Hi, my name is Dr. Marilyn Pacheco. In this presentation, we'll be talking about oral pharmacology as a treatment option for spasticity. I do not have relevant financial relationships to disclose. At the end of this presentation, participants will be able to identify the use of oral medications for treatment of spasticity, distinguish the most widely used oral agents for reduction of spasticity, its pharmacology, mechanism of action, and dosages, differentiate the unwanted side effects of oral spasticity medication, and familiarize with other oral agents for reduction of spasticity. The use of oral medications for treatment of spasticity may be very effective. Benzodiazepine, Baclofen, Dantrolene sodium, Clonidine, and Tizanidine are the most widely used oral agents for the reduction of spasticity. The challenge is to establish a treatment plan that will strike a vital balance between improved function, patient satisfaction, and possible side effects. At high doses, oral medication can cause unwanted side effects that include sedation as well as changes in mood and cognition. A number of oral medications have various levels of effectiveness in producing an antispasticity result, and the most effective are listed on this slide. Of those that are centrally acting, the main effect is that of enhancement of neuronal inhibition. In the case of Dantrolene sodium, the site of action is primarily at the level of the musculature. Among the centrally acting medication, benzodiazepines and Baclofen affect processes involving gamma amino butyric acid, or GABA, one of the main inhibitory neurotransmitters in the central nervous system. Tizanidine and Clonidine exert effects related to norepinephrine receptors. Cyproheptadine affects serotonin, acetylcholine, and histamine. Cannabinoid drugs activate cannabinoid receptors, which have a number of effects on autonomic functions as well as relaxation. Finally, Orfenadrine has mild antispasticity effect, possibly through its dopaminergic agonist effect. In general, the pharmacologic and antispasticity effects of benzodiazepines are mediated by a functionally coupled benzodiazepine GABA receptor, chloride ionophore complex. There are high affinity and low affinity receptors, as well as long-acting and short-acting benzodiazepines. The relative length of action is related to the duration of activity and the rate of metabolism of the parent compound, as well as the production and elimination of pharmacologically active metabolites. Diazepam, chlordiazepoxide, and clonazepam are considered to be long-acting benzodiazepines, whereas oxazepam, alprazolam, and lorazepam are considered to be short-acting without significant production of active metabolites. Generally, benzodiazepines cross the placental barrier and are secreted in breast milk. The benzodiazepines are metabolized extensively, mostly by the microsomal enzymes of the liver. The receptors are located in many areas of the central nervous system, particularly in the reticular formation of the brainstem. Inhibition of the receptors relates to the anxiolytic and sedation properties of benzodiazepines. Mechanistically, benzodiazepine receptors are postsynaptic to GABA-nergic synapse. From the perspective of the sensory afferent motor efferent synapse, benzodiazepine potentiate the inhibition of transmitter release from the presynaptic terminal, hence enhancement of the presynaptic inhibition. Diazepam is a typical benzodiazepine that suppresses behavioral arousal, agitation, or anxiety. It reduces polysynaptic reflexes, has muscle relaxation, sedation, and antispasticity effects. Diazepam have been used in the treatment of spasticity in patients with spinal cord injury and multiple sclerosis to improve passive range of motion and to decrease painful spasms. For patients with anxiety and difficulty sleeping, these effects of diazepam may be also helpful. The 2 mg diazepam formulation can be given for daytime use to minimize dose-related sedation. Diazepam is well-absorbed after oral dose. Peak level occurs in 1 hour. It is metabolized to the active compounds. The half-life of diazepam, including active metabolites, is 20 to 80 hours. The dosage titration should be slow and stop once the therapeutic goal or the maximum dose of 60 mg per day is reached. For patients who complain of sleep disturbance due to painful spasms, diazepam therapy can be initiated with a bedtime dose of 5 or 10 mg. For children, the recommended dose is 0.12 to 0.8 mg per kg per day. However, low-dose clonazepam has been suggested to be useful treatment in children with problematic spasticity. Although benzodiazepines are generally regarded to have a wide margin of safety, there is a serious abuse potential and fatal overdose has been reported. The problem is particularly prevalent among veterans with spasticity. The symptoms of adverse effects are summarized on this slide. Symptoms of withdrawal from high-dose diazepam greater than 40 mg per day are as follows. Anxiety and agitation, restlessness, irritability, tremor, muscle fasciculation and twitching, nausea, hypersensitivity to touch, taste, smell, light and sound, insomnia and nightmares, seizures, hyperpyrexia, psychosis, and possible death. Symptoms of withdrawal from low-dose benzodiazepine, which is less than 40 mg per day, are more likely if the patient has been taking the drug consistently for more than 8 months. Baclofen, which is 4-amino-3-4-chlorophenylbutanoic acid, is a structural analog of GABA. Baclofen binds to and activates bicuculline-insensitive GABA receptors, termed as GABA-B receptors. GABA-B receptors occur both pre- and post-synaptically. Upon binding with the pre-synaptic terminal, the influx of calcium is restricted. Membrane hyperpolarization occurs, and endogenous transmitter release is reduced. Post-synaptic binding on the 1A sensory afferent terminals increases potassium conductance and cause membrane hyperpolarization. The net effect of baclofen is to produce inhibition of monosynaptic spinal reflexes and to lesser extent polysynaptic spinal reflexes. Numerous reports corroborate the clinical efficacy of oral baclofen in the treatment of spasticity related to multiple sclerosis and spinal cord injury in terms of improved passive range of motion, reduced hyperreflexia, fewer painful spasms, and reduced anxiety related to uncontrolled spasticity. Baclofen is well-absorbed after oral administration. It is eliminated mostly by the kidney, unchanged. However, 15% is metabolized in the liver. Therefore, liver function parameters should be monitored periodically during baclofen treatment, and the dosage should be reduced in patients with impaired renal function. The therapeutic half-life ranges from two to six hours. Baclofen dosing may be initiated with 5 mg three times a day and increase gradually to the therapeutic level. The recommended maximum dosage is 80 mg per day in four divided doses. However, there are reports of improved therapeutic effects with higher dosages and an indication that higher dose prescription is not uncommon. Caution is required, however, since baclofen treatment can produce sedation, complaints of weakness, ataxia, confusion, hypotonia, fatigue, nausea, or dizziness. And in some patients, seizure control has been lost during treatment with baclofen. Baclofen may potentiate hypotension, particularly in patients who are currently taking antihypertensive medication. Abrupt discontinuation of baclofen can produce seizures, confusion, hallucination, rebound muscle spasticity with fever. Dantrolene sodium is a hydantoin derivative formulated for treatment of muscle overactivity. Unlike centrally acting spasmolytics, dantrolene acts at the muscle, where it blacks the release of calcium at the sarcolemma, thus uncoupling neural excitation from muscle contraction. Preclinical and clinical studies indicate it reduces low-frequency twitch tension to a greater degree than high-frequency titanic tension. This suggests that dantrolene should have a significant clinical effect on low-frequency muscle overactivity, such as clonus. Clinical studies tend to support this, although dantrolene's clinical effects are broader than its simplistic model suggests. Oral dantrolene is approved for the control of manifestation of clinical spasticity resulting from upper motor neuron disorders, like spinal cord injury, stroke, traumatic brain injury, cerebral palsy, or multiple sclerosis. As an IV solution, it is also indicated for emergency treatment of malignant hypertermia. The pivotal trial for FDA approval of dantrolene was by Monster in 1974, who reported results of 147 patients, the majority of whom had stroke or spinal cord injuries, and all whom had a pathological stretch reflex, increased muscle stretch reflexes, and decreased function in affected limbs. Patients were randomly assigned to dantrolene or placebo and cross over after 5 weeks. Objective physiologic measures were obtained using a mechanical transducer at the ankle joint in conjunction with EMG. Patients in function were graded as 0, 1, or 2. Dantrolene was begun at 50 mg four times daily and maintained if tendon tap or the overall clinical response, which incorporated a wide variety of clinical parameters, was seen to improve. If not, the dose was increased to 100 mg increments, up to a maximum of 400 mg per day. The optimal dose achieved was maintained for 2 weeks. The maximum improvement for both tendon tap decreased by 30% and overall clinical response moderate improvement occurred at the dose of 200 mg per day. Overall clinical response was positive in 83% of patients while activity of daily living assessment improved in 43%. Slowness was improved in 90% of patients taking 200 mg or more per day. Basmajan and Super in 1973 conducted a double blinded cross over trial of dantrolene versus placebo in 23 patients, the majority of whom had multiple sclerosis, reduction in peak force of the knee jerk from dantrolene, dose not specified during this time, was approximately 25%. Clowness was markedly reduced in several patients with additional improvements noted in spasticity and spasms. Muscle weakness limited the maximum dose of several patients. The report reported on 77 patients ranging from ages 10 to 64 years. Approximately half of this patient had spinal cord pathology. One quarter had multiple sclerosis and the remainder a wide range of other etiologies. One quarter of patients discontinued within 6 weeks commencing treatment for either side effects or lack of benefit, or both. Among the remainder of patients, treatment continued for up to 2 years. Daily dosage ranged from 100 to 800 mg. Muscle tone was reduced in 62% of patients and 20% showing moderate to mark improvement. Moderate to mark improvement is defined as the reduction of hypertonia by at least two thirds. Spasms was reduced in 88% of patients with 21% showing moderate to mark improvement. Clowness was reduced in 89% of patients with moderate to mark improvement in 43%. Muscle tone reflexes were reduced in 47% of patients with moderate to mark improvement in 9%. Reduction in strength was seen in 12% of patients but no measurements were performed to determine differential effects on agonists and antagonists. Mobility improved in 48% of patients and self-care in 35%. Muscle and bladder function remained unchanged in 62% with the rest either worsened or improved. It was also noted that the variable functional benefit contrasted with the larger and more uniform reduction in objective clinical parameters. Mayer and his colleagues gave detailed clinical reports on 13 patients receiving Dantroline for muscle overactivity of either spinal or cerebral origin. While quantitative measures were not used, the detail provided of clinical and functional changes thus allow for some generalizations to be made. Particularly striking was the effect of Dantroline on clowness, which markedly improved or completely resolved in all patients for which it was a problem. This decrease allowed functional gains in 3 patients including improved gait stability from reduced lower limb clowness and improved dressing and splinting from reductions of upper extremity clowness. Reduced mass reflex patterns also led to functional gains in several patients including transfers, dressing and comfort in bed. Spasticity reduction led to improved dressing in several patients. Haslam compared Dantroline up to 12 mg per kg per day to placebo in 5-week crossover trial in 23 children with spasticity. Compared to placebo, Dantroline led to significant improvement in reflexes and scissoring as well as activities of daily living, but not in nursing care or gross motor function. Molnar examined the long-term safety and efficacy of Dantroline in children. 27 children ages 2-14 received open-label Dantroline for 4-41 months and the mean of 16 months. The maximum daily dose ranged from 2 mg to 8.5 mg per kg per day. Clinical evaluations were performed regularly for tone, clowness, muscle stretch reflexes, knee position, foot fall and hand function. Not all assessments were done in all children. Over the course of the treatment, slight improvement or better was seen in all measures in all over half of those assessed. Clonus improved in virtually all patients and muscle stretch reflexes in 84%. Footfall pattern improved moderately in a third of the patients and clonus improved moderately and to markedly in a quarter. Adverse events include weakness, drowsiness, fatigue, dizziness, increased frequency of urination, diarrhea, abdominal discomfort, and skin rash, each of which resolved within one week. Despite its peripheral mode of action, drowsiness and dizziness are among the most frequent adverse reactions resulting from the use of dantrolene. Others include general malaise, fatigue, diarrhea, and acne. All of these effects are generally transient and can often be obviated by beginning with a low dose and increasing gradually until optimal regimen has been established. In addition, dantrolene may also cause weakness in patients who have marginal strength due to their pathologies. The side effect of most common concern is hepatotoxicity. In a 1977 study of 1,044 patients receiving dantrolene during clinical trials, 19, which is about 1.8%, experienced hepatic injury with the use of dantrolene for at least 60 days. 6, which is 0.6%, had symptomatic hepatitis and 3, which is equivalent to 0.3%, died. This marketing data indicates severity is dose-related, with greatest risk at dosages above 400 mg per day. Women over the age of 30 are more at risk for dantrolene-associated death. The rate of liver injury is comparable to the package insert data for several widely used medication including tizanidine and dastatins. According to the package insert, dantrolene should only be used in conjunction with appropriate monitoring of hepatic function, including frequent determination of SGOT and SGPT. Baseline liver function tests should be obtained before starting dantrolene. If baseline liver abnormalities suggest pre-existing liver disease, the risk of dantrolene-induced is enhanced and dantrolene should not be initiated. If baseline liver function tests are normal, repeated monitoring of these lab values should occur during dose titration, which is usually at 1, 3, 6 and 12 months after initiation of the dantrolene therapy. If no observable benefit is derived from the administration of dantrolene after 45 days, dantrolene therapy should be discontinued. If abnormal liver function tests are recorded at any time, repeated testing should be done at 1-week intervals. Should transaminases increase above normal by 2 or 3 times, or should the patient develop signs or symptoms of hepatitis, dantrolene should be discontinued immediately. In the event of an asymptomatic patient has transaminases or transaminitis that is 2 times the upper limit of normal and remain there for unrepeated testing, the physician must weigh the benefit of the medication in improving function against the potential risk of symptomatic hepatitis or rarely fulminant hepatic failure. Beyond the first year of dantrolene use, it is recommended that liver function tests may be obtained every 6 months for 1 year, then yearly after. Dose titration schedules are provided on the package inserts and are indicated for children and adults. 400 mg per day is the maximum for adults and 8 mg per kilogram per day is the maximum for children. The fourth medication on the list is Tizanidine. Tizanidine is an imidodazoline derivative and alpha-2-adrenergic agonist with receptor sites both spinally and supraspinally. Tizanidine has been shown to decrease reflex activity, specifically, polysynaptic reflex activity and has an antinosusceptive effect. These effects of Tizanidine are related to the complex action on inhibition of the excitatory neurotransmitter release in the spinal cord and inhibition of cells in the locus ceruleus. Several European and American studies have shown that Tizanidine is safe and equal in effectiveness to Baclofen and Diazepam, but with a favorable tolerability profile. The clinical effectiveness of Tizanidine has been shown by significant decreases in resting muscle tone and spasm frequency. One trial in which muscle strength was carefully tested in a variety of spastic patients showed improvement during Tizanidine treatment. Tizanidine is extensively metabolized in the liver. Hepatic impairment would be expected to have significant effects on the pharmacokinetics of Tizanidine, although no formal studies have been conducted to evaluate the pharmacokinetics in this situation. Tizanidine has occasionally caused liver injury, most often hepatocellular in type. In controlled clinical trials, approximately 5% of patients treated with Tizanidine had elevations of liver function tests, the ALT or AST or SGPT and SGOT, to have a greater than 3 times of the upper limit of normal or 2 times if the baseline levels were elevated, compared with 0.4% in the controlled patients. Most cases resolve rapidly upon drug withdrawal or no reported residual problems. In occasional symptomatic cases, nausea, vomiting, anorexia, and jaundice have been reported. Based on post-marketing experiences, death associated with liver failure has been a rare occurrence reported in patients treated with Tizanidine. Therefore, Tizanidine should ordinarily be avoided or used with extreme caution in patients with hepatic impairment and monitoring of aminotransferase levels is recommended during the first 6 months of treatment, baseline 1, 3, and 6 months and periodically thereafter based on clinical status. The absorption and metabolism of Tizanidine are quite variable, requiring the initiation of therapy at low dose, 2-4mg using a 4mg scored tablet of the immediate release formulation preferably at bedtime. The dose should be carefully titrated for each patient, increasing slowly and gradually by 2-4mg every 2-4 days until the desired therapeutic goals are achieved with minimal side effects. The average maintenance dose of Tizanidine is 18-24mg per day. The maximum recommended dose is 36mg per day. Significant improvements in patients with mild to moderate cerebral vascular spasticity have been reported after the use of Tizanidine at 3-9mg per day. Women taking oral contraceptives appear to reach and maintain higher than average plasma concentrations requiring more gradual dosages increases. Patients with impaired kidney function also require gradual titration since they show a 2-fold increase in plasma concentration. The plasma concentration is linear to the drug's beneficial antispasticity effects and severity of side effects. In both single-dose and multiple-dose studies, mean changes in muscle tone using Ashward Scale improved significantly, minus 2 to minus 3 from a baseline of 0. The most commonly reported side effects are drowsiness, dizziness, dry mouth, and orthostatic hypotension. A less commonly reported side effect is near-sleep hallucination, which is usually vivid but not threatening. Somnolence may be reduced by titrating the dosage over the day. Some clinicians recommend a larger nighttime loading dose, particularly for MS patients, to minimize side effects and maximize spasticity control and sleep throughout the night. Under fasting conditions, Tizanidine tablets and capsules are bioequivalent, with time to peak plasma concentration of 1 hour and half-life of 2 hours. However, under fed conditions, the two forms of Tizanidine are not bioequivalent. With tablets, the mean peak plasma concentration is increased by 30%, with the time to peak plasma concentration increasing to 1 hour, 25 minutes. With capsules, the mean peak plasma concentration is decreased by 20%, with the median time of peak plasma concentration increasing to 3 hours. Absorption is about 80% higher with the use of tablets as compared to capsules in fed conditions. While capsules are opened and the contents are sprinkled in apple sauce, the concentration max increases by 15% to 20% and time to peak concentration decreases by additional 15 minutes over the intact capsule form. The use of Tizanidine is contraindicated in patients taking fluvoxamine or ciprofloxacin. Concomitant use of these drugs have been shown to potentiate the hypotensive and sedative effects of Tizanidine and may lead to psychomotor impairment. Caution is also urged with the use of Tizanidine and other CYP142 inhibitors such as xyliton, fluoroquinolones, amiodarone, mexilatine, propafenone, verapamil, cimetidine, famotidine, acyclovir, and ticlopidine. Tizanidine clearance is decreased by about 50% in women taking oral contraceptives. Physicians should counsel patients who take Tizanidine to inform all of their healthcare providers and pharmacists when any medication is added or removed from their regimen. Tizanidine should ordinarily be avoided or used with extreme caution in patients with hepatic impairment. The antispasticity effect of clonidine treatment in spinal cord injury patients has been consistent with enhancement of alpha-2-mediated presynaptic inhibition of sensory afferents. Clonidine is 95% bioavailable after oral dose and 62% is excreted in the urine and half-life is 5-19 hours. Since some patients may be sensitive to hypotension and bradycardia effects of clonidine, the initial dose should be low. The 25-microgram formulation available in Canada can be taken orally twice a day to begin treatment. Alternatively, clonidine is available as a transdermal patch with two dosages formulation 0.1mg or 0.2mg per day which have been reported as useful treatment for spasticity. The patch is designed to deliver indicated amount of clonidine daily 7 days. Additional side effects are dry mouth, ankle edema and depression. Cyproheptadine is a treatment for itching associated with hives and anorexia. It has acetylcholine, histamine, serotonin antagonist effects. Cyproheptadine has been reported to decrease clonus in people with spasticity due to spinal cord injury or multiple sclerosis. The patient whose gait is limited by clonus, cyproheptadine normalizes muscle firing patterns and increasing walking speed. In comparative clinical trials, cyproheptadine have similar antispasticity efficacy to clonidine and baclofen in the spinal cord injured patients. Cyproheptadine is available in 4mg tablets. Treatment should be initiated as 4mg at bedtime and increasing by 4mg dose every 3-4 days. The most commonly effective and tolerable dose is 16mg in divided doses such as 4-4 times a day. Maximum recommend dose is 36mg per day. One of the active alkaloids from marijuana is delta-9-tetrahydrocannabinol THC available as a prescription dronabinol. A synthetic cannabinoid nabilone is also available in Canada but is not available in the United States. The clinical indication for dronabinol and nabilone are nausea related to chemotherapy treatment. In 1890 Reynolds described the toxic effects and therapeutic use of cannabis in the treatment of epilepsy, chorea and nocturnal spasms. Anecdotal reports by patients with spasticity due to multiple sclerosis or spinal cord injury suggest that smoking marijuana has a muscle relaxing effect. In a double blind trial in a single patient showed reduction of spasticity and pain. In multiple sclerosis model cannabinoids show usefulness in suppressing spasticity and tremor. Dronabinol after an oral dose of 4-12% bioavailability, less than 1% is excreted via the urine and 95% of the drug is bound to plasma proteins. The half-life is 20-44 hours. It is formulated as 2.5mg, 5mg or 10mg capsules. Nabilone is formulated as a pool fuel containing 1mg with a recommended dose of 1-2mg twice per day. Orphanedrine citrate is shown some efficacy as an antispasticity medication in spinal cord injury patients when given as an intravenous infusion. A related compound Orphanedrine chloride is a treatment for Parkinson's disease. Which of the following is the mechanism of action of Dantrolene? A. GABA-B selective agonist B. Acts on pre and post-synaptic actions C. Acts on mono and polysynaptic pathways D. Blacks calcium release at the sarcolemma The correct answer is D. Dantrolene is a hydantoin derivative with a unique peripheral mechanism where it blacks calcium release at sarcolemma and uncouples excitation and contraction. A, B and C are mechanism of action for Baclofen. In summary, at the end of this lecture, you are now able to distinguish the most widely used oral agents for reduction of spasticity, its pharmacology, mechanism of action, and dosages. The five widely used oral agents are Baclofen, Tizanidine, Clonidine, Dantrolene, and Diazepam. You are now able to differentiate the unwanted side effects of oral spasticity medication. And we've also touched on oral agents for reduction of spasticity. This table is a summary of the mechanism of action, starting dose, max dose, and side effect of the five widely used oral antispasticity medication. Please read this on your own. The next few slides shows the references of this presentation. Thank you for listening.

oral pharmacology

spasticity treatment

Benzodiazepine

Baclofen

Tizanidine

neurotransmitter GABA

pharmacokinetics