulation

to treat obesity was first suggested in 1974 [23], while an application for a patent for the use of DBS

to manage craving was filed in 1984 [24]. There have since been several modern patents awarded

for versions of DBS treatment of addiction.

Interest in the use of DBS to “cure” addiction was re-ignited by a recent report on the effects on

smoking in patients with lesions to the insula cortex. These patients were easily able to stop smoking

when they attempted to do so and reported no cravings for cigarettes [25]. On the basis of this

finding, some scientists have advocated the use of DBS of the insula to “cure” addiction [8, 26]. At

the 2008 Society for Neuroscience meeting, the National Institute of Drug Addiction (NIDA) director

declared that this research had given her “a renewed hope for a cure *of addiction+” (Carter,

personal observation). Despite the widespread interest in this study, there have not yet been any

human studies investigating DBS to target this region, nor are any clinical trials of DBS for the

treatment of addiction currently listed in the US or World Health Organization clinical trials

registries.

Preclinical evidence for DBS of addiction

Evidence suggesting the possible efficacy of DBS in the treatment of addiction consists of animal

studies and clinical reports of the effects of DBS on addictive behaviours in patients treated with DBS

for other disorders.

Animal studies have suggested that stimulation of regions of the dopaminergic reward pathway can

reduce animal analogues of addictive behaviour, such as drug self-administration. The nucleus

accumbens (NAc), a key neural structure in the rewarding effects of drugs [27], has been a target for

neurosurgical treatment of addiction [28]. Stimulation of the NAc in rats reduces self-administration

of opiates [29], cocaine [30], and alcohol [31]. DBS of the STN in rats also reduces self-administration

of cocaine, while increasing motivation for “natural reinforcers”, such as food [32]. Similar results

were found in an earlier study of lesions to the STN [33], supporting the hypothesis that DBS causes

a functional lesion of the target region.

DBS of the lateral hypothalamus (LH) and the prefrontal cortex (PFC) in rats reduces cocaine self-

administration and some neuronal adaptations induced by repeated exposure to cocaine [34].

Stimulation of the LH reduced cue-induced drug seeking, while stimulation of the PFC reduced both

cocaine-seeking behaviour and the willingness of animals to work for drug self-administration.

Stimulation of the LH has also been shown to reduce obesity in rats [21]. The authors of these

studies claim that: “our findings validate ... DBS as the appropriate technique for a promising

therapeutic strategy in the treatment of cocaine addiction” [32, p.1196]

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Clinical reports on DBS and addictive behaviour in PD

There is very limited clinical evidence on the effects of DBS on addictive behaviour in humans. Most

reports consist of case studies of the effects of DBS on addictive behaviour in patients who were

treated for other disorders. These results have not always been positive.

The first such evidence came from two patients with PD who were undergoing DBS to treat their

motor symptoms [35]. These patients also suffered from dopamine dysregulation syndrome (DDS),

an addictive pattern of use of their dopamine replacement medication (e.g. using increasing doses of

their medication despite adverse side effects). DBS of the STN in these two patients completely

abolished the addictive use of their dopaminergic medication and greatly reduced their motor and

behavioural symptoms of PD. Witjas and colleagues suggested that DBS “might even cure addiction”

[35, p. 1052].

Recent case studies of the effect of DBS on DDS have been less positive. A 2009 study found that 12

of 17 Parkinson’s disease patients with DDS were either unimproved or worse post-operatively [36].

Two other patients without any symptoms of DDS developed DDS after undergoing DBS, while

another developed pathological gambling (PG).

DBS has also been used to treat PD patients who have developed an impulse control disorder (ICD) –

a form of addiction-like behaviour, such as problem gambling or hypersexuality – in response to

dopamine replacement therapy (DRT) [36, 37]. Ardouin and colleagues reported a case series of 7

patients who had severe PG that was resistant to changes in their PD medication. DBS of the STN

relieved their motor symptoms and allowed a 74% reduction in their dopaminergic medication [38].

PG resolved post-operatively in all patients after 18 months on average, but the time course of

improvement in their PG symptoms also coincided with the reduction in their dopaminergic

medication. This suggests that the improvements may have been attributable to the reductions in

their medication allowed by the surgery, rather than the DBS itself. Two of these patients also

developed persistent apathy.

DBS has also been shown to induce addictive behaviour in some individuals. Halbig and colleagues

reported a higher rate of compulsive behaviour in PD patients who received DBS (19%) than in

patients given drug therapy (8%) [37]. Smeding and colleagues described a patient with advanced PD

who developed pathological gambling within a month of bilateral STN stimulation [39]. The patient

had no history of gambling. The condition disappeared after discontinuing dopaminergic medication

and changing the stimulation parameters.

DBS has also been associated with significant weight gain [40] and increases in impulsivity [37, 41].

There are also reports that some PD patients treated with DBS engage in self-stimulation [42],

reminiscent of Olds and Milner’s seminal 1954 study of electrical self-stimulation in rodents [43].

While initial reports seemed to suggest that DBS may reduce addictive or compulsive behaviours in

Parkinson’s patients, subsequent studies have suggested that DBS may in fact increase or induce

addictive behaviours or impulsivity in some individuals, thereby calling into question its use as a

treatment of addiction.

DBS is not a unitary treatment: the site of stimulation in the brain produces a unique set of cognitive

and psychological effects (and side-effects). An ethical analysis of the use of DBS needs to examine

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the issues raised by the stimulation of these specific targets. Future studies of DBS for the treatment

of addiction will likely target structures other than those most often stimulated in PD, such as the

STN. Although, optimistic reports by researchers studying the effect of DBS of the STN in rodents

suggest that it will be a site of interest for some neurologists. These reports in Parkinson’s patients

should highlight the potential for serious unanticipated consequences that indicates the need to

proceed cautiously. It also indicates the necessity for stronger preclinical and other clinical evidence

before proceeding to trial DBS in addicted patients. As we argue below, many of the concerns

regarding the use of DBS to treat addiction stem from the nature of the procedure itself, and not

from the specific target of stimulation.

Case studies of DBS for the treatment of addiction

A search of PubMed identified 4 case reports of the effect of DBS on addiction to alcohol, nicotine,

and heroin [44-47]. A fifth report was provided by an anonymous reviewer [48]. The majority of

these patients were primarily treated with DBS for other neurological or psychiatric conditions such

as PD, anxiety disorders or Tourette’s syndrome [45, 46]. We also found a conference abstract of a

case of a heroin dependent individual from China treated with DBS [47], but it has not yet been

published in the peer-reviewed literature.

In 2007, European neurologists reported a case of an agoraphobic woman whose comorbid alcohol

dependency was alleviated by bilateral DBS of the NAc [46]. Significantly, the intervention had no

impact upon the patient’s depressive or anxiety symptoms. Depression and anxiety are often

comorbid with substance dependence and a significant trigger for relapse. If DBS does not

successfully address these underlying psychiatric symptoms, then patients may still be at a

significant risk of relapse while having been subjected to invasive neurosurgery with its attendant

risks [49].

The same group reported a small impact upon smoking cessation in patients who underwent DBS of

the NAc for Tourette’s syndrome, OCD or an anxiety disorder [45]. Three of the ten patients were

able to quit smoking following DBS although these patients were also less dependent and more

motivated to quit than the rest of the sample.

There have been two papers published examining the effect of DBS on individuals treated

specifically for drug addiction [44, 48]. Both of these papers report on the treatment of the same

three individuals treated with DBS for alcohol dependence. These researchers hypothesised that DBS

of the NAc would reduce the craving-related neural activity, and therefore subsequent drug use.

They treated three alcohol dependent individuals who had been highly dependent for many years,

were unable to abstain from drinking, and had repeated relapses before being treated with DBS to

the NAc. Craving for alcohol and alcohol consumption were greatly reduced in all three patients, and

all abstained from drinking for extended periods of time [44]. At a one-year follow up, two remained

abstinent while the third displayed a marked reduction in the number of drinking days [48].

While these results are promising, it is too early to draw any firm conclusions about the long-term

safety and efficacy of this intervention, especially from such a small sample. As the authors of the

study note, the study was unblinded and there was no control condition with which to compare the

results [48]. The positive results may be due to the extra care and attention that these individuals

received. As Strang et al. [50] showed, even the most treatment refractory heroin addicted

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individuals can respond positively to a new episode of a previously failed treatment. The history of

neurosurgical treatment of psychiatric disorders is filled with cases of initially positive results that

were only later discovered to be less effective than first thought and to carry significant side-effects

[51].

Neurosurgical Treatment of Heroin Addiction

Some advocates of trialling DBS to treat addiction justify this by appealing to positive reports on

neurosurgery for addiction using cingulotomy (ablation of the anterior cingulate) [52-55],

hypothalamotomy (ablation of the ventromedial nucleus of the hypothalamus) [56, 57], and

resection of the substantia innominata and NAc [58]. These forms of neurosurgery began in 1962

and continued throughout the 1970s. Nearly all of these studies reported reasonable success in

preventing subsequent drug use with little or no cognitive impairment. These results were seen by

some authors as warranting neurosurgical lesioning as a “first line treatment” for addiction [54]. The

neurosurgical treatment of addiction fell out of favour during the 1970s when it became apparent

that related procedures for other psychiatric disorders were not as effective as first thought and also

caused significant cognitive deficits.

Advocacy of neurosurgical addiction treatment has recently been renewed and justified by appeals

to neurobiological theories of addiction. Up until 2002-03, Russian and Chinese surgeons used

stereotactic neurosurgery to treat 305 heroin dependent patients in Russia [59] and over 500 in

China [60]. In China, neurosurgeons began bilaterally ablating the NAc in heroin addicted individuals

to prevent the self-administration of heroin [28]. Gao et al. [28] believed that ablating this area

would reduce the rewarding effects of heroin, and decrease the likelihood of relapse after

abstinence. In Russia, neurosurgeons performed bilateral lesions on the anterior cingulate gyrus

(aCG); a brain region that has previously been lesioned to treat obsessional disorders [61]. The aim

of the surgery was to interrupt obsessional thoughts about drug use [61]. Clinicians in China have

reportedly started a clinical trial of neurosurgical treatment of opioid addiction [62].

These uncontrolled studies did not properly evaluate the cognitive and behavioural effects of

destroying such important neurological regions [28, 63]. There were also major concerns about the

effects of producing irreversible lesions in neural centres that are not only implicated in drug-

mediated reward, but also in the control of food intake, sexual behaviour and social relationships.

Proponents of DBS have cited this experience to argue that DBS represents a “reversible” way of

obtaining the same benefits as neurosurgery, without the permanent harms associated with ablative

surgery [7, 8, 36]. Based on the evidence reviewed above, this hypothesis has weak support.

Should We Trial DBS Treatment of Addiction?

An analysis of the ethical warrant for a trial of DBS in the treatment of addiction requires an analysis

of the risk of harm arising from the disorder against the risk of harms and benefits associated with

the intervention.

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Addiction: harms and treatments

We currently have a good understanding of the risk of harm associated with addiction, and some

understanding of the acute risks associated with DBS neurosurgery in PD patients. The likely harms

and benefits of DBS in the treatment of addiction are highly uncertain. In order for the experimental

trial of DBS to be justified, the condition being treated needs to carry a high probability of significant

harm (e.g. life threatening or extreme and irreversible morbidity) that is not amenable to other

forms of treatment. A reasonable case has been made for using DBS to treat treatment resistant PD

but the nature and severity of this disorder differs in important ways from addiction. PD patients

have a progressive deterioration of structure and function in specific regions of the brain that are

not easily reversed or slowed using medication. We also have a clearer understanding of the

neurocircuitry of PD, an organic disorder that arises from degeneration of dopaminergic neurons in

the substantia nigra.

While DBS in PD is used to ameliorate the effects of neurobiological degeneration, the proposal to

use DBS to treat drug addiction would involve using an invasive neurological approach to treat a

disorder that is much more amenable to treatment. Unlike PD, the course of addiction is not

inexorably one of deterioration towards severe disability, dementia and death. Addictive disorders

vary in severity, duration and outcome and effective pharmacological and psychotherapeutic

treatments are available for many types of addiction [64, 65]. Consequently, the justification for the

use of DBS to treat addiction is not prima facie as compelling as it is for PD.

Safety and efficacy

As we have indicated, there is a paucity of evidence on the safety and efficacy of DBS for addiction,

and no evidence of the long-term harms or benefits. The few case reports of the impact on DBS on

drug addiction show that it is of only limited efficacy: in the largest trial to-date, less than a third of

those treated were able to refrain from drug use [45]. These trials have not systematically assessed

the occurrence of adverse side effects such as cognitive impairment that may impair quality of life.

Given the very significant risks associated with DBS, these results are not encouraging.

While DBS may be significantly less harmful than traditional ablative neurosurgery, it is still an

invasive intervention that carries significant risks. These include severe short and long-term risks on

both biological and psychosocial levels. For example, 1-2% of patients who undergo DBS for PD

suffer major adverse surgical outcomes, such as intra-cerebral haemorrhages, that can lead to

significant loss of cognitive or motor function, and possibly death. Even the successful insertion of

stimulating electrodes can cause serious infection and produce cognitive, behavioural or emotional

disturbances, that include difficulty speaking, worsening of apathy, depression, anxiety and severe

panic [66], impulsivity [41], cognitive impairments [67], walking disturbances [68], and sudden

symptom recurrence or exacerbation on interruption of stimulation [15]. PD patients treated with

DBS may also suffer from significant psychosocial challenges in adapting to the effects of stimulation,

including marital conflict [69, 70]. The failure to achieve an expected outcome or relieve intractable

psychiatric conditions can also lead to severe disappointment, worsening of symptoms, and

increased suicide risk [69-73].

Based on this analysis, we believe that the uncertainty about the balance of the harms and benefits

does not justify the trial of DBS in the treatment of addiction at this time. We believe that

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considerable caution needs to be exercised in using DBS to treat addiction given the limited and

conflicting empirical evidence, the availability of a range of effective treatments for drug addiction,

the need for, in advance, improving the provision of these current treatments, and the ethical issues

raised by the use of DBS in neurological motor disorders. Most would agree that its use as a first line

treatment in unselected addicted individuals is ethically unjustifiable. Our assessment, however, is

that trials of DBS in individuals with treatment refractory addiction should not be done until more

basic research has been conducted on animal models to identify the optimal neural regions used,

thereby minimising side-effects. We believe that we should also wait until more clinical experience

has been obtained in using DBS to treat patients with other psychiatric disorders, such as intractable

depression.

It could be argued that the use of DBS in treatment resistant depression faces many of the same

ethical challenges as trials of DBS in addiction. There are however important differences between

the two conditions and their responsiveness to available treatments that have an impact on the

ethical warrant for trials of DBS in the two conditions. Patients with major depression who have

undergone DBS have usually failed to respond to a number of common treatments, including

antidepressant and neuroleptic medications (often more than 6) as well as electroconvulsive therapy

(ECT), a form of treatment usually considered the treatment of last-resort in depression. These

patients are at elevated risk of suicide because there is very little else that can be done for them. By

contrast, the risks of addiction are rarely as serious or as imminent (e.g. drug overdose). There are

also a range of effective treatments to reduce this risk, including opioid substitution treatment for

opioid addiction; the form of addiction that carries the highest risk of overdose. The major problem

for many addicted persons is not their failure to respond to effective treatment so much as their

inability to access such treatment.

Conducting Trials of DBS for the Treatment of Addiction: Strong Science, Pragmatic Ethics

While we believe that trials of DBS in addiction should not proceed at this stage, it is likely that there

will be severely addicted persons who may wish to undergo DBS because of their failure to respond

to current treatments. There will also be neurosurgeons who are prepared to operate on these

patients. Favourable media reports of any cases of DBS used to treat addiction could also elicit

patient demands for trials of DBS in addiction [74] which, if supported by the media, may become

difficult for governments to resist. This proved to be the case with the use of ultra-rapid opioid

detoxification (UROD) for heroin addiction in Australia in the late 1990s. UROD involved using the

opioid antagonist, naltrexone, to accelerate opioid detoxification under general anaesthesia [4]. It

was heavily promoted via the popular media as a neurobiological “cure” for heroin addiction. Media

reports gave patients unrealistic expectations of the long-term efficacy of the treatment which, by

reducing their opioid tolerance, increased their risk of overdosing when they returned to opioid use,

as most did [4]. Individuals and families consequently paid large sums to undergo a procedure that

proved to be ineffective, doubled their risk of dying from a drug overdose and involved a small

increased risk of mortality from the general anaesthesia [75, 76].

If clinical trials of DBS are to be performed, it is critical that they are undertaken with good ethical

oversight of patient recruitment and the process of obtaining consent to participate [77, 78]. Such

trials should be well designed, and the outcomes of treatment rigorously and independently

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evaluated, including adverse effects and cost effectiveness. Trial design could include randomisation

to DBS or delayed entry to DBS (e.g. after 6 months). Patients who are randomised to delayed entry

to DBS should be offered the best available treatment for their addiction while waiting. Researchers

involved in these trials would also need to encourage and facilitate responsible media reporting of

results to avoid creating unrealistic patient expectations of benefit [74, 79].

The history of previous putative “cures” of behavioural disorders suggests that caution will be

required in deciding which types of addicted individuals will be recruited into these trials, how their

consent to participate is obtained, how the intervention is evaluated, and how the results of the

trials are interpreted. We also need to consider how the treatment may be used, if it is shown to be

safe and effective in some patients. A careful analysis that considers the particular context in which

addiction treatment is offered is critical if trials of DBS for this indication are conducted in an

ethically appropriate manner. We provide such an analysis below that is summarised in Table 1.

Careful patient selection

One suggestion for patient selection would be to only treat addicted individuals who had another

condition for which DBS was indicated (e.g. PD, OCD, Tourette’s syndrome). There are several

scientific and ethical problems with this proposal. Many addicted individuals would be excluded

from studies of DBS, which they may reasonably see as unjust. The presence of comorbid conditions

would also make it difficult to interpret any effects that DBS had on addictive drug use. Treatment

might also involve targeting brain regions that are not optimal for reducing drug use.

Given the risks associated with DBS, the uncertainty surrounding its effectiveness in the treatment of

addiction, and the availability of alternative treatments, the use of DBS for addicted individuals

should be restricted to those who are highly dependent, whose condition causes significant personal

harm and who have failed to respond to the best available treatments.

Researchers will also need to consider the types of addiction that should be given the greatest

priority, based on the harms that they cause and the availability of alternative treatments. Opioid

addiction carries significant risk of personal harm (such as fatal overdose) but there are very

effective pharmacological treatments available for its treatment. These include methadone and

buprenorphine [80, 81]. There are a range of psychosocial and pharmacological treatments available

for alcohol dependence (e.g. disulfiram, naltrexone, acamprosate) and nicotine dependence (e.g.

nicotine replacement therapy, varenicline). There are only modestly effective psychosocial and no

effective pharmacological treatments for cocaine and psychostimulant addiction. The use of DBS

would be most justified in treating persons with forms of addiction for which there are no effective

pharmacological treatments or those who had failed to respond to indicated treatment, and whose

addiction presented serious risks to their life and well being. This would give prima facie priority to

opioid, stimulant and severe alcohol dependence.

Informed consent: competency and realistic expectations

Obtaining informed consent to participate in research requires that individuals: 1) have the capacity

to understand the risks and benefits of participating in research, (2) are free to make decisions (i.e.

internally or externally uncoerced), (3) are fully informed of the risks and benefits of participating in

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the trial, as well as those of not participating, and (4) have equal access to all effective forms of

treatment, where treatment is appropriately managed and resourced [82].

Chronic drug use can cause serious cognitive deficits that can interfere with a patient’s ability to give

consent, particularly if the person is intoxicated or in acute withdrawal [82]. This is likely to be

particularly challenging in trials of DBS that are limited to intractable cases of severe addiction.

Researchers need to ensure that the symptoms of withdrawal and intoxication have abated, either

by supervised withdrawal or stabilisation on agonist maintenance, if available, before they are asked

to consent to participate in a trial of DBS.

Once stabilised, individuals should be accurately informed of the uncertain benefits of the treatment

and the risks related to it. The latter should include a discussion of the risks that may occur during

the surgery as well as the risks of postoperative complications and the challenges in modulating the

stimulation and maintaining the batteries and implant. Participants should also be informed of all

other effective treatments available, and be actively assisted in obtaining these should they wish to

undertake them.

Free and informed consent presupposes realistic expectations of the likely effectiveness and safety

of new treatments. As in the case of UROD, addicted individuals may be desperate for a “cure” of

their condition or be under duress from family and friends to accept the risks of untried treatments.

Such patients may not properly consider the risks of a trial. Expectation of the benefits of these

interventions may also be based on uncritical media reports of their success. It is accordingly

important that researchers take significant steps to minimise unrealistic expectations by strongly

communicating the limited effectiveness of the procedure and the high risks of harm both to

potential participants and their friends and family members.

Experience with DBS for PD suggests that it may be a special challenge to ensure that potential

patients have realistic expectations of benefit. A study of American and British media coverage of

DBS for PD found increased coverage and marked enthusiasm for the clinical use of DBS [3]. Many

articles reported “miracle stories” of patients whose disease was allegedly “cured”. A recent survey

of healthcare providers involved in Canadian DBS programs identified problematic media portrayals

of DBS as a leading challenge in obtaining informed consent [73]. Historical accounts of early

psychosurgery suggest biased media coverage in the 1930s and 1940s may have similarly

encouraged its widespread adoption as a first line treatment [1].

Free and uncoerced choice

Because it can be difficult to persuade addicted individuals to enter treatment, some forms of soft

coercion or incentives are often used to encourage treatment entry, such as offering treatment as an

alternative to imprisonment or as a condition of parole. The use of an invasive technology such as

DBS under such forms of legal coercion should not be permitted during the process of trialling the

treatment. Trials should be confined initially to patients who have not been legally coerced into

treatment

In some countries, addicted individuals may have little choice about participating in trials of invasive

treatments. In the case of neurosurgical treatment of heroin addiction in Russia and China, for

example, there are doubts about whether patients gave free and informed consent to participate in

12

this surgery. Chinese and Russian policies towards opioid dependence are highly punitive, with

imprisonment and compulsory detoxification as the first line, and indeed, primary forms of

“treatment”. Patients cannot be said to provide informed consent when they are offered only

ineffective treatment options such as detoxification. In the absence of controlled outcome studies or

preclinical studies of safety, it is unclear how well-informed patients can be about the risks of the

procedure to which they are asked to consent. Asking addicted individuals to participate in trials of a

risky and invasive procedure in such settings fails to meet the conditions of free and informed

consent.

Providing access to already available treatments

For many patients who suffer from a drug addiction, there are effective pharmacological and social

treatments available (e.g. substitution treatments for opiate addiction). A significant hurdle in the

treatment of addiction is the difficulty in providing access to these treatments because of a lack of

resources or a societal preference for imprisonment. Where treatments are available, they may be

provided in a suboptimal fashion that reduces their effectiveness (e.g. insufficient doses of

substitution medications or punitive responses to positive drug urines that can see patients

involuntarily removed from treatment programs) [83]. Evidence that an addictive disorder is

intractable requires evidence that participants have failed at “gold-standard” forms of treatments

that also include high quality psychosocial interventions. DBS should not become a surrogate for a

failure or unwillingness to provide established and effective forms of treatment. For example, it

would arguably be inappropriate to trial DBS for the treatment of opioid addiction when patients do

not have access to effective treatments, such as methadone or buprenorphine maintenance, as is

the case in Russia [84].

Motivated by a need to treat a medical condition

There is a concern that some medical “fixes” of addiction have been used to address social goals

other than the treatment of a harmful psychiatric illness, such as to reduce the social harm of drug

use or reduce crime and social deviance [85]. The US National Commission for the Protection of

Human Subjects of Biomedical and Behavioral Research recommended that psychosurgery always be

done for the benefit of individuals, never for social or institutional control [86, p. 58]. As the

selection of treatments offered to individuals is not solely governed by medical and scientific

considerations but is also contingent upon broader attitudes toward addiction, we believe that the

motivations for trialling DBS should always be the patient’s good, and not for institutional or social

purposes.

Opportunity costs of DBS trials

DBS is an expensive procedure, costing over US$ 50,000 for the initial surgery, with recurrent costs

of over US$ 10,000 p.a. for replacement of batteries, maintenance of the electrodes and adjustment

of the stimulation to retain therapeutic effects [87]. Unlike Tourette’s and PD, addiction is a common

disorder, affecting approximately 5% of the population in any one year [88], more if nicotine

dependence is included. The costs of trialling DBS are also likely to be much more substantial than

trialling pharmacological and psychosocial treatments. Even if DBS proves successful in intractable

cases of addiction, its costs will limit the scale of its use even in developed countries, where there is

often an enormous shortfall in access to much less expensive and effective forms of addiction

13

treatment. While these resource limitations may not warrant a moratorium on trials of DBS, they

suggest that funding bodies may justifiably give it a lower priority than research on less resource-

intensive forms of addiction treatment.

Psychosocial support and commitment to follow-up and integration

DBS is an expensive and resource intensive procedure. The device is inserted by a neurosurgical

team and patients require extensive follow up that include post-operative stimulator adjustments.

This care is best offered by multidisciplinary teams in specialised treatment centres. Over-

enthusiasm for DBS has led to it being performed by clinicians with inadequate training, experience

or resources resulting in significant side-effects that subsequently required secondary treatment in

appropriately qualified clinical centres at significant cost [6]. Optimal care may also hinge on a

patient’s social support network. It has been suggested that the family’s ability to provide adequate

physical and moral support after the procedure should be evaluated during patient selection [89]. In

addition, Okun et al. [90] maintain that patients’ ease of access and travel to the specialised centre is

also integral to preventing device failures. Any new clinical trials of DBS in addiction should take into

account factors such as social support and ease of access, particularly because patients suffering

from addiction may already face challenges in these areas. DBS teams will also have to devote

significant resources to assuring the long term management of these patients. Clear expectations

about the need for long term care should be built into any clinical trials, including considerations

about advance planning with regards to future treatment decisions and stimulation. Finally, DBS

trials in addiction would benefit from the integration of patient reported outcomes, specifically

designed to capture its effects on quality of life and psychosocial adaptation. There is a specific

literature demonstrating that PD patients who have undergone DBS may experience psychosocial

adaptation challenges, issues related to identity, and marital difficulties following DBS [69].

Responsible publishing and media reporting

Given the media excitement that treatments such as DBS can create, and the willingness of some

addicted individuals to undergo invasive procedures in pursuit of a “cure”, it is important that

researchers provide balanced reporting of their research results in the clinical literature and the

popular media. This includes clearly reporting negative results and study limitations to avoid the

“hype and hope” of previous “magical cures” of addiction [4, 74]. This is particularly true in

individual patient trials of DBS that only report success stories [79]. These can give a biased and

overly optimistic impression about the safety and efficacy of the intervention. For example, it has

been suggested that the failure of DBS to alleviate anxiety in an agoraphobic patient by Kuhn and

colleagues was only reported because DBS had a positive impact on the patient’s alcohol

dependence [79]. The selective reporting of positive results may give potential patients an overly

optimistic understanding of the effectiveness of DBS. Failure to report negative results can also lead

to a duplication of efforts as researchers unwittingly repeat studies in which the trialled treatments

have failed. Schlaepfer and Fins argue that a registry should be created for all case studies of DBS,

similar to that for clinical trials, so that all results, positive and negative, can be accessed [79]. This is

a suggestion that we support.

14

Table 1. Minimum Ethical Requirements for Trials of DBS for Addiction

Participant requirements:

1. Severe dependence that causes significant personal harm

2. Demonstration of treatment refractoriness

3. Access to all existing treatment provided to the highest standard

4. Capacity to consent to participate in research

5. Awareness of the risks of operation, the uncertain and limited benefits, as well as

post-operative requirements (e.g. programming, battery replacement)

6. Participation that is free from coercion

Treatment and researcher requirements:

7. Motivation of the medical team to treat a medical illness and not as a form of

extrajudicial punishment

8. Provision of psychosocial support post-DBS

9. Commitment of the research group to subsequent maintenance of the device

10. Performed in appropriately resourced clinics with qualified staff

11. Balanced publishing of research results, including negative results

Conclusions

DBS has recently been advocated for investigation as a treatment of addiction on the basis of animal

models, suggestive case study evidence and poorly controlled studies of stereotactic neurosurgery

for opioid addiction. These proposals raise important ethical issues. We believe that there is

insufficient evidence to warrant clinical studies of DBS in addiction at this stage. More basic

preclinical work is needed to identify the optimal targets in the brain for treating addiction with DBS

and we should await the results of current trials of DBS in other psychiatric disorders, such as

intractable depression.

Some minimum standards for the ethical conduct of future trials of DBS would include: restricting

trials to severely intractable cases of addiction (as defined by documented failure to respond to

optimally provided treatments); independent oversight of the consent process to ensure that

patients have the capacity to provide free and uncoerced consent that is based on a realistic

appreciation of the potential benefits and risks of DBS; and rigorous assessments of the

effectiveness and safety of this treatment compared to the best available treatment that is currently

provided.

15

Acknowledgements

We would like to thank Ms Danielle Herbert for her assistance in researching this paper and Ms

Sarah Yeates for comments on an earlier draft. This manuscript was prepared with financial

assistance from a National Health and Medical Research Council Australia Fellowship (Grant No.

3020774) awarded to Professor Wayne Hall.

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Response to Reviewer 2 (in italics): "Its use as a first line treatment in unselected addicted individuals is, we believe, ethically unjustifiable. Our assessment is also that trials should not be done until more basic research has been conducted on relevant animal models to establish the safety and efficacy of the procedure, and to identify the optimal neural regions used in the treatment of addiction with DBS, thereby minimising side-effects." p 8

Is there anyone supporting "a firstline treatment in unselected addicted individuals"? Sounds a bit like a strawman.

We agree with the reviewer that its use as a first-line treatment in unselected individuals is an extreme view that would receive little support, and hence could be seen as a strawman. We have edited the text to acknowledge that this view lacks widespread support. We would argue that it is still worth stating however, because there are examples in the past of proponents proposing the use of neurosurgery for addiction as a first line treatment. Ablative neurosurgery was proposed in 1978 (Kanaka, T.S., and V. Balasubramaniam. 1978. Stereotactic cingulumotomy for drug addiction. Applied Neurophysiology 41: 86-92) as a first-line treatment of addictive individuals. One of the authors also recently reviewed an article that argued that DBS should not be restricted to use as a treatment of last-resort in psychiatric disorders.

Are there reliable animal models? Addiction is a condition for which there are a number of animal models that have been used for over half a century. These include: drug self-administration, conditioned place preference, reinstatement of drug use following extinction, progressive ratios for drug self-administration (how much an animal is going to work in order to receive a drug). Animal models in drug addiction are some of the most reliable in the study of psychiatric disorders but they are not without limitations. Ignoring the very obvious and important differences between highly controlled experiments in animal (usually rodent) models of addiction and the human use of addictive drugs, these models vary considerably in their ability to model human drug addiction. The animal models that are used to study the reinforcement potential of drug use (e.g. self-administration and CPP) have been shown to be reliable and robust predictors of the addictiveness of drugs in humans. The relapse models (extinction/reinstatement models) also appear to mirror the ability for cues to induce a relapse to drug use, and correlate with cognitive studies in humans. There are however, significant debates about the validity of animal models of motivation and craving. See Markou A., Weiss F., Gold L. H., Caine S. B., Schulteis G., Koob G. F. Animal models of drug craving. Psychopharmacology (Berl) 1993; 112: 163-82 and Epstein D. H., Preston K. L., Stewart J., Shaham Y. Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology (Berl) 2006; 189: 1-16 for further debate about these issues. Both the reinforcement and relapse models of addiction would be instructive in deciding how best to conduct DBS in addiction in humans. There are of course limits to what these studies could tell us, which is why we argue that these need to be interpreted in conjunction with clinical evidence from the use of DBS in other psychiatric and neurological conditions. What is important is that there are a number or reliable and valid animal models that could be used to identify targets for DBS in human drug addiction. As our review showed, there is a wide range of brain regions that have been targeted, with very little discussion of their pros and cons. For example, the NAc has been targeted in both drug addiction and depression: in depression, stimulating the NAc was hypothesised to overcome anhedonia by increasing motivation for rewarding activities (Schlaepfer T. E., Cohen M. X., Frick C., Kosel M., Brodesser D., Axmacher N. et al. Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology 2008; 33: 368-77); whereas in addiction, the same stimulation was hypothesised to block rewarding effect of the addictive drug (Heinze H. J., Heldmann M., Voges J., Hinrichs H., Marco-Pallares J., Hopf J. M. et al. Counteracting incentive sensitization in severe alcohol dependence using deep brain stimulation of the nucleus accumbens: Clinical and basic science aspects. Front Hum Neurosci 2009; 3: 22). It is these apparent contradictions that should be resolved by preclinical studies before anyone proceeds to trials in humans.

*Response to reviewer's commentsClick here to download Response to reviewer's comments: Response to Reviewer 2_20100818.docx

Does the recommendation to do more preclinical research before testing on therapy refractory and otherwise well selected addicted patients follow from the minimum ethical requirements. It seems to me there must be at least one more presupposition for excluding clinical trials even temporarily. It might well be the right way, but I am searching for the argument. Is it solely a risk too high to be consented to?

We agree that this recommendation doesn’t follow from the minimum ethical requirements in table 1. These are what we believe are the minimum ethical requirements if one was to undertake a trial of DBS. The justification for our claim that more research is required before conducting trials in human addicts is based on balancing the risks of harm and benefits of drug addiction with those of undergoing DBS and alternative forms of treatment. The discussion begins on page 7. First, addiction differs from PD and refractory depression in that the risk of harm is not as large or as certain. Addiction is also more amenable to less invasive and risky treatments than these conditions such as maintenance on a drug with similar effects to that of the drug of addiction. At the current stage of research, the risks of most types of addiction are not great enough to justify the risks incurred in using DBS. It maybe that this point was not as clear as it could have been. We have therefore edited this discussion to make this clearer.

DBS for major depression is also experimental. Doesn't face this line of research the same obstacles? Why is it in your eyes preferable compared to DBS research in addiction?

We agree that DBS for major depression is also experimental, and faces many of the same objections as the use of DBS in addiction. There are however important differences between the two conditions, and their responsiveness to available treatments, that has an important impact upon the ethical warrant for current trials of DBS in the two conditions. Patients with major depression who have undergone DBS have usually failed to respond to a number of common treatments, including antidepressant and neuroleptic medications (usually more than 6) as well as ECT, a form of treatment usually considered the treatment of last-resort in depression. These patients are at elevated risk of suicide because there is very little else that can be done for them. By contrast, the risks of addiction are rarely as serious or as imminent. e.g. drug overdose. There are also a range of effective treatments to reduce this risk, including the most effective form of treatment in the case of the opioids that carry the highest risk of overdose death– that of opioid substitution treatment. Also, the major problem for many addicted persons is an inability to access the treatments that are most effective (e.g. methadone maintenance, heroin maintenance, oral tobacco such as snus). We have added a brief summary of this discussion in the paper.