This is what we will be looking at in this section.

Slide 1: Introduction

  1. Understanding why baclofen’s side effects occur.
  2. The common side effects at the start of treatment.
  3. The uncommon side effects occurring later in treatment.
  4. Baclofen issues in epilepsy and renal dysfunction.
  5. Practical examples of dose adjustments for side effects.

Introduction

The list of potential side effects from baclofen treatment is long and contains a surprisingly variety, from tinnitus to diarrhoea. It’s easy to get spooked by a list of baclofen side effects. Keep in mind that all are reversible and that the risks of baclofen treatment and its side effects are well and truly outweighed by substantial health risks of alcoholism.

My experience is that most patients will get some side effects with baclofen but get through them because they can feel beneficial effects and really want to stop alcohol. They generally just need reassurance, strategies and symptomatic treatment.

Section 1: Understanding why baclofen’s side effects occur:

It’s important to discuss baclofen side effects with patients when starting treatment. Patients should know that baclofen has been widely used for 40 years and its side effects are very well known. They can be bizarre and unpleasant but are benign and never permanent. They always go away completely if the baclofen is stopped.

The key to keeping side effects from baclofen to a minimum is increasing the dose slowly enough that the patient’s brain has enough time to adjust to the change in dose. Side effects generally occur when the dose is raised too fast for that patient. When the brain is given more time to adjust, the side effects go away and the baclofen dose can be further increased.

This explains the major strategies for dealing with baclofen side effects – keeping the baclofen at the same dose until the side effect disappears or lowering the dose back to the previous level which was ok, waiting longer there, then raising the dose again but more slowly this time.

We’ll give practical examples of how to do this in a later section.

Some lucky patients have no side effects at all, especially if they only need a low dose of baclofen to suppress their cravings. Most patients have some side effects when starting baclofen, especially in the first couple of weeks, but they are manageable. The side effects generally go away within a few days while continuing baclofen at the same dose but they can reappear at the next dose increase, only to disappear again with time.

Some patients develop new side effects only when the dose gets into the higher ranges. If distressing side effects appear after a dose increase, the dose should be taken straight back down to the previously tolerated dose and left there for 1-2 weeks. The dose increases can then restart but more slowly than before – smaller dose increments and with more days between dose increases than previously. In most cases, the side effect will not reappear as the dose rises and the patient will be able to get up to and beyond the dose which previously caused side effects.

Rapid rises in baclofen dose trigger side effects which are not seen with slower increases in dose. It becomes a balance between the patients’ impatience to get to their effective dose and the need to go slowly enough for the brain and body to adapt to baclofen. Some patients are prepared to tolerate side effects to get to their effective dose quickly but others need a very cautious and slow titration of dose. A few patients are so spooked by a side effect that they do not want to continue treatment. Often the side effect could be managed but the patient is not willing to try, having lost confidence in baclofen’s benefit.

However what is more common is that patients persist with baclofen, despite even unpleasant side effects, when it is effective in keeping them off alcohol. The benefits of sobriety are so rewarding that many patients persevere with treatment. In most cases, the patient is rewarded by the side effect diminishing or disappearing with time and continued treatment.

A few patients are simply not able to tolerate a dose of baclofen sufficient to achieve the anti-craving effect, despite all efforts and must stop the treatment permanently.

Section 2. The common side effects at the start of baclofen treatment.

Slide 2: Here are the commonest side effects seen in the early stages of baclofen treatment:

  1. Fatigue
  2. Insomnia
  3. Nausea
  4. Dizziness/vertigo
  5. Headache
  6. Gastrointestinal problems

Fatigue:

Fatigue is the commonest side effect of baclofen but decreases with time. It can be either a generalised tiredness or a sudden overwhelming tiredness which appears at certain times.

This is a problem for people who need constant vigilance at work eg operating dangerous machinery or for driving. In this case, the patient may need to do alternative work for the first couple of weeks or raise the baclofen dose very slowly.

Fatigue is also a problem for patients who are physically frail or who are at risk of falls, especially if they drink large amounts of alcohol. This risky group is better off with a planned inpatient withdrawal in which baclofen treatment is initiated.

Some patients complain that the baclofen treatment is making them very sleepy but the real culprit is an ongoing large alcohol intake combined with baclofen and should prompt the patient to start cutting back on the alcohol rather than the baclofen.

It is also worth a careful inquiry about what other medications the patient is taking. It may include sedative medications like benzodiazepines, painkillers or sedating antihistamines which are being used for anxiety or insomnia.

A simple lack of sleep can also contribute to daytime fatigue. Many alcoholic patients use alcohol to get to sleep but it’s of very poor quality. Stopping or reducing alcohol often causes a frustrating inability to get to sleep. That’s up for discussion in the next section.

Insomnia:

There can be a paradoxical effect where baclofen causes the patient to feel tired during the day but unable to sleep at night. Most alcohol addicted patients have very poor sleep already, often drinking themselves into sleep but waking a few hours later and unable to get back to sleep until dawn breaks. Baclofen usually helps these patients sleep better but in some patients, it has the opposite effect and makes it hard to get to sleep. This can be minimised by giving the last baclofen dose of the day at around 6pm so it covers the evening but is wearing off by bedtime.

It’s important to manage sleep issues actively in the early treatment phase because sleep is an important respite from the day and bolsters the resilience to face challenges and anxiety.

My usual practice is to offer medication for sleep initially. If can be continued until life is more settled or it is no longer needed. Sobriety itself will dramatically improve sleep quality. The first two medications below, mirtazapine and mianserin, are often good for underlying anxiety in which case they are continued for as long as needed, as part of overall management.

My commonest choice is mirtazapine, 30mg at bedtime (range 15-60mg). Its sedative effect provides reliable, pleasant sleep without onerous morning drowsiness. It also has useful anxiolytic and antidepressant effects. Because mirtazepine doesn’t have serotonergic effects, it can be combined with SSRIs or SNRIs if these are required for additional anxiolytic or antidepressant effect. The commonest side effect of mirtazapine is increased appetite. This can be useful for some patients and is initially hard to distinguish from the normal return to good eating when alcohol intake decreases or stops. However a few patients develop an unstoppable desire to eat, especially during the night, and this requires ceasing the mirtazepine.

An alternative is the old tetracyclic antidepressant mianserin, 30mg at bedtime (range 15-60mg) although it also sometimes increases appetite. Mianserin can also be used in combination with SSRIs or SNRIs without causing serotonergic syndrome.

A good alternative is melatonin at a dose of 5-10mg at bedtime to reset normal sleeping patterns. The only drawback is expense as it needs to be made at a compounding chemist at a cost ranging from $50-90 for 100 capsules. The PBS subsidised preparation of melatonin is only 2mg and this seems to be insufficient for effect.

Amitriptyline is an alternative for patients who overeat on mirtazapine and mianserin. It is reliably sedative at 10- 25mg at bedtime but has more unpleasant side effects of morning tiredness and dry mouth and constipation. These effects will lessen with continuing use. Amitriptyline cannot be used with SSRI/SNRIs because the combination often precipitates a serotonergic syndrome with disagreeable symptoms of agitation, anxiety and tremor.

My practice is to avoid using benzodiazepines or antipsychotics for night sedation.

Nausea:

This is common when baclofen is first started and during the early increases in dose. It lasts 2-3 days and always goes away with continuing baclofen at the same dose. Patients are often very tolerant of this side effect which can re-occur then disappear with further dose increases.

It is effectively treated with prochlorperazine (Stemetil) orally, 5-10mg, taken as needed (6-8 hourly prn) or regularly with each baclofen dose if the nausea is severe.

My practice is to put prochlorperazine on the first script for baclofen as a precaution. An over-the-counter alternative from chemists is Nausetil, an anti-migraine combination containing 5mg prochlorperazine and 500mg paracetamol per tablet.

Dizziness/Vertigo/Lightheadedness:

Baclofen treatment can produce a sensation of dizziness or unsteadiness which is not true vertigo. It’s often accompanied by nausea. Again, prochlorperazine is effective for this and the dizziness disappears anyway with continuing baclofen therapy although it can reappear then disappear again when the dose is further increased.

Headaches:

These often occur in the mornings, respond to simple analgesia and generally also fade with time.

One of my patients developed severe headaches for the first hour after each dose of baclofen was taken, corresponding to the peak concentration. This settled with fractionating the daily dose of baclofen into more frequent, smaller doses over the day and using a slow release NSAID daily for a week.

Gastrointestinal Problems:

It can be hard to know if these are related to baclofen when there are concurrent changes in alcohol consumption and food intake. Nevertheless patients can get diarrhoea which is clearly related to baclofen and generally responds to anti-diarrhoeal medications such as loperamide and/or dietary modifications. Occasionally constipation is seen for which simple symptomatic treatment will help – laxatives, increased fruit and vegetables and other ways to increase dietary fibre.

Section 3. The uncommon side effects occurring later in treatment.

There are also a wide variety of unusual and uncommon side effects. As previously mentioned, these tend to appear at the higher dose range of baclofen, typically at doses above 120mg per day. Any odd symptom which appears de novnovo on baclofen treatment could well be related and reducing the dose back down to the previous asymptomatic level is a useful test.

Here are some of the possibilities:

Slide 3: Uncommon side effects of baclofen:

  1. Urinary problems
  2. Sexual side effects
  3. Mania or aggression
  4. Odd neurological symptoms
  5. Other miscellaneous side effects
  6. Depression

Urinary problems:

Baclofen can cause increased urinary frequency and even incontinence, especially at night. The baclofen may be unmasking a milder problem or causing it de novo. It’s easily treated with oxybutynin. This can be as a regular or a prn dose of 5mg three times a day with each baclofen dose or as a single 5mg dose at bedtime if the problem occurs only during the night.

Sexual side effects:

Baclofen can have a variety of effects on sexual function from improving libido and desire through to erectile dysfunction and anorgasmia. For decreased sexual functioning, minimising the dose of baclofen and a trial of sildanifil (Viagra) may overcome problems for both men and women.

Mania or aggression:

Treatment with baclofen can produce an elevation in energy and mood which is beneficial to patients. It can be hard to tell if this is due to the effect of the baclofen itself or to the loss of the depressant effects of heavy alcohol use.

A few patients will become hypomanic or even frankly manic on baclofen treatment. The latter are generally patients who already have bipolar affective disorder but occasionally mania appears de novo, especially if the patient increases the baclofen dose very fast. The baclofen dose should be dropped to the previously tolerated dose or slowly ceased and short term use of a low dose antipsychotic may be needed.

The risks and benefits of treating the alcoholism with baclofen should be carefully evaluated. In many cases, alcoholism is the biggest obstacle to good control of the psychiatric condition. In these cases a mood stabiliser such as Sodium Valproate used with baclofen may allow both conditions to be treated when other options for treating the alcoholism have failed.

A variant of the appearance of mania is the sudden onset of episodes of aggressive behaviour. This necessitates a reduction in dose or cessation of baclofen.

Odd neurological symptoms:

These include tinnitus, painful paraesthesias of the limbs, noises in the head, sudden dropping of objects, double vision, slurred speech, clumsiness or unsteadiness, tremor of hands, itch, abnormal taste.

These generally disappear with the usual measures of waiting at the same dose until they go or dropping the dose back down, waiting and raising it more slowly. However if the side effect is persistent and unpleasant, it may require ceasing the baclofen.

Other uncommon side effects:

Muscle or joint pains, rashes, face and ankle swelling, nasal congestion, hot flushes, excessive sweating. These generally respond to time and simple symptomatic treatment.

Depression

The experience of baclofen prescribing clinicians, myself included, is that depression is common in the recovering alcoholic on baclofen but this is not clearly related to baclofen itself, which is more likely to cause mania than depression.

Although reducing and ceasing alcohol intake will remove the depressant effects of alcohol, facing the reality of life without the numbing effects of alcohol can be daunting. The best outcome for the patient will generally be to treat the depression as a separate entity along standard lines, especially if the baclofen is having good effects on alcohol cravings/intake.

Section 4: Baclofen issues in epilepsy and renal dysfunction.

Two conditions which can cause issues with baclofen therapy are:

Slide 3:

  • Epilepsy
  • Renal Dysfunction

Epilepsy:

Baclofen at higher doses can reduce the threshold for seizures. This can present a dilemma because many alcoholic patients have seizures. The seizures are usually related to their drinking in some way – withdrawal seizures, seizures when they are intoxicated, seizures due to old head injuries while intoxicated and seizures due to previous subdural haematomas which are particularly common after falls in alcoholics. In the alcoholic patient group there is is often also poor compliance with any anti-seizure medications and many have frequent seizures with their attendant risks.

The most effective way by far to reduce seizures in alcoholics is to drastically reduce or stop drinking alcohol. So if they have failed to benefit from other treatments, a risk vs benefit analysis will favour trying baclofen. Some alcoholic patients on baclofen treatment need to be on concurrent anti-epileptic medication while others become free of seizures simply by being sober.

Renal dysfunction:

Baclofen is 80% excreted by the kidney, largely as the unchanged drug with only 15% being metabolised by the liver. This is a very useful feature of baclofen and makes it safe to use in patients who already have severe liver dysfunction from alcoholism or other causes.

However because baclofen is excreted from the body by the kidneys, great care must be taken in patients with renal impairment.

A graph from a French study shows why:

Slide 4: Vlavonou R et al. J Clin Pharmacol 2014:

 

VlavonouRetalJ ClinPharmacol2014

The half life of baclofen increases in a linear fashion as renal function decreases and this means that the interval between doses needs to be lengthened to avoid toxicity.

In patients with renal insufficiency, baclofen treatment carries increased risks. If kidney function is abnormal but stable, it would be feasible to treat with baclofen in motivated patients under specialist supervision, especially if they have failed all other options for alcohol addiction and the health risks of continued drinking are sufficiently high. The patient needs to be able to work out how long it takes baclofen’s effect to wear off to judge the time intervals required between doses, which may run into days. They also need to be closely watched for symptoms of baclofen toxicity in conjunction with regular monitoring of their renal function.

 

 

 

Section 5: Practical examples of dose adjustments for side effects.

Here are a couple of examples of how to adjust dosing regimes to help with side effects.

Example 1:

A patient starts on baclofen at 5mg at bedtime but even with that dose, has severe nausea and is reluctant to take any doses in the day because she needs to go to work.

Slide:

patientbaclofenat5mgatbedtime

Reduce the dose to 2.5mg (1/4 of a 10mg tablet) at bedtime taken with an antinausea tablet (prochlorperazine 5mg) and work slowly up to taking this up to 2.5mg 3 times a day, doing the increases on non-working days. Once at 2.5mg three times daily, wean off the antinausea tablets.  Once stable, repeat this process going slowly from 2.5mg three times daily to 5mg three times daily. The patient can then continue to work the dose upwards as fast as they can tolerate but it is generally much easier after the first few dose increases.

 

Example 2:

A patient feels fine on baclofen 10mg three times a day. The dose is raised to 15mg three times a day over a standard three day period (10/10/10 to 10/10/15 to 10/15/15 to 15/15/15) but he gets a severe headache after taking each 15mg dose.

Here are some options:

Slide:

Option 1:

option1_15mg dose

Drop back to 10/10/10 and wait another 5 days at this dose. Then increase to 10/10/15 for 3 days, then 10/15/15 for 3 days then go up to 15/15/15.

Option 2:

option2_10_10_12-5.png

Drop back to 10/10/10 for 1-2 days then raise the dose to 10/10/12.5 (1/2 of a 25mg tablet) and if that’s ok then over a few days, increase to 12.5/12.5/12.5. Then wait 3-4 days and go up slowly again to 15/15/15.

The number of days between each dose increase can vary. If a headache appears, the dose rise has been too fast. Go back to the comfortable dose, wait there a few days and try going up again.

Option 3:

option3_15mgx3

Fractionate the total daily dose of 45mg (15mg x 3) over the day: 10 breakfast/5 mid morning/10 lunchtime/5 mid afternoon/10 dinner time/5 bedtime

Here the daily dose is the same but the smaller, more frequent doses mean that the baclofen concentration in the brain doesn’t rise as high after each dose. After 3-7 days of this 6x/day regime, start the switch back to 15mg three times daily.

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