Back Off the Baclofen: Increased Risk of Encephalopathy

 

I hated baclofen, it made me too tired to function and the stupidity of tiring all your muscles in the hope that your barely working ones will improve seems silly. But that is for your medical persons to decide on such stupidity. I couldn't see any progress in fixing any problems, spasticity or muscle movement. In my opinion baclofen is absolutely fucking worthless! You doctor can't point to ANY specific research that proves it works! Challenge him/her to produce such research!

Make sure your competent? doctor knows about this; you wouldn't want to be in a coma! Baclofen overdose!

 Back Off the Baclofen: Increased Risk of Encephalopathy

• By 
• Suchita Shah Sata, MD, FACP, SFHM

May 1, 2024

Dr. Sata

Clinical question: Compared to other muscle relaxants, does baclofen increase the risk of encephalopathy?

Background: Baclofen is a GABAergic muscle relaxant that is useful for patients with neuromuscular disorders including spasticity. It is also prescribed for low back pain, similar to cyclobenzaprine and tizanidine. It is known that, as baclofen is primarily renally excreted, it should not be used in patients with chronic kidney disease (CKD) due to the risk of encephalopathy. However, it is not known if this risk is shared by all these medications or in patients without CKD.

Study design: Retrospective cohort study

Setting: Tertiary health system administrative data over 13 years

Synopsis: Over the study period there were two active-comparator cohorts created of adult patients: Cohort 1, 16,192 new baclofen users versus 9,782 new tizanidine users, and Cohort 2, 9,330 new baclofen users versus 50,076 new cyclobenzaprine users. To address potential confounding, the authors applied a logistic regression model using demographics, comorbidities, and medication interactions to achieve inverse probability treatment weighting (IPTW). The 30-day risk of encephalopathy was higher in patients treated with baclofen compared with tizanidine (IPTW incidence rate per 1,000 person-years, 64.7 versus 28.3, subdistribution HR, 2.29; 95% CI, 1.43 to 3.67) and compared with those treated with cyclobenzaprine (52.6 versus 22.3, subdistribution HR, 2.35; 95% CI, 1.59 to 3.48). The increased risk of encephalopathy with the new use of baclofen over cyclobenzaprine and tizanidine persisted over the first year of treatment. A limitation of the study was the reliance on coding data to quantify rates of encephalopathy and the use of prescription fill data as a surrogate for medication use and adherence.

Bottom line: Baclofen initiation is associated with a higher risk of encephalopathy compared to other common muscle relaxants, and caution should be used when selecting this medication over tizanidine or cyclobenzaprine.

Citation: Hwang YJ, Chang AR, et al. Baclofen and the risk of encephalopathy: a real-world, active-comparator cohort study. Mayo Clin Proc. 2023;98(5):676-688.

Dr. Sata is a hospitalist at Duke University Hospital and an associate professor of medicine at Duke University School of Medicine in Durham, N.C. n

Novel Form of Muscle Relaxant Shows Benefit

 Notice that it is used in Europe, Asia, South America, and Africa to treat post-stroke spasticity. I hated baclofen, made me too drowsy to function.

Or are your doctors up-to-date and giving you this drug?

The New-Generation Muscle Relaxant MPH-220 Dissolves Spasticity in Muscles After Cns Injury - a Promising Drug to Address Post-Stroke Spasticity

February 2020 

The latest here:

Novel Form of Muscle Relaxant Shows Benefit

Tolperisone may help pain from acute back spasms without causing drowsiness

by Judy George, Senior Staff Writer, MedPage Today September 5, 2020

Tolperisone, a centrally-acting muscle relaxant, may treat symptoms of acute muscle spasms without the sleepiness and cognitive effects associated with other skeletal muscle relaxants, data from the phase II STAR trial suggested.

In the dose-ranging study, patients with acute, painful back muscle spasms who received 200 mg of oral tolperisone three times a day experienced the largest clinically meaningful decrease in "right now" pain intensity relative to placebo, reported Randall Kaye, MD, chief medical officer of Neurana Pharmaceuticals in San Diego, at the American Society of Interventional Pain Physicians (ASIPP) virtual meeting.

Tolperisone did not increase sleepiness compared with placebo. In earlier research, Kaye and colleagues also showed that patients who took 150 mg tolperisone three times a day experienced no effects on a driving simulator test, self-reported sleepiness, or cognition compared with placebo. In that study, most individuals on cyclobenzaprine (Flexeril) performed similar to people with a blood alcohol concentration above 0.05% (above the legal limit in most states) on the driving test and were unaware of their impairment.

"Tolperisone, if approved, could be the first muscle relaxant for the treatment of symptoms associated with acute and painful muscle spasms of the back without the drowsiness and cognitive function impairment typically seen with currently available skeletal muscle relaxants," Kaye told MedPage Today.

While its mechanism is not fully known, tolperisone inhibits spinal reflexes through presynaptic blockade of voltage-gated sodium and calcium channels. "In a pre-clinical model, analgesic effects have been observed," Kaye said.

Tolperisone is used in Europe, Asia, South America, and Africa to treat post-stroke spasticity, and in some countries, acute and painful muscle spasms, Kaye noted. In Germany, hypersensitivity reactions to tolperisone have been reported post-marketing.

"The formulation available outside the U.S. contains a degradant, 4-MMPPO [2-methyl-1-(4-methylphenyl) propenone], that exceeds ICH guidelines," Kaye pointed out. Neurana has developed an ultra-pure formulation of tolperisone not available in other countries that has a lower degradant yield and meets ICH guidance, he said.

In the U.S., acute muscle spasms currently are treated with non-pharmacologic therapy (such as superficial heat compresses or physical therapy), and oral or topical drugs like NSAIDs and acetaminophen. Skeletal muscle relaxants are effective but central nervous system adverse events, mainly sleepiness, limit their use. Opioids also are sometimes used.

In STAR, researchers evaluated the safety and efficacy of four doses of tolperisone -- 50 mg, 100 mg, 150 mg, or 200 mg three times a day -- versus placebo. A total of 415 patients, ages 18 to 65, with acute back muscle spasm were included and treated for 14 days; approximately 80 participants were in each group.

All participants had back pain or stiffness due to acute, painful muscle spasm starting at least 7 days before joining the study and continuing for more than 8 weeks. Pain was localized below the neck and above the inferior gluteal folds, with an intensity of 4 or higher on a "right now" pain numerical rating scale (NRS) in which 0=no pain and 10=worst possible pain. Patients discontinued all other medications used to treat pain or muscle spasm on day 1 of the study.

Participants in the tolperisone groups had an average age of about 44; 54.6% were female, 37.4% were Black, and 21.7% were Hispanic or Latino. In the placebo group, mean age was about 42; 62.8% were female, 38.5% were Black, and 20.5% were Hispanic or Latino. Average BMI was about 28.5 across all groups.

Adverse events occurred in 14.1% of placebo patients and ranged from 12.2% in the 50-mg group to 23.5% in the 200-mg group. No serious adverse events or deaths were reported.

Headache was the most common adverse event in the treatment groups, ranging from 3.7% in the 50-mg group to 9.6% in the 150-mg group and 9.4% mg in the 200-mg group. Headache generally resolved over the first 24 to 48 hours of dosing. Somnolence was reported by 1.2% of patients receiving tolperisone and 2.6% of placebo patients. Four people treated with tolperisone reported hypersensitivity events; all were mild or moderate.

The overall trend of decreasing pain "right now" ratings trended toward statistical significance across dose groups (P=0.0539). Three of four doses were within range of expected results, with the greatest numerical difference and statistical significance emerging between the tolperisone 200-mg group and placebo, the researchers said.

"Based on the efficacy and safety results from this study, a tolperisone dose of 200 mg TID may be a promising treatment for the management of acute muscle spasm without the somnolence typically experienced with skeletal muscle relaxants," they wrote.

"The current phase III study of tolperisone is designed to assess the safety and efficacy of tolperisone in the management of pain due to muscle spasm that are of acute onset," Kaye said. "The tolperisone doses selected for the phase III study -- 100 and 200 mg three times a day -- are based on efficacy and safety results from the phase II STAR study, which assessed tolperisone for 14 days of treatment in a similar patient population."

• Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow

Disclosures

The study was supported by Neurana Pharmaceuticals. Kaye disclosed owning stock in Neurana Pharmaceuticals.

Primary Source

American Society of Interventional Pain Physicians

Source Reference: Nalamachu S, et al "Tolperisone for acute muscle spasm: Dose-Ranging STAR Study" ASIPP 2020.

 

Baclofen: Its effectiveness in reducing harmful drinking, craving, and negative mood. A meta-analysis

And you thought baclofen was just for spasticity. I hated baclofen, it made me too tired to function and the stupidity of tiring all your muscles in the hope that your barely working ones will improve seems silly. But that is for your medical persons to decide on such stupidity.

Baclofen: Its effectiveness in reducing harmful drinking, craving, and negative mood. A meta-analysis

Cumulative Use of Strong Anticholinergics and Incident Dementia

Where Can I Find A List of Anticholinergic Drugs?

But you need to know none of this since your doctor will know about this study from March 2015 and have already updated your drug taking protocols.

Notice that baclofen, Tizanidine (Zanaflex) and Zantac may have some anticholinergic activity.

The latest here:

Cumulative Use of Strong Anticholinergics and Incident Dementia

Shelly L. Gray, PharmD, MS¹; Melissa L. Anderson, MS²; Sascha Dublin, MD, PhD^2,3; et al Joseph T. Hanlon, PharmD, MS⁴; Rebecca Hubbard, PhD^2,5,6; Rod Walker, MS²; Onchee Yu, MS²; Paul K. Crane, MD, MPH⁷; Eric B. Larson, MD, MPH^2,7

Author Affiliations Article Information

JAMA Intern Med. 2015;175(3):401-407. doi:10.1001/jamainternmed.2014.7663

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Articles

• Invited Commentary
  Adverse Cognitive Effects of Medications
  Noll L. Campbell, PharmD; Malaz A. Boustani, MD, MPH

• Comment & Response
  Anticholinergic Use With Incident Dementia
  Roy Fried, MD, MHS
• Comment & Response
  Anticholinergic Use With Incident Dementia
  Shelly L. Gray, PharmD, MS; Melissa Anderson, MS; Rebecca Hubbard, PhD

Abstract

Importance  Many medications have anticholinergic effects. In general, anticholinergic-induced cognitive impairment is considered reversible on discontinuation of anticholinergic therapy. However, a few studies suggest that anticholinergics may be associated with an increased risk for dementia.
Objective  To examine whether cumulative anticholinergic use is associated with a higher risk for incident dementia.
Design, Setting, and Participants  Prospective population-based cohort study using data from the Adult Changes in Thought study in Group Health, an integrated health care delivery system in Seattle, Washington. We included 3434 participants 65 years or older with no dementia at study entry. Initial recruitment occurred from 1994 through 1996 and from 2000 through 2003. Beginning in 2004, continuous replacement for deaths occurred. All participants were followed up every 2 years. Data through September 30, 2012, were included in these analyses.
Exposures  Computerized pharmacy dispensing data were used to ascertain cumulative anticholinergic exposure, which was defined as the total standardized daily doses (TSDDs) dispensed in the past 10 years. The most recent 12 months of use was excluded to avoid use related to prodromal symptoms. Cumulative exposure was updated as participants were followed up over time.
Main Outcomes and Measures  Incident dementia and Alzheimer disease using standard diagnostic criteria. Statistical analysis used Cox proportional hazards regression models adjusted for demographic characteristics, health behaviors, and health status, including comorbidities.
Results  The most common anticholinergic classes used were tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics. During a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia (637 of these [79.9%] developed Alzheimer disease). A 10-year cumulative dose-response relationship was observed for dementia and Alzheimer disease (test for trend, P < .001). For dementia, adjusted hazard ratios for cumulative anticholinergic use compared with nonuse were 0.92 (95% CI, 0.74-1.16) for TSDDs of 1 to 90; 1.19 (95% CI, 0.94-1.51) for TSDDs of 91 to 365; 1.23 (95% CI, 0.94-1.62) for TSDDs of 366 to 1095; and 1.54 (95% CI, 1.21-1.96) for TSDDs greater than 1095. A similar pattern of results was noted for Alzheimer disease. Results were robust in secondary, sensitivity, and post hoc analyses.
Conclusions and Relevance  Higher cumulative anticholinergic use is associated with an increased risk for dementia. Efforts to increase awareness among health care professionals and older adults about this potential medication-related risk are important to minimize anticholinergic use over time.

Baclofen facilitates sleep, neuroplasticity, and recovery after stroke in rats

Of course it's going to facilitate sleep, I hated it because it just caused massive amounts of fatigue and I couldn't see any progress in fixing any problems, spasticity or muscle movement.
Baclofen facilitates sleep, neuroplasticity, and recovery after stroke in rats

1. Aleksandra Hodor^1,†,*,
2. Svitlana Palchykova¹,
3. Francesca Baracchi¹,
4. Daniela Noain² and
5. Claudio L. Bassetti¹

Article first published online: 14 OCT 2014

DOI: 10.1002/acn3.115

Abstract

Objective

Sleep disruption in the acute phase after stroke has detrimental effects on recovery in both humans and animals. Conversely, the effect of sleep promotion remains unclear. Baclofen (Bac) is a known non-rapid eye movement (NREM) sleep-promoting drug in both humans and animals. The aim of this study was to investigate the effect of Bac on stroke recovery in a rat model of focal cerebral ischemia (isch).

Methods

Rats, assigned to three experimental groups (Bac/isch, saline/isch, or Bac/sham), were injected twice daily for 10 consecutive days with Bac or saline, starting 24 h after induction of stroke. The sleep–wake cycle was assessed by EEG recordings and functional motor recovery by single pellet reaching test (SPR). In order to identify potential neuroplasticity mechanisms, axonal sprouting and neurogenesis were evaluated. Brain damage was assessed by Nissl staining.

Results

Repeated Bac treatment after ischemia affected sleep, motor function, and neuroplasticity, but not the size of brain damage. NREM sleep amount was increased significantly during the dark phase in Bac/isch compared to the saline/isch group. SPR performance dropped to 0 immediately after stroke and was recovered slowly thereafter in both ischemic groups. However, Bac-treated ischemic rats performed significantly better than saline-treated animals. Axonal sprouting in the ipsilesional motor cortex and striatum, and neurogenesis in the peri-infarct region were significantly increased in Bac/isch group.

Conclusion

Delayed repeated Bac treatment after stroke increased NREM sleep and promoted both neuroplasticity and functional outcome. These data support the hypothesis of the role of sleep as a modulator of poststroke recovery.

ChronoDose – Transdermal Drug Delivery

Why not use this to deliver baclofen or warfarin? Whom is going to take on that challenge?
ChronoDose – Transdermal Drug Delivery

July 15, 2014 by Staff

I can’t imagine the addictive pull of a cigarette. Having been lucky enough to have never started smoking, I find it amazing how many people still light up, despite the fact that it can, well… kill you.  I guess it must be an overwhelming task to try and stop doing something your brain has become hardwired to expect. They say the benefits of quitting begin almost immediately. What’s on the horizon that might help? Other than gum, pills, and patches?

 Check out ChronoDose, a programmable transdermal drug delivery system that’s worn as an armband. The ChronoDose will someday offer many different drugs the ability to be programmed, and administered via this transdermal device, but the buzz is all about it’s use as the world’s first programmable nicotine replacement method. ChronoDose’s use with SmartStop™ gives the device the ability to be programmed to anticipate the users cravings, and offer nicotine dosing scheduled to take effect before the urge to smoke strikes.

So, unlike gums, and pills that take time in order to work, the ChronoDose offers personalized treatment that can be synchronized with your cravings, offering you higher dosages before the cravings begin, say, when you wake up in the morning. This interesting device offers folks struggling with nicotine addiction a system that makes compliance easier, and with its delivery automated to your schedule, it anticipates your needs and helps make quitting just a little bit easier.

If you, or someone you love needs to quit smoking, find out more about the ChronoDose nicotine delivery system with SmartStop™ Pending FDA approval, this system could actually be available soon, and at a price that’s comparable to current over-the-counter smoking cessation products. This may be just what you’ve been waiting for.

Treatment failure of intrathecal baclofen and supra-additive effect of nabiximols in multiple sclerosis-related spasticity: a case report

Your doctor can tell you about this if you use ITB.  And look at the cannabinoid(marijuana) use.
Treatment failure of intrathecal baclofen and supra-additive effect of nabiximols in multiple sclerosis-related spasticity: a case report

Abstract

Multiple sclerosis (MS)-related spasticity is associated with disability and impairment in quality of life. We report on a patient with secondary progressive MS and spastic tetraparesis (Expanded Disability Status Scale score 8.5). The right arm exhibited flexor spasticity resulting in functional disability despite multimodal symptomatic treatment. Intrathecal baclofen led to side effects despite decreasing efficacy. Low-dose nabiximols improved spasticity and function with recovery of daily-life activities and spasticity-related symptoms. Reduction of intrathecal baclofen ameliorated adverse drug reactions. Add-on cannabinoid therapy was effective in therapy-refractory spasticity with supra-additive effect in combining intrathecal baclofen and nabiximols, hypothetically explained by mutually complementing mechanisms of action.

Spasticity rant - failures in stroke rehab

I wrote this 3 years ago, nothing in it has really changed. Ask your doctor about this stupidity, its the only way we will get this researched.
Sorry about ranting on spasticity. I guess if I look at it objectively I have a mild form, it is just that if I was truly paralyzed and only had to recover function instead of suppressing spasticity/tone first and then work on the paralyzed muscle it would be much easier. I have done both baclofen and zanaflex which didn't help the spasticity at all, just made me tired so I quit them. I have had several rounds of botox which helped with knocking out my bicep so my tricep could start working. Finger flexors were also knocked out but since my finger extensors need to move control to a different spot in my brain that didn't result in any improvement.
Found an interesting site Movement Disorder Virtual University that has lots of detail on spasticity. Here is the link http://www.mdvu.org/library/disease/spasticity/spa_mpath.asp

If you follow it down quite a few levels  you can find this
Subject: Incidence and Consequences of Spasticity After Stroke

Date: 2/20/2004

Spasticity affects less than one quarter of stroke victims, according to this study.
Muscle overactivity and its consequences were assessed in 95 patients both immediately after and three months a first-time stroke. Seventy-seven (81%) were initially hemiparetic, of whom 20 had spasticity. Among these 20 patients, 14 had hyperreflexia. Within these patients, 3 had clonus, and 3 had muscle stiffness. Modified Ashworth score was grade 1 in 10 patients, grade 1+ in 7, and grade 2 in 3. None had grades of 3 or 4. At three months, 64 patients (67%) were hemiparetic, and 18 spastic, reflecting 5 whose tone normalized and 3 who became spastic in the interim. The correlation between muscle tone and a range of motor and activity scores was low for most measures at both time points, except for active movements initially, and rapid movement scores and 9-Hole Peg Test scores at three months.
The authors conclude, “spasticity seems to contribute to motor impairments and activity limitations and may be a severe problem for some patients after stroke,” but, given the relatively low numbers of patients with spasticity, they note, “Our findings support the opinion…that the focus on spasticity in stroke rehabilitation is out of step with its clinical importance. (What the hell?  - (they wouldn't say this if they had to recover from spasticity. )

Basically since only 25% of stroke survivors have it and most seem to be able to do ADL's, clinical research seems unlikely. So we are on our own unless we can somehow change that mindset. I really disagree with these authors, I want to recover everything , not just good enough for my ADLs

As a final comment, my ADL's are just fine. If I can get past the spasticity I can start doing all the normal stuff I did pre-stroke which is why I am extremely interested in this.
Posted in 6 stroke forums with no positive answers

One would think that you should be able to interrupt the signals telling your muscles to fire. This is why eStim seems stupid, you are sending electrical signals to the antagonist muscles hoping to fire them stronger than the spastic ones. Why not send electrical signals to your spastic muscles telling them to relax? Or do we not know this and need to research it?

Baclofen overdose

From the Lifeinthefastlane blog at:
Baclofen overdose

Comes these side effects;
Baclofen is a synthetic derivative of GABA, used primarily for management of painful muscle spasms in conditions such as spinal cord injury, cerebral palsy and multiple sclerosis. It is closely related to the recreational drug, Gamma-Hydroxybutyrate (GHB).

In overdose, it causes a picture similar to barbiturate coma:

Profound CNS depression with loss of brainstem reflexes.
Flaccid tone with absent deep tendon reflexes.
Bradycardia.
Respiratory depression.
Need for intubation and mechanical ventilation.
Hypothermia.
Other effects seen with baclofen overdose:

Hypertension or hypotension (the former is more commonly reported — the mechanism of this is unknown).
Paradoxical seizures.
Pupil abnormalitites — miosis or mydriasis.
Agitated delirium.
1st degree AV block and QT prolongation are rarely reported.

The duration of coma is usually 24 to 48 hours but may be prolonged (i.e. several days) with massive doses or in patients with renal failure.
PubMed has this:

Baclofen overdose: defining the spectrum of toxicity

Abstract

OBJECTIVES:

To describe the spectrum of toxicity of baclofen in overdose, and investigate dose-related clinical effects.

METHODS:

Consecutive baclofen overdoses were identified from a prospective database of all poisoning admissions presenting to a regional toxicology service. Ingestion was corroborated on more than one occasion and from multiple sources. Demographic, clinical and outcome variables were extracted for each presentation for a retrospective review, and the data sets were divided into high dose (> or = 200 mg) and low dose (< 200 mg) groups for comparison of clinical effects.

RESULTS:

There were 23 presentations, of which eight patients ingested baclofen alone. Seizures were reported in four cases, a decreased level of consciousness (GCS < 9) occurred in eight patients and delirium was recorded in eight patients. Five patients had miosis and seven patients had dilated pupils, 13 patients had absent or depressed reflexes. The only arrhythmias were sinus bradycardia in six patients and sinus tachycardia in five. Hypertension occurred in 13 patients and hypotension in one. The reported total ingested dose of baclofen was known in 19 patients (Mean 630 mg, SD 730 mg; 80-2500 mg). A higher ICU admission rate, rate of mechanical ventilation and prolonged length of stay occurred in those ingesting 200 mg or more. Coma, delirium and seizures occurred only with doses of 200 mg or more, and hypertension was more common with higher doses.

CONCLUSIONS:

Baclofen overdose causes mainly neurological effects and excepting hypertension cardiovascular effects were uncommon. Doses greater than 200 mg were predictive of patients developing delirium, coma and seizures, requiring long hospital admissions and ICU admission.

This should have been one of your doctor warnings to you.

Be careful out there.