Primary lateral sclerosis is a motor neuron disease. Muscle spasticity and resulting intense pain from primary lateral sclerosis are very debilitating. Adequate treatment of spasticity improves patients’ function and quality of life. Oral muscle relaxants are generally ineffective for severe spasticity. Intrathecal baclofen is efficacious and is considered the treatment of choice for spasticity.1–3 However, patients can develop tolerance to this medication.
Intrathecal ziconotide, an N-type calcium channel blocker, has been approved by the Food and Drug Administration for the treatment of severe chronic neuropathic pain.4 At high doses, it was reported to successfully treat severe spasticity after spinal cord injury.5 In another case series, the combination of a relatively low dose of intrathecal ziconotide and baclofen provided pain relief in patients with neuropathic pain and spasticity.6 In this report, we present a case of primary lateral sclerosis, the spasticity of which, refractory to intrathecal baclofen, was successfully managed with low-dose intrathecal ziconotide as a monotherapy.
The patient’s power of attorney signed a written Health Insurance Portability and Accountability Act authorization to publish this case report.
A 41-year-old woman with a diagnosis of primary lateral sclerosis presented at our pain clinic in January 2009 for a potential intrathecal baclofen pump. She had progressively ascending severe spasticity affecting primarily her lower extremities. She also had dysarthria, dysphagia, and spasticity of abdominal wall muscles. She uses a 3-wheeled motorized scooter for mobility at home. She does stand-pivot transfers with assistance. She uses her right upper limb for activities of daily living. Oral baclofen (80 mg/d) and diazepam (5 mg twice a day) failed to control her spasticity. She could not tolerate a higher dose of baclofen due to side effects and failed other antispasmodics due to lack of efficacy. During physical examination, she had very brisk reflexes throughout and 1–2 beats of clonus in the lower extremities. The spasticity in her bilateral lower extremities was 3 on the Modified Ashworth Scale of Spasticity, worse on the left than the right. She had a positive Hoffman sign bilaterally in the upper extremities.
A single-shot trial of 50 μg of intrathecal baclofen provided 70% relief in the spasticity in her lower extremities for 14 hours, with some improvement in her upper extremities as well. In February 2009, a permanent intrathecal pump was thus implanted with the catheter tip at T10 vertebral level. Baclofen infusion was started at 80 μg/d based on the trial dose. However, the patient’s spasticity became worse than before the pump implant. The baclofen daily dose, including both the basal infusion dose and patient therapy management dose, was then gradually increased during the next 4 months up to 1100 μg/d in June 2009, and the oral baclofen dose was weaned down to 10 mg 3 times a day. Her spasticity was not controlled, and her diazepam was increased to 5 mg 3 times a day. A catheter study showed a patent pump catheter, and the pump was functioning well with appropriate residual volumes. Interestingly, spasticity was paradoxically worse at the higher dosages. Therefore, the baclofen infusion rate was then slowly decreased during the next 2 years to 25 μg/d in May 2012 and continued at this dose until July 2014 with some improvement. During this time, intrathecal ziconotide was discussed multiple times with the patient and her husband, who were reluctant to try it and wanted to discuss with her neurologist. Although a high dose of intrathecal ziconotide was reported to control severe spasticity after spinal cord injury,5 ziconotide was completely new to her neurologist, who did not support a trial of intrathecal ziconotide. Her spasticity then worsened due to disease progression and did not respond to dose increases in intrathecal baclofen. Catheter and pump malfunction was excluded. Given the patient’s previous history of paradoxical worsening of spasticity with dose increases, the intrathecal baclofen dose was decreased further down to 15 μg/d by April 2015. Her spasticity remained uncontrolled. Intrathecal ziconotide was discussed again. The patient and her husband finally decided to proceed with a trial of intrathecal ziconotide.
In June 2015, without changing the pump or catheter, intrathecal baclofen was replaced with ziconotide starting at 0.6 μg/d with noticeable but inadequate relief in spasticity and pain. The infusion rate was then slowly increased, and optimal relief was achieved at 3 μg/d by August 2015. The patient was able to move her lower extremities with significantly greater range of motion, participate in physical therapy, and stand to transfer to and from the wheelchair. Her oral diazepam and baclofen were both weaned off. Ziconotide infusion was continued at 3 μg/d. So far, the patient and her husband have been very satisfied. She continues to get botulinum toxin A injections for upper extremity spasticity.
Primary lateral sclerosis is a type of motor neuron disease, only affecting, at least initially, upper motor neurons. The prominent symptom of primary lateral sclerosis is the gradual-onset, progressive spasticity that typically starts in the lower extremities and later involves the trunk, upper extremities, and facial muscles, in that order.7,8 The muscle spasticity and intense pain when these muscles are stretched are the debilitating aspects of primary lateral sclerosis. These subsequently result in joint immobility. Adequate control of spasticity is very important in improving patients’ quality of life and function.
Degeneration of upper motor neurons can cause disinhibition of the lower motor neuron activities, leading to spasticity.9 Intrathecal baclofen is currently the therapy of choice for severe spasticity.1–3 Baclofen is hydrophilic and readily dissolves in cerebral spinal fluid. It acts at γ-aminobutyric acid B receptors to inhibit the monosynaptic and polysynaptic reflexes at the spinal level, possibly by hyperpolarization of afferent terminals, decreasing excitatory neurotransmitter release from these terminals.10 Baclofen also acts at supraspinal sites that may contribute to its effect.10 These actions lead to a decrease in muscle tone.10 In our case, the patient had a favorable response to the single-shot intrathecal baclofen trial, but the pump implant with baclofen infusion did not work as expected for her, despite a wide range adjustment of both the basal infusion rate and patient therapy management doses. This could be due to tolerance to baclofen developed from years of oral baclofen use and short-term intrathecal baclofen infusion. It is not clear why higher doses made spasticity worse. However, paradoxical effect is not uncommon in medicine. Opioid-induced hyperalgesia is an example.11
Ziconotide is a synthetic version of hydrophilic conotoxin ω-MVIIA from the venom of the Pacific fish-hunting marine snail Conusmagus.12 Intrathecal ziconotide was approved by the Food and Drug Administration for treating chronic pain.4 Studies in rats showed that ziconotide binds to the dorsal horn of the spinal cord, where primary afferents synapse onto the secondary neurons or interneurons.13 Ziconotide is thought to provide analgesic effect by blocking presynaptic N-type voltage-gated calcium channels on primary nociceptive endings in the dorsal horn, thus decreasing the release of nociceptive neurotransmitters and neuropeptides.4,14 During a clinical trial using intrathecal ziconotide to treat neuropathic pain, Ridgeway et al5 observed that 2 cases of severe spasticity from spinal cord injury were relieved with high doses of intrathecal ziconotide. In comparison, the severe spasticity from primary lateral sclerosis in our case, although refractory to intrathecal baclofen, was managed with a very low dose of intrathecal ziconotide.5 The doses of intrathecal ziconotide in our case are within the recommended dose range of 0.5–19.2 μg/d for neuropathic pain.15 The dose difference between our case and the cases reported by Ridgeway et al5 is likely due to the fast titration in Ridgeway’s cases, which may have overshot the lowest effective dose; and the spasticity from primary lateral sclerosis, which may be different from the spasticity due to spinal cord injury.
The mechanisms for the antispasmodic effect of intrathecal ziconotide are unclear. There exist several possibilities. First, ziconotide may exert its antispasmodic effect by similar upstream mechanisms to its analgesic effect in the spinal cord and similar downstream pathways to baclofen. Blocking the presynaptic N-type voltage-gated calcium channels on primary afferent terminals causes decreased release of excitatory neurotransmitters, resulting in less excitation of excitatory interneurons in the spinal cord, thus restoring the balance between the excitatory and inhibitory pathways in the control of the monosynaptic and polysynaptic reflexes at the spinal level. Second, in human beings, ziconotide may directly act on the ventral horn cells such as motor neurons, interneurons, and glial cells, in addition to the observed target areas in rats. It may decrease the release of excitatory neurotransmitters in the ventral horn by blocking the presynaptic calcium channels. Finally, it may also work at supraspinal sites. A case series reported that the combination of relatively low doses of intrathecal ziconotide and baclofen provided pain relief in patients with neuropathic pain and spasticity.6 There may be additive, or even synergistic, effects between ziconotide, which inhibits the excitatory pathways, and baclofen, which excites the inhibitory pathways. More studies are needed to determine the working sites and mechanisms of intrathecal ziconotide in spasticity control. In patients with severe spasticity refractory to intrathecal baclofen, intrathecal ziconotide should be considered as a monotherapy or adjuvant to other treatments.
Name: Xiaoying Zhu, MD, PhD.
Contribution: This author helped write the manuscript.
Name: Lynn R. Kohan, MD.
Contribution: This author helped revise the manuscript.
Name: Robert B. Goldstein, MD.
Contribution: This author helped revise the manuscript.
This manuscript was handled by: BobbieJean Sweitzer, MD, FACP.
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