hyperpolarization by three distinct actions: 1) closure of presynaptic calcium channels, 2) increased postsynaptic K+ conductance, and 3) inhibition of dendritic calcium influx channels. Through reduced release of excitatory transmitters in both the brain and the spinal cord, baclofen suppresses activity of Ia sensory afferents, spinal interneurons, and motor neurons (Figure 27–10). Baclofen may also reduce pain in patients with spasticity, perhaps by inhibiting the release of substance P (neurokinin-1) in the spinal cord.
Baclofen is at least as effective as diazepam and tizanidine (discussed below) in reducing spasticity and is less sedating than diazepam. Baclofen does not reduce overall muscle strength as much as dantrolene. It is rapidly and completely absorbed after oral administration and has a plasma half-life of 3–4 hours. Dosage is started at 15 mg twice daily, increasing as tolerated to 100 mg daily. Studies have confirmed that intrathecal catheter administration of baclofen can control severe spasticity and muscle pain that is not responsive to medication by other routes of administration. Owing to the poor egress of baclofen from the spinal cord, peripheral symptoms are rare. Therefore, higher central concentrations of the drug may be tolerated. Partial tolerance to the effect of the drug may occur after several months of therapy, but can be overcome by upward dosage adjustments to maintain the beneficial effect. This tolerance was not confirmed in a recent study and decreased response may represent unrecognized catheter malfunctions. Although a major disadvantage of this therapeutic approach is the difficulty of maintaining the drug delivery catheter in the subarachnoid space, risking an acute withdrawal syndrome upon treatment interruption, long-term intrathecal baclofen therapy can improve the quality of life for patients with severe spastic disorders. Adverse effects of high-dose baclofen include excessive somnolence, respiratory depression, and coma. Patients can become tolerant to the sedative effect with chronic administration. Increased seizure activity has been reported in epileptic patients. Withdrawal from baclofen must be done very slowly. Baclofen should be used with caution during pregnancy; although there are no reports of baclofen directly causing human fetal malformations, animal studies using high doses show that it causes impaired sternal ossification and omphalocele.
Oral baclofen has been studied in many other medical conditions, including patients with intractable low back pain, stiff person syndrome, trigeminal neuralgia, cluster headache, intractable hiccups, tic disorder, gastroesophageal reflux disease, and cravings for alcohol, nicotine, and cocaine (see Chapter 32).
As noted in Chapter 11, α2-adrenoceptor agonists such as clonidine and other imidazoline compounds have a variety of effects on the CNS that are not fully understood. Among these effects is the ability to reduce muscle spasm. Tizanidine is a congener of clonidine that has been studied for its spasmolytic actions. Tizanidine has significant α2-agonist effects, but it reduces spasticity in experimental models at doses that cause fewer cardiovascular effects than clonidine or dexmedetomidine. Tizanidine has approximately one tenth to one fifteenth of the blood pressure-lowering effects of clonidine. Neurophysiologic studies in animals and humans suggest that tizanidine reinforces both presynaptic and postsynaptic inhibition in the cord. It also inhibits nociceptive transmission in the spinal dorsal horn. Tizanidine’s actions are believed to be mediated via restoration of inhibitory suppression of the group II spinal interneurons without inducing any changes in intrinsic muscle properties.