Abstract
Intrathecal neurolysis is considered when the patient’s cancer pain is intractable and refractory to medical and interventional therapies. The pain should be unilateral, located in the thorax and abdomen, and restricted to 1–4 dermatomes. In intrathecal neurolysis, the needle tip is placed at the vertebral level where the target dorsal root leaves the spinal cord and not where it passes the intervertebral foramen. The physician should observe all the recommended precautions to prevent spillage of the alcohol or phenol to unintended nerve roots. In epidural neurolysis, the needle or catheter tip lies closer to the vertebral level that corresponds to the dermatomal level of pain. An epidural catheter is usually inserted, and repeated injections are done over a few days. Complications include extremity weakness or bowel/bladder paresis. Peripheral neurolysis is rarely performed; it is usually done in the trunk (e.g., intercostal nerves) to avoid weakness of the extremities.
Keywords
cancer pain, intrathecal neurolysis, neurolysis, neurolytic block, neuropathic pain
Introduction
Chemical neurolysis is a modality that has been used for pain control for almost a century. Multiple agents have been evaluated through the years, but only a few are still clinically relevant. Glycerol is used for the treatment of trigeminal neuralgia. Phenol and ethyl alcohol are the only two agents commonly used in the epidural or intrathecal space, as well as for neurolysis of the sympathetic chain, celiac plexus, and splanchnic nerves. The decision to use neurolytic agents usually is made after many other modalities have failed to provide benefit. Chemical and surgical neurolysis potentially have very serious side effects. Their use is primarily limited to patients with pain associated with terminal malignancies. These procedures provide the most benefit in the oncology patients in whom more conservative measures were unsuccessful or possessed too high a side-effect burden. In patients in extremis, neurolysis represents a palliative measure to provide pain relief while maintaining the patient’s ability to interact with family and friends in their final days to months of life. It can improve pain control in patients who have developed tolerance and hyperalgesia or severe side effects from high-dose opioids. Neurolysis is an alternative to allow patients the ability to control their pain with less systemic medication, significantly improving their quality of life.
Patient Selection
After a patient is deemed to have a pain pattern or pathology that is appropriate for neurolytic therapy ( Table 72.1 ), it is imperative to clearly explain the specific goals and expectations. Neurolysis can provide substantial analgesia and will usually allow a significant reduction of systemic pain medications. The limitations and complication profile of this modality are not insignificant and are an important part of the decision process for the patient and provider. Although neurolysis can provide analgesia in the nerve distribution affected by the block, it will not necessarily provide pain relief from an expanding tumor or new metastasis. In addition, the effects of this therapy can be temporary and will diminish over time, requiring readministration of the neurolytic agent. Although these agents usually provide good to excellent pain relief, sometimes the level of analgesia is inadequate to meet patient expectations or the duration of pain relief is too short. There have also been reports of limb weakness and loss of bowel or bladder tone. Typically, the patient subset chosen for epidural or intrathecal neurolysis has been escalated through the rungs of the World Health Organization (WHO) analgesia ladder ( Fig. 72.1A ) without relief, and they are experiencing pain that cannot be adequately controlled by standard analgesics, or the analgesic doses are producing intolerable side effects. These patients will also fall into a category in which advanced interventional pain medicine strategies have been tried, but without inadequate analgesia, or the patient possesses contraindications to these procedures (see Fig. 72.1B ). Patients with complaints of neuropathic pain will typically not get the desired results compared with those with visceral or somatic pain. Due to the nature of neurolytic administration, it is ideal for controlling unilateral pain in the trunk that is focused to a few adjacent dermatomes. However, in the presence of an intraspinal tumor, the effectiveness of these techniques will decrease, making these patients unsuitable candidates. Neuraxial neurolytic therapy is ideal for patients with advanced or terminal malignancy and unilateral somatic pain.
| Intractable cancer pain (advanced or terminal malignancy) |
| Failure of medical and interventional analgesic therapy |
| Intolerable side effects of current therapy |
| Unilateral pain |
| Pain restricted to one to four dermatomal levels |
| Pain located in the trunk, thorax, abdomen |
| Primary somatic pain mechanism |
| Absence of intraspinal tumor spread |
| Effective analgesia with local anesthetic block |
| Informed consent of patient |
| Realistic expectations and family support |
Patient Preparation
Prior to attempting any neurolytic block, it is essential to have a clear and accurate pain diagnosis and the location needs to be accurately mapped with a dermatomal chart ( Fig. 72.2 ). Multiple modalities are available to achieve an accurate diagnosis and should be used to ensure an effective block that is appropriate for the underlying condition. After a definitive plan is established, informed consent should be obtained from the patient, outlining all the risks associated with the particular procedure in detail. A thorough neurologic examination before any invasive techniques are attempted is vital not only for assessing the effectiveness, but also in providing a baseline assessment in the event of any potential complications. In an ideal treatment scenario, a member of the patient’s multidisciplinary cancer team will perform these blocks, with all providers aware of the status and progression of the primary and metastatic malignancies throughout the treatment period. The patient and primary oncology team should be aware that in cases of rapidly growing tumors, expanding tumor growth may compromise the efficacy of a block. Before any neurolytic agents are used, it is advisable to perform a prognostic blockade with a local anesthetic that reproduces the planned intervention. This “diagnostic” maneuver helps to confirm needle placement and can provide information about the level of effectiveness of the neurolysis. The patient and practitioner should be aware that the agents used for neurolysis have a longer time to onset of pain relief compared with local anesthetics and that the effects may not be as profound or immediate. The choice of neurolytic agent is based upon the location of needle placement, the ability of the patient to get in the required position, and the volume of injectate required ( Table 72.2 ). Baricity may play a role in determining which neurolytic agent to use for the patient. Phenol is a hyperbaric agent that would be more appropriate for intrathecal and saddle blocks compared with a hypobaric agent such as ethanol.
| Alcohol | Phenol | |
|---|---|---|
| Physical properties | Low water solubility | Absorbs water on air exposure |
| Stability at room temperature | Unstable | Stable |
| Concentration | 100% | 4%–7% |
| Diluent | None | Glycerin |
| Relative to cerebral spinal fluid | Hypobaric | Hyperbaric |
| Patient position | Lateral | Lateral |
| Added tilt | Semiprone | Semisupine |
| Painful side | Uppermost | Most dependent |
| Injection sensation | Burning pain | Painless, warm feeling |
| Onset of neurolysis | Immediate | Delayed (15 min) |
| Cerebrospinal fluid uptake ends | 30 min | 15 min |
| Full effect | 3–5 days | 1 day |
Neurolytic Agents
Alcohol
Ethyl alcohol (ethanol) is one of the classic neurolytic agents and was first reported by Dogliotti in 1931 for intrathecal injection. Anhydrous ethyl alcohol is commercially available in the United States in undiluted (100% concentration) 1- and 5-mL ampoules. Although commercial preparations are undiluted, exposure to the atmosphere will cause dilution via absorption of water.
Ethyl alcohol injections administered perineurally are associated with burning dysesthesias running along the course of the nerve. This sensation is often extremely unpleasant for the patient and can last from a few minutes to a few weeks. To alleviate this known effect, most practitioners inject a local anesthetic preceding the use of ethyl alcohol. The use of this initial dose of local anesthetic can also provide guidance on the correct location of the injectate.
The neurolytic action of alcohol is produced by the extraction of neural cholesterol, phospholipids, and cerebrosides, and the precipitation of mucopeptides. These actions result in sclerosis of the nerve fibers and myelin sheath, leading to demyelination. The basal lamina of the Schwann cell sheath remains intact, allowing for new Schwann cell growth, thereby providing the framework for subsequent nerve fiber growth. This framework encourages the regeneration of axons but only if the cell bodies of these nerves are not completely destroyed. The pathway of degeneration is nonselective and can be observed in peripheral nerves and spinal nerve roots following intrathecal injection. Areas of demyelination can be seen in posterior columns, Lissauer tract, and the dorsal root, followed by wallerian degeneration to the dorsal horn. Intrathecal alcohol injection results in rapid uptake of alcohol and variable injury to the surface of the spinal cord.
Ethyl alcohol is quickly absorbed from the cerebrospinal fluid (CSF) so that only 10% of the initial dose remains in the CSF after 10 minutes and only 4% after 30 minutes. The rapid spread from the injection site means larger volumes are required than for phenol, which in turn may result in local tissue damage. In the case of celiac plexus blocks, alcohol is rapidly absorbed into the bloodstream. It has been shown that serum ethanol levels up to 54 mg/dL can occur after a celiac plexus block, which may be high enough in some people to result in psychomotor effects. However, following intrathecal administration of alcohol, it is unlikely that there will be significant vascular uptake.
The use of ethanol as a neurolytic agent has been associated with a disulfram-like effect due to the inhibition of the enzyme acetaldehyde dehydrogenase. Case reports include patients taking moxalactam, a β-lactam antibiotic that inhibits aldehyde dehydrogenase, and another taking 1-hexyl carbamoyl-5-fluorouracil, an anticancer drug, who experienced similar symptoms. The patients experienced flushing, hypotension, tachycardia, and diaphoresis within 15 minutes of alcohol administration. The symptoms resolved 4 to 6 hours later, and efforts were undertaken to stabilize hemodynamics. Both cases occurred after celiac plexus blocks. It is important for the pain practitioner to recognize medications that may cause disulfiram-like effects, such as chloramphenicol, β-lactams, metronidazole, tolbutamide, chlorpropamide, and disulfiram, before peripheral neurolytic blocks performed with alcohol.
Ethyl alcohol has a specific gravity of less than 0.8, and CSF has a specific gravity of slightly greater than 1.0. Within the CSF, alcohol is hypobaric and will move against gravity, “floating” upwards. Therefore positioning of the patient is an extremely important factor to consider when planning their procedure.
The administration of ethanol for the purpose of neurolysis can have catastrophic consequences. It has been associated with both transient and permanent paraplegia in both celiac plexus and intrathecal blocks. It has been postulated that these effects are secondary to vasospasm of the spinal arteries by the direct action of alcohol. In the case of transient effects, paraplegia developed within 22 minutes and resolved within 90 minutes. The patient had good pain relief for several weeks after his injection, suggesting appropriate needle placement, and frequent negative aspirations during injection indicated that no significant intravascular injection of the alcohol had occurred. In the permanent paraplegia case the patient received an intrathecal block, and symptoms did not develop until 12 hours after the procedure. This patient also had good pain relief; however, she did not regain the use of her lower extremities. She died several weeks later secondary to her primary condition.
Phenol
Phenol is a benzene ring with one hydroxyl group substituted for a hydrogen atom. It is usually prepared by the hospital pharmacy because it is not commercially available in premixed liquid form. Phenol is poorly soluble in water and, at room temperature, forms only a 6.7% aqueous solution. Consequently, phenol is frequently prepared with contrast dyes and either sterile water, saline, or glycerin. When phenol is exposed to room air, it undergoes oxidation and turns a reddish color; however, it has a shelf life of approximately 1 year if refrigerated and shielded from light exposure. When phenol is prepared with glycerin, it has limited spread, and hence injections are well localized. In rats the aqueous solution of phenol has a greater ability to penetrate the perineurium and produce greater endoneurial damage than glycerin preparations, but there is no difference in results following intraneural injection. Unlike alcohol, phenol injection has an initial local anesthetic effect. It is not associated with localized burning but instead creates a sensation of warmth and numbness. The distribution of this sensation can help the practitioner to verify proper needle placement. Concentrations of 4%–10% are typically used for neurolysis. When phenol is prepared in glycerin, it has a specific gravity of 1.25, making it hyperbaric. Preparations of phenol in glycerin are highly viscous, which may make administration through a spinal needle difficult. Warming the injectate in a heated water bath before drawing it up into a tuberculin syringe may facilitate the ease of injection. Careful patient positioning to allow phenol to settle into the desired location is important and contrary to the concepts associated with patient positioning for alcohol neurolysis.
Putnam and Hampton first used phenol as a neurolytic agent in 1936. Mandl used it for a sympathetic ganglion block in animals in 1947. Phenol was first used as a medication in an intrathecal injection in humans in 1955. Originally, it was surmised that phenol had a selective effect on small-diameter nerve fibers, such as unmyelinated C-fiber afferents and Aδ afferents. Subsequent studies have shown that phenol concentrations determine the type and extent of nerve disruption. Dilute intrathecal phenol can produce a transient local anesthetic blockade, whereas increased concentrations can produce significant neural damage. Phenol concentrations have a direct correlation with the extent of neural damage. At concentrations less than 5%, phenol instigates protein denaturation of axons and surrounding blood vessels. At concentrations greater than 5%, phenol can produce protein coagulation and nonselective segmental demyelination. The nonselective effects of phenol were confirmed by Nathan et al. using histologic studies combined with evidence of electrophysiologic changes to Aα and Aβ fibers. Smith has shown that intrathecal phenol injections in cats and humans primarily destroyed axons in dorsal rootlets and in the dorsal columns of the spinal cord. It was also noted to exert some effects on ventral root axons. Maher and Mehta noted that motor blocks by phenol were possible at concentrations greater than 5%, whereas intrathecal injections of less than 5% produced mostly sensory blocks. At higher concentrations, the extent of damage can increase quite significantly, with the potential for axonal nerve root damage and spinal cord infarcts. Injections of high-concentration phenol have also been associated with arachnoiditis and meningitis.
When compared with alcohol, phenol seems to facilitate axonal regeneration in a shorter period of time. Electrophysiologic studies comparing peripheral nerve destruction in cats showed that those patients injected with phenol had returned to normal by 2 months, whereas at the end of the same time period, those injected with alcohol still demonstrated depression of compound action potentials. However, another study by Smith suggests regeneration is not completed until approximately 14 weeks after the administration of phenol.
It was once believed that phenol’s neurolytic effects might be due to local ischemia because of its greater affinity for vascular tissue compared with neural tissue. Racz et al. found that unlike epidural injection, tissue destruction resulted after intrathecal injection even though the vasculature remained intact in the areas of spinal cord destruction. This finding points towards direct neurotoxic effects rather than effects secondary to local ischemia. It is possible that phenol’s effects may be a combination of direct neurotoxic and ischemic effects.
Romero-Figuero and colleagues demonstrated that vascular thrombosis is likely due to a caustic effect of phenol on the endothelium. The vascular effects of any of the neurolytic agents are salient, particularly when these agents are injected in close proximity to prosthetic vascular grafts. The effect of neurolytic agents on prosthetic grafts seems to depend on the type of graft itself. Gore-Tex grafts appear to be able to withstand exposure to neurotoxic agents unharmed, whereas Dacron grafts show diminished tensile strength after a 72-hour exposure to either 6% phenol or 50% alcohol. Systemic doses of phenol in excess of 8.5 g are associated with toxic side effects. These effects initially are convulsions, followed by central nervous system (CNS) depression, and, finally, cardiovascular collapse. Intravascular injection at lower doses can also produce systemic toxicity. Chronic long-term exposure may be associated with renal toxicity, skin lesions, and gastrointestinal effects. However, phenol is not classically used in long-term settings, and the customary doses of less than 100 mg are unlikely to produce any systemic effects.
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