Clinical Experience With Baclofen in the Management of Alcohol-dependent Patients With Psychiatric Comorbidity

A Selected Case Series

G.M. Dore; K. Lo; L. Juckes; S. Bezyan; N. Latt

Disclosures

Alcohol Alcohol. 2011;46(6):714-720. 

In This Article

Discussion

There is a growing literature assessing the safety and effectiveness of naltrexone and acamprosate in comorbid psychiatric conditions. Petrakis et al. (2005) randomized 178 patients with major depression to treatment with disulfiram, naltrexone, placebo and a combination of disulfiram/naltrexone. All groups showed high rates of abstinence, with the active medication groups showing greater improvement, but no advantage for the combination group. Pettinati et al. (2010), in a double blind placebo-controlled trial, found that depressed alcohol-dependent patients had higher rates of abstinence and more resolution of depressive symptoms with a combination of sertraline and naltrexone. Latt et al. (2002) noted a significant improvement in depression scores during alcohol dependence treatment in both naltrexone and placebo groups. However, a significantly greater number of patients in the naltrexone group had Beck Depression Inventory scores exceeding 20 at 3 months. The authors advised ongoing monitoring of depression in alcohol-dependent patients in treatment with naltrexone.

The effectiveness and safety of naltrexone in patients with bipolar disorder and alcohol dependence have also been assessed in several studies (Salloum et al., 2003; Petrakis et al., 2005; Brown et al., 2006, 2009). All studies found naltrexone to be well-tolerated, with reduced drinking days and alcohol cravings. A recent, open-label pilot study of add-on acamprosate in alcohol-dependent bipolar patients found acamprosate to be safe and well-tolerated with likely efficacy in reducing alcohol consumption (Tolliver et al., 2009).

In comparison, detailed studies investigating the potential effectiveness and safety of baclofen in patients with psychiatric comorbidity are lacking. At the same time, baclofen is potentially an important addition to the armamentarium when treating this patient group, when other alcohol pharmacotherapies are not beneficial or inappropriate.

The patients presented in this case series all had comorbid mental illness treated with psychotropic medication, and would normally be excluded from RCT's, yet are commonly patients encountered in day-to-day practice. While previous studies (Addolorato et al., 2007, 2011; Garbutt et al., 2010) found baclofen to be well-tolerated, the patients were a highly selected group, and more likely to have lower rates of adverse effects than patients with more complex comorbidities. While baclofen was generally well-tolerated in the group of patients we have described here, transient side effects were common—particularly, tiredness and sedation. Two patients experienced problematic side effects at higher doses of 120 and 275 mg.

In the general literature, the incidence of adverse effects with oral baclofen has been reported as 10–75% (Dario and Tomei, 2004), usually with doses greater than 60 mg daily. The most common side effects are sedation or somnolence, weakness, vertigo, nausea, dry mouth and psychological disturbances. Side effects can be minimized by initiating treatment with low doses and gradually titrating the dose upwards. Sedation and unsteadiness are likely to be exacerbated with concurrent alcohol consumption (Rossi, 2010). Baclofen has also been reported to cause impairments of cognitive function—particularly, confusion—in up to 11% of patients in controlled studies (Jones and Lance, 1976; Skausig and Korsgaard, 1977; Sandyk and Gillman, 1984) and this adverse event should be closely monitored for.

The majority of neuropsychiatric effects reported in the literature involve rapid dose reduction or abrupt cessation of baclofen. A review by Leo and Baer (2005) found that such psychiatric symptoms were consistent with delirium, and included hallucinations (auditory, visual, tactile), delusional beliefs, confusion, disorientation, fluctuating level of consciousness, anxiety, agitation and formal thought disorder. These symptoms were associated with autonomic changes, seizures, spasticity and sometimes dyskinesia. Other possible causes for delirium had been eliminated, and the delirium abated rapidly after reinstatement with the usual dose of baclofen. Abrupt cessation of baclofen is more likely to increase the risk of withdrawal delirium, and discontinuation by gradual tapering over several weeks is recommended. Cases reviewed by Leo and Baer (2005) had a minimum of 5 months of treatment with baclofen, and it has been suggested that delirium is unlikely with abrupt cessation after only 1–2 months of exposure (Terrence and Fromm, 1981). Withdrawal delirium did not appear to be dose-dependent, with a range of doses from 10 to 160 mg daily (mean 70.3 mg/day).

There are also limited reports of adverse psychiatric effects associated with ongoing baclofen use rather than withdrawal. Dario and Tomei (2004) noted rates of depression from 1.7 to 6.2%. Other case reports have noted the development of psychiatric symptoms with complete resolution after baclofen cessation. The psychiatric sequelae include psychotic depression (one case: Sommer and Petrides, 1992), catatonia (one case: Pauker and Brown, 1986) and psychosis (two cases: Roy and Wakefield, 1986; Chawla and Sagar, 2006). One case of acute mania in paranoid schizophrenia has been reported (Wolf et al., 1982) and one case of mania precipitated by baclofen in a bipolar patient (Yassa and Iskadar, 1988).

Two of the patients in this series experienced an overdose of baclofen in combination with other CNS depressants in the first week of treatment, despite close monitoring and supervision. One patient with a prior history of accidental overdoses took an excessive amount of promethazine and alcohol as well as the prescribed dose of baclofen (30 mg daily), becoming confused and disoriented. He required monitoring in the emergency department overnight and made a full recovery. He was later re-trialled on baclofen after a period of stabilization, but found it unhelpful in managing cravings for alcohol. The other patient (Mr B described earlier) experienced an acute anxiolytic effect from baclofen, which led him to rapidly escalate the dose without consultation, resulting in an overdose in combination with other CNS depressants. While some of the other patients in this series reported a reduction in anxiety on baclofen, it was gradual in onset, unlike the acute effect Mr B experienced. While baclofen is considered to have limited abuse potential (Evans and Bisaga, 2009), some cases of baclofen abuse have been reported (May, 1983; Perry et al., 1998; Nasti and Brakoulias, 2011), and clinicians should be vigilant about the possibility of overuse.

Accidental or deliberate overdose of baclofen can cause profound central nervous system depression, including delirium, coma, respiratory depression, seizures, hypotonia, hypothermia and cardiovascular effects, including bradycardia and hypertension (Perry et al., 1998; Leung et al., 2006; Wall et al., 2006). Leung et al. (2006) found that coma, delirium and seizures occurred only with doses of 200 mg or more in adults. The respiratory depression associated with baclofen overdose may be exacerbated by the concurrent ingestion of alcohol (Van Dierendonk and Dire, 1999) or other sedatives (May, 1983). Generally, the prognosis with baclofen overdose seems to be good if adequate supportive care is provided, including mechanical ventilation if necessary, until the patient recovers (Wall et al., 2006). Some patients with a high risk of self-harm or suicide may be unsuitable for treatment with baclofen. Where baclofen is initiated in such patients, high levels of monitoring and supervision should be available, such as daily dispensing of tablets with regular psychiatric reviews.

Notable in this case series is the variation in doses of baclofen tolerated by patients and reported by patients to be helpful in reducing alcohol cravings and consumption, from 30 mg to 275 mg daily. Neurologists have safely used high doses of baclofen, up to 270 mg daily, to treat spasticity (Smith et al., 1991) and there are case reports in the literature of high doses used in alcohol dependence (Ameisen, 2005; Bucknam, 2007). However, there has been no systematic study of safe and effective doses in patients with psychiatric comorbidity.

We recommend that a risk/benefit analysis be conducted to determine the suitability of patients with psychiatric comorbidity for baclofen treatment. In our opinion, baclofen is not a first-line treatment for relapse prevention in alcohol dependence in patients with psychiatric comorbidity. However, baclofen could be considered when first-line agents are ineffective, poorly tolerated or contraindicated. As already mentioned, we recommend caution when offering it to patients with a history of recurrent overdoses or suicide attempts and patients with other unstable substance use disorders. Care should be taken when combining baclofen with other CNS depressants, and monitoring should be more frequent, particularly early in treatment and during dose escalation.

Limitations of this report include the selected nature of the patient group, and the retrospective audit of clinical data. Furthermore, the lack of a control group, and the initiation of psychiatric medication in conjunction with baclofen as part of a comprehensive treatment programme, obviously restrict the report's potential to comment on the efficacy of baclofen in this context.

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