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National Amphetamine-Type Stimulant Strategy Background Paper: Monograph Series No. 69

5.6 Pharmacotherapy

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Various drug treatments, or pharmacotherapies, are used in relation to ATS dependence, to aid in withdrawal, to block drug effects, as replacement or substitution therapy, and/or to treat co-occurring and related psychological disorders. In reviewing the literature, Shearer and Gowing (2004) found the following pharmacotherapies had been used in response to psychostimulant use:

• Antidepressants;
• Dopamine agonists and antagonists;
• Disulfram;
• Central nervous system stimulants;
• Modafinil;
• Vaccines;
• Calcium blockers; and
• Opioid agonists and antagonists.

Despite this diverse range of options, clinical studies of pharmacotherapies for ATS are sparse and controlled studies are rare. However, research is ongoing and a number of trials are currently being conducted to determine the utility of a range of medications. Vocci and Appel (2007) provide an overview of the approaches currently being used to develop medications for the treatment of methamphetamine dependence. This includes medications that limit brain exposure to methamphetamine; modify the effects of methamphetamine at vesicular monoamine transporter-2 (VMAT-2); or act on dopaminergic, serotonergic, GABAergic, and/or glutamatergic neurological pathways that play a role in the reinforcing effects of methamphetamine. Vocci and Appel (2007) conclude that there is evidence to support the rationale that pharmacotherapies to decrease methamphetamine use or reduce cravings following cessation of use may be developed by:

...altering the pharmacokinetics and pharmacodynamics of methamphetamine or its effects on appetitive systems in the brain (p.96).

Following is a brief summary of some of this research with a focus on the main areas of investigation.

Managing withdrawal

As already noted, there is limited evidence about pharmacotherapies to manage withdrawal. Given the presentation of acute toxicity (outlined above), symptoms related to mood and sleep require management. Antidepressants have been used to alleviate mood-related symptoms of withdrawal with mixed results. There is some suggestion that fluoxetine could decrease cravings in the short-term, and imipramine may increase duration of adherence to treatment in the medium-term, however, the evidence is limited (Shearer & Gowing, 2004). It has also been suggested that diazepam be used to treat anxiety and temazepam for insomnia (Dyer & Cruickshank, 2005). Finally, mirtazepine (medication that helps promote sleep and alleviate depression) has also been implicated in withdrawal management. Preliminary results from a joint investigation in Western Australia and NSW found no evidence that mirtazepine improved treatment retention, alleviated withdrawal symptoms, improved sleep or reduced methamphetamine use (Cruickshank et al., unpublished). Modafinil, an agent used to treat narcolepsy, has also been suggested as having some utility in withdrawal management. The medication enhances wakefulness, vigilance and alertness, and may therefore alleviate withdrawal symptoms such as hypersomnia, poor concentration and low mood (Shearer & Gowing, 2004). A number of studies are underway, in Australia and overseas, to investigate the potential of this drug and others in managing ATS withdrawal. For example, DASSA is currently investigating the safety and efficacy of mirtazepine, modafinil and bupropion (antidepressant shown to be effective as a nicotine cessation aid) in the treatment of withdrawal symptoms following cessation of amphetamine use among dependent users. There are a number of other studies currently underway: the WA DAO and NSW Langton Centre are currently testing the efficacy of mirtazapine in the treatment of amphetamine withdrawal and narrative therapy as an adjunctive treatment; Turning Point in collaboration with DASWest, Hunter Area Health Service and University of Queensland are currently conducting a pilot randomised placebo controlled trial of Modafinil as an aid for methamphetamine withdrawal and entry into further treatment. Assessed outcomes include drug use, mental health, cognitive functioning and withdrawal symptomatology.

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Substitution therapy

Substitution therapy for ATS has most commonly involved prescribing central nervous system stimulants, in particular, dexamphetamine, especially to patients for whom other interventions have not been effective.

Substitution therapies aim to replace harmful drug use with safer modes of drug use in terms of dose, route of administration and adverse effects. Effective substitutes may allow patients to stabilise on doses that prevent withdrawal and craving and to reduce the harms associated with illicit drug use. (Shearer & Gowing, 2004, p.125).

The potential benefits of substitution therapy for amphetamine users were outlined by Fleming (1998) and include:

• Attracting and engaging amphetamine users into treatment, particularly those who would not otherwise seek out help;
• Engaging users in treatment provides a valuable opportunity to provide harm reduction information, health care interventions, and referral;
• Substitution acknowledges that there are problems associated with amphetamine use and thus, conveys messages about the potential harms of amphetamine use;
• By reducing amphetamine use through substitution, related harms are also reduced; and
• Potential short-term risks of prescribing substitutes may outweigh the potential long-term harms of continued illicit amphetamine use.

It has been suggested that substitution may be indicated for individuals who are dependent and for whom other attempts at abstinence have failed and maintenance is considered to be less risky than continued illicit use (Mattick & Darke 1995). However, it is noted that substitution therapy is not without risks, and may include the risk of relapse to psychotic episodes, risk of cardiovascular problems, risk of diversion of therapeutic doses and continued use of prescribed and illicit amphetamine (Shearer et al., 2002).

In the United Kingdom, dexamphetamine has been used to treat ATS dependence since the 1990s. Despite a number of relatively large clinical trials, there is little scientific evidence to support this treatment, but rather, self-report or case note studies (Bradbeer et al., 1998). White (2000) conducted a retrospective study of 220 amphetamine users receiving dexamphetamine prescriptions in the UK and found it had an immediate effect in reducing amphetamine use, but less impact on treatment retention (White, 2000). In this study, oral and intravenous amphetamine users had similar outcomes, although intravenous users made more overall gains in treatment.

The first randomised controlled trial of dexamphetamine as a substitute for methamphetamine dependence was conducted in Sydney (Shearer et al., 2001). This study compared 21 long-term dependent users receiving 60mg dexamphetamine daily to a control group of 20 similar users. Both groups received standard drug counselling and both were found to respond positively to intervention. Reductions were found in injecting behaviour, methamphetamine-positive urine samples and severity of dependence. The only significant difference was in the uptake of counselling, which was greater in the dexamphetamine group. The most serious adverse consequence of dexamphetamine cited has been the potential development of psychotic symptoms, particularly for those who have experienced amphetamine-induced psychosis. Another potential risk is the diversion of prescribed amphetamine (Shearer et al., 2002). On the other hand, some clinical trials have reported that such risks do not necessarily eventuate in adverse outcomes (e.g., Carnwath et al., 2002). Further research is currently underway, in South Australia, which involves a randomised double blind placebo controlled trial of dexamphetamine as maintenance treatment for amphetamine dependence.

Aside from dexamphetamine, more recently both methylphenidate (e.g., Ritalin) and the antidepressant bupropion (e.g., Zyban) have been studied as potential amphetamine substitutes. Tiihonen and colleagues (2007) compared aripiprazole, a partial dopamine agonist, oral methylphenidate and a placebo among a sample of intravenous meth/ amphetamine users. They reported that while aripiprazole was associated with significantly more amphetamine-positive urine samples, methylphenidate was associated with significantly fewer such samples. Bupropion is currently being trialled through several phases and has been shown to decrease subjective effects of methamphetamine and reduce cravings (Newton et al., 2006).

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At present, evaluations suggest that ATS users find services offering substitution therapy attractive when offered in addition to advice and counselling, and results from international trials indicate that pharmacological treatment is most effective when used in conjunction with psychosocial intervention (Mattick & Darke, 1995). Thus, from both the perspective of the consumer and as indicated by the research, safe and effective medication potentially represents a valuable adjunct to psychosocial interventions that may enhance both participation and retention. However, as noted in the written submission from NDARC:

NDARC, in collaboration with St Vincents’ Hospital and the Kirketon Road Centre, conducted the first randomised controlled trial of dexamphetamine as a substitute for methamphetamine dependence (Shearer et al., 2001). This trial found modest benefits from dexamphetamine treatment which needed to be confirmed in larger trials. … Overall, existing evidence suggests that modest benefits from dexamphetamine substitution are outweighed by problems associated with this treatment, including diversion and sideeffects from interactions with concurrent illicit drug use (Mattick & Darke, 1995).

Antidepressants

Depression is commonly associated with ATS use, sometimes predating use, and also emerging as a consequence of use. As noted by Shearer and Gowing (2004):

Antidepressants have been investigated in the treatment of comorbid depression, depressive symptomatology associated with psychostimulant withdrawal, or for their dopamine agonist properties (p.121).

The range of trials, with various agents, has provided equivocal results. One interpretation of the data is that those with pre-existing affective disorders may be responsive to antidepressant treatment, whereas those with symptoms that emerge as a consequence of ATS use may be less responsive. Some evidence exists to suggest this differential responsiveness (e.g., Donovan & Nunes, 1998). A final concern is the combined effect of using SSRIs (selective serotonin reuptake inhibitors) with people who are using ATS. Research suggests that the SSRI fluoxetine may potentiate acute toxic effects of MDMA in susceptible individuals (e.g., Hegadoren et al., 1999) and thus, more research is needed to investigate the interaction of SSRIs and MDMA and its potential contribution to serotonin toxicity. This all suggests the need for more research, particularly research identifying subgroups with whom antidepressants may be indicated and contraindicated.

Shearer and Gowing (2004) have observed that in fact the evidence for pharmacotherapies is generally limited, except for managing co-existing dependence on other drugs (such as using evidence-based pharmacotherapies for opioid dependence) or managing co-existing conditions (such as attention deficit hyperactivity disorder (ADHD) or affective disorders). These researchers provide a succinct and useful summary of the pharmacotherapy research:

…with the exception of pharmacotherapies targeted towards accurately and appropriately diagnosed comorbid conditions such as affective disorders, psychotic disorders, attention deficit disorders and opioid dependence, the use of pharmacotherapies for the promotion or maintenance of psychostimulant abstinence or the management of psychostimulant withdrawal continues to be experimental. The inherent risks of pharmacotherapy may suggest that the use of pharmacotherapeutic agents should be limited to users diagnosed with more severe dependence who experience the greatest burden of psychostimulantrelated harms (Shearer & Gowing, 2004, p.130).

The potential role of pharmacotherapy in treatment for ATS abuse was repeatedly raised during the consultation process. There were many appeals for more research into substitution therapy in recognition that, at present, there is no strong evidence base for pharmacotherapy for ATS related problems. Furthermore, it was suggested that substitution therapy could make treatment more appealing, at least to some ATS users. However, the view that substitution therapy was problematic and only served to replace one form of dependence with another was also expressed. Thus, it was argued, use of substitution in the long term needs to be carefully considered on a case-by-case basis.

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It was also recognised that pharmacotherapy may be more beneficial when used in conjunction with other forms of treatment, such as psychosocial interventions. In particular, the initial role of pharmacotherapy in crisis management was acknowledged, but that there was a need for this to be followed by helping clients to cope with the underlying psychosocial issues. Thus, the need for better relations and collaboration between services and treatment options was again emphasised.

Finally, pharmacotherapies were discussed in relation to the management of psychotic presentations, detoxification and withdrawal. In relation to the former, it was suggested that there was a need for improved protocols due to the risks associated with administering antipsychotics to those with methamphetamine-induced psychosis, as opposed to psychosis unrelated to drug use. The appropriateness of sedation regimes for those in heightened arousal due to a combination of amphetamine use and alcohol consumption was also questioned due to pre-existing levels of intoxication. Medically-assisted detoxification through the use of antipsychotics and antidepressants was also raised. Issues of managing withdrawal were also seen as an issue for detention centre staff who were usually not medically trained.

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