Victor Andrei Georgescu
Drugs Used in Neurolysis
Neurolysis is the long-lasting or permanent interruption of neural transmission as a result of therapeutic application of a chemical or physical destructive agent to a nerve, usually for pain control purposes. Chemical neurolytic agents include alcohol, phenol, glycerol, ammonium compounds, hypotonic or hypertonic solutions, and alkyl tetracaine derivatives. Among these, alcohol and phenol have remained the neurolytics of choice.
Alcohol (Ethyl Alcohol)
Doglioti first used alcohol for neurolytic purposes in 1931, which makes it, perhaps, the neurolytic agent that has been in use the longest. Alcohol is a potent neurolytic agent that destroys both spinal and peripheral nerves. It has a wide application, having been used for trigeminal ganglion, subarachnoid, celiac plexus, and lumbar sympathetic chain blockade.
The mechanisms of action of alcohol include dehydration; extraction of phospholipids, cholesterol, and cerebrosides; and precipitation of mucoproteins and lipoproteins. These actions result in sclerosis and separation of the myelin sheath, edematous Schwann cells, and axons. The basal lamina of the Schwann cell tube is often spared and the axon can regenerate along the previous course; if the ganglion is injected, it may produce cell destruction with no subsequent regeneration.
Concentration and Use
The usual concentrations are 50%, 75%, and 100%. Concentrations of at least 35% to 50% are needed to produce neurolysis. There is a relationship between the concentration used and the degree of block provided.
· Ethanol 30% in the subarachnoid space temporarily destroys sensory but not motor function.
· Concentrations below 50% produce no motor dysfunction.
· Concentrations of 50% can produce neurolysis of C fibers.
· Concentrations above 60% may produce paralysis for an unpredictable duration.
· Alcohol of 75% concentration can produce neurolysis of sensory and C fibers.
· At concentrations of 95% and above (absolute alcohol), the destruction involves all fibers (sympathetic, sensory, and motor), with a success rate up to 58%; injection of absolute alcohol is followed by considerable fibrosis.
1. Subarachnoid block: Between a minimum of 0.3 mL to a maximum of 1.5 mL per segment. Generally, concentrations of 50% and 100% are preferred.
2. Celiac plexus and lumbar sympathetic blocks: 10 to 20 mL absolute alcohol bilaterally.
Prior to injection, alcohol 100% may be diluted 1:1 with local anesthetic for better patient tolerance.
Effective duration of neurolysis with intrathecal alcohol is usually 4 months or less. In animal models, topical application of alcohol results in depression of action potentials lasting for 8 weeks.
Complications and Disadvantages
Neuritis has been defined as “the great disadvantage” of using alcohol as a neurolytic agent. It may cause pain that is worse than the original pain. It follows an incomplete destruction of a somatic nerve, more frequent during neurolysis of thoracic sympathetic nerves. In most instances, the symptoms subside within a few weeks or a month. Other complications/disadvantages of alcohol include:
· Alcohol is an irritant for soft tissue, and its injection is associated with an uncomfortable burning dysesthesia, which requires prior or concomitant injection of local anesthetic.
· Alcohol has a high solubility in body fluids and spreads quickly from the injection site. This high solubility makes it difficult for alcohol to reach its target tissue and necessitates a larger volume, increasing the chance of damage to tissue in the immediate vicinity.
· Vasospasm accounts for the paraplegia reported after celiac plexus block. Injection of alcohol triggers an intense burning sensation along the target nerve tract, followed after approximately 1 minute by a warm, numb sensation. Prior or concomitant administration of local anesthetic has been used in practice. Advantages of this technique include improved patient comfort and local anesthetic effects in the area of distribution of target nerve with confirmation of correct needle placement. An advantage of not using a local anesthetic is that pain along the target nerve will confirm correct needle placement. Denervation and pain relief occur over approximately 1 week. If no pain relief has been accomplished after this period, repeat neurolysis may be considered.
Doppler first used phenol for deliberate nerve destruction in 1925. Putnam and Hampton were the first to report phenol use for neurolysis in 1936. Nachaev reported its use as a local anesthetic in 1933. Since 1959, phenol has been used as a neurolytic agent for the treatment of both chronic pain and spasticity. The block produced by phenol tends to be less profound and of shorter duration than that produced by alcohol.
The mechanism of action of phenol depends on its concentration: Protein denaturation occurs at concentrations less than 5%, and concentrations higher than 5% produce protein coagulation, nonspecific segmental demyelination, and orthograde degeneration (i.e., wallerian degeneration). Axons of all sizes are affected and appear edematous; however, posterior root ganglia are unaffected by phenol. It has been suggested that phenol has a greater affinity for vascular than neuronal tissue (causing neuronal tissue damage by interfering with blood flow), but this observation has not been supported by further studies.
Concentration and Use
Phenol has been prepared in sterile water, normal saline, Renografin (Bristol-Meyers Squibb, New York, NY), metrizamide, and glycerin. The composition of phenol solution determines the potency: Aqueous solutions are more potent than glycerin solutions. (Note: Phenol is relatively insoluble in water, and aqueous solutions with concentrations above 6.7% usually need additional glycerin.)
Phenol is not available in a “ready-to-use” pharmaceutical compound; it should be prepared by the hospital pharmacist. The most commonly used concentrations are between 6% and 8%. More recent studies have shown that 12% phenol in Renografin is a better neurolytic agent than phenol in lesser concentrations. There is also a gradation of intensity of the block according to the concentration used.
· Concentrations of 3.3% and below are ineffective.
· Injection of the subarachnoid space with concentrations of less than 5% produces mostly sensory blocks, whereas concentrations above 5% produce motor blockade as well.
· Pain transmission is blocked at concentrations of 5%.
· Touch and proprioception are blocked at concentrations above 5%.
· Concentrations between 5% and 6% produce destruction of nociceptive fibers with minimum side effects.
· Concentrations higher than 6% may cause axonal abnormalities, nerve root damage, spinal cord infarcts, arachnoiditis, or meningitis. This may explain the long-lasting effects of neurolytic blocks using 10% phenol in the sympathetic axis.
· Phenol in glycerin at concentrations varying between 6% and 12% can achieve a neurolytic blockade of motor, sensory, and C fibers (success rate of 60%).
Glycerin solutions of phenol are hyperbaric as compared with cerebrospinal fluid. Also, they are very stable given the high solubility of phenol in glycerin. The diffusion of phenol from the solution is slow, with a limited spread and highly localized tissue fixation. This is particularly important for intrathecal injections. When mixed with glycerin, both phenol and glycerin should be totally water-free; otherwise, the spread of the solution is unpredictable and the narcotic effect much greater than anticipated. Because of their high viscosity, glycerin solutions of phenol are difficult to inject through smaller than 20-gauge needles.
A biphasic action of phenol has been observed clinically. It has an initial local anesthetic-like effect with subjective warmth and numbness, which lasts for about 24 hours, followed by neurolysis, with pain less intense than that caused by alcohol. As with alcohol, the neurolytic effect should become clinically evident after about 1 week. If neurolysis does not occur in 2 weeks, a repetition of the procedure may be considered. Neuritis is less common with phenol injection than with alcohol. For this reason, most physicians prefer phenol to treat neurolysis in patients with unknown life expectancy, minimizing the chance of neuritis as a late complication of the neurolysis.
Solutions with volumes between 1 and 10 mL and concentrations between 1% and 10% (up to 1 g) are unlikely to cause serious toxicity. Systemic doses of 8.5 g and above cause convulsions followed by depression of the central nervous system and cardiovascular collapse. A potency equivalence of 3% phenol and 40% alcohol has been supported by studies.
There is no consensus about the duration of phenol neurolytic block; however, it is accepted that it is shorter than the block provided by alcohol. Histopathologic studies have revealed that the damage of perineural vascular elements reaches a maximum in 2 weeks, followed by maximum recovery in 14 weeks.
Alcohol and phenol are still the most commonly used neurolytic agents for pain treatment. Some of the recommended concentrations of alcohol and phenol solutions used for various neurolytic blocks are as follows:
· Intrathecal neurolytic blocks: Alcohol 100% or phenol 4% to 5% in glycerol.
· Epidural neurolytic blocks: Alcohol 30% or 100%; phenol 10% in 10% glycerol or 7% in water.
· Celiac plexus blocks: Alcohol 50%.
· Sympathetic ganglion neurolytic block: Alcohol 100% or phenol 10% in 10% glycerol.
· Pituitary gland block: Alcohol 100% or phenol 7% in water.
Note: Alcohol 100% is hypobaric, while phenol 4% to 5% is hyperbaric in relation to cerebrospinal fluid. This is important for patient positioning. The dorsal roots to be blocked should be in the most superior position when alcohol is used as a neurolytic agent and in the most dependent position when neurolysis is accomplished with phenol. Phenol is the agent of choice for epidural neurolysis.
Glycerol is a mild neurolytic agent used for trigeminal ganglion block with preservation of facial sensation in most patients.
Although not completely understood, the mechanism of action of glycerol appears to affect primarily damaged myelinated axons. Injection in the vicinity of the nerve causes perineural damage, while intraneural injection results in Schwann cell edema, axonolysis, and wallerian degeneration. Intraneural injection destroys all fibers.
Concentration and Use
100% glycerol is used for gasserian ganglion block.
Complications and Disadvantages
Poor control of spread in the area close to the subarachnoid space.
The first report of ammonium salts used for long-term pain relief was in 1935, by Judovich.
Ammonium salts produce acute degenerative neuropathy with obliteration of C fibers and only a small effect on A fibers. However, the degeneration is nonselective and may affect all types of fibers.
Concentration and Use
Neuronal degeneration, including C-fiber neurolysis, appears at concentrations of 10% and greater, with a success rate of 40% (a 10% concentration provides adequate analgesia and no motor block).
Complications and Disadvantages
Complications are transient and include nausea and headache. Paresthesia and burning sensation occur in 30% of patients at doses of 500 mg of ammonium salts, lasting 2 to 14 days.
Hypertonic and Hypotonic Solutions
The agents of choice are hypertonic salt solutions, distilled water, or even normal saline.
Cold hypertonic saline produces C-fiber neurolysis with a success rate of 30%. Normal saline is thought to act specifically on C fibers, sparing larger fibers of sensory, motor, and autonomic functions. Likewise, application of distilled water on the dorsal root ganglia for 5 minutes produces a differential C-fiber block similar to that seen with in vitro normal saline. The mechanism of action seems to be an intrathecal shift of water with extracellular change in osmolarity.
Cerebrospinal fluid is withdrawn and quickly replaced with 40 to 60 mL of normal saline (a very distressing procedure).
Duration is short-lived.
Complications and Disadvantages
Cardiac complications have been seen during or after saline injection. Complications consist of tachycardia, premature ventricular contractions and myocardial infarction, localized paresis (which may last for many hours), paresthesia (which may last for many weeks), hemiplegia, pulmonary edema, pain in the ear, vestibular disturbances, and loss of sphincter control with sacral anesthesia.
N-Alkyl Tetracaine Derivatives
The disadvantage of alcohol as a neurolytic agent is an immediate progressive burning paresthesia that fades over several hours. Although phenol may alleviate the pain, it may gradually return in a few hours. These inconveniences led to the search for new neurolytic agents, such as tetracaine derivatives. Derivatives of tetracaine, such as N-alkyl tetracaine compounds, are being examined for both their anesthetic and their neurolytic properties. N-butyl tetracaine has both rapid-onset local anesthetic and neurolytic properties, which may last several weeks.
While the mechanism of action of alkylated tetracaine derivatives is not known, it has already been shown that tetracaine is neurotoxic and causes nerve damage when applied at high concentrations. All derivatives are strong sodium channel blockers, more potent than tetracaine. Neurolysis occurs as long as the compound can cross the cell membrane and enter the cytoplasm; only derivatives having ≥ 3 carbons can cross the cell membrane and cause neurolysis. The longer duration of alkylated tetracaine derivatives may be explained by their permanent positive charge that causes compound to be trapped within the cell; the alkylated derivatives of tetracaine display superior local anesthetic properties compared with the original compound.
The overall potential advantage of alkylated derivatives of tetracaine (like N-butyl tetracaine), apart from their neurolytic properties, is a strong local anesthetic activity that prevents patient discomfort at the time of injection.
Other Neurolytic Agents
Renografin and metrizamide are less commonly used neurolytic agents. At a concentration of 3%, metrizamide can provide a block of C fibers.
Drugs Used in Fluoroscopy
In pain medicine, injection of radio-opaque substances is commonly used for identification of anatomic structures to be injected subsequently with local anesthetics and antiinflammatory drugs. Although our purpose is not to inject contrast media intravascularly or intrathecally, these compounds still may inadvertently reach the bloodstream or subarachnoid space. Concerning allergic reactions, the dose of radio-opaque material used in this medical field is usually not much, but that may not make a difference in an already sensitized patient.
The most important precaution to take in using contrast agents, besides avoiding compounds that the patient is allergic to, is to make sure that any radio-opaque agent that may reach the epidural or intrathecal space is nonionic. Serious adverse reactions have been reported due to inadvertent intrathecal administration of iodinated contrast media that are not indicated for intrathecal use. These serious adverse reactions include: death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema.
The ideal radio-opaque contrast product is one that is nonionic and with low osmolality. The osmolality of a contrast medium is classified as high (≈1.500 mOsm/kg) or low (≈350 to 600 mOsm/kg), depending on the ionic content of the agent components.
Commonly Used Radio-Opaque Agents
Diatrizoate (Renografin, Hypaque, Amersham Health, Princeton, NJ) and iothalamate (Conray, Tyco, Pembroke, Bermuda) are both ionic contrast media. Their use should be limited to peripheral blockade (e.g., muscle injection, sacroiliac joint injection). Metrizamide (Amipaque, Nycomed Amersham, Amersham, UK), iopamidol (Isovue, Bracco Diagnostics, Princeton, NJ), and iohexol (Omnipaque, Amersham Health, Princeton, NJ) are all nonionic compounds and therefore may be used for central neural blockade.
In general, undesirable side effects are less frequent following the use of nonionic than ionic contrast media. They are usually mild and include a feeling of warmth, transient metallic taste, gastrointestinal discomfort, hypersensitivity, vagal reactions (hypotension, bradycardia), headache, hypertension, pyrexia, and iodism (“iodine mumps”). Severe manifestations, such as laryngeal edema, bronchospasm, or pulmonary edema, are very rare.
The effects of iodinated contrast agents on the human fetus are unknown, and they should be used during pregnancy only if clearly needed. These agents may be excreted in breast milk. It is recommended that bottle-feeding be substituted for breast-feeding for 24 hours postprocedure.
A previous history of allergy or hypersensitivity does not absolutely contraindicate the use of a contrast agent when a diagnostic procedure is thought essential, but caution should be exercised and preparations should be made. A prophylactic regimen, consisting of antihistamine medication and corticosteroids, may be considered.
If the contrast is injected intrathecally (accidentally or intentionally), maintain the patient in the “head-up” position during and after the procedure. Observe the patient for at least 30 minutes after contrast injection because the majority of side effects occur within this period of time; however, delayed reactions may also occur. If intrathecal injection is suspected, the patient should be advised not to drive a car or use machines for the first 24 hours postprocedure.
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