Local anesthetics, corticosteroids, contrast agents, neurolytic agents, and viscosupplementation are used commonly in pain management procedures. At times, medications to treat adverse reactions are required. As emphasized throughout this text, every interventional physician must be knowledgeable of the pharmacology, pharmacokinetics, and potential adverse reactions of the drugs he or she administers. Furthermore, the physician needs to be familiar with medications used to treat potential procedure complications. This chapter examines medications commonly employed during pain management procedures.
Local Anesthetics
Local anesthetics are widely used and are generally safe when administered properly. Local anesthetics are therapeutically employed in most injections to provide local anesthesia or analgesia of a painful structure. The ability of local anesthetics to relieve pain can also be used diagnostically to help confirm a pain generator. Common applications include skin and soft tissue anesthesia for other procedures; intraarticular injections; injection for bursitis, tenosynovitis, entrapment neuropathies, painful ganglia; spinal injections; and nerve blocks.
Local anesthetics are subdivided into esters and amides, referring to the bond that links the hydrophilic and lipophilic rings. The amide class is less allergenic and more commonly employed in local, intraarticular, and spinal injections. The most widely used agents in pain management practice are lidocaine (Xylocaine) and bupivacaine (Marcaine), both amide local anesthetics.
Amide local anesthetics are hydrolyzed by the liver microsomal enzymes to inactive products. Thus, patients with hepatic failure or reduced hepatic flow are more sensitive to those agents. For this reason, patients taking beta blockers or who have congestive heart failure, have a lower maximum dosage because of their reduced hepatic flow and decreased elimination rates of the amide local anesthetics.
In contrast, the ester anesthetics are rapidly hydrolyzed by plasma cholinesterase into para-aminobenzoic acid (PABA) and other metabolites that are excreted unchanged in the urine. Para-aminobenzoic acid is a known allergen in certain individuals. However, the rapid metabolism of ester local anesthetics lowers their potential for toxicity. Procaine is an amino ester commonly, but not exclusively, employed in differential spinal blocks. 2-Cholorprocaine can be used for infiltration, epidural or peripheral nerve block, and is also an ester.
Mechanism of Action
Local anesthetics exert their effect by reversibly inhibiting neural impulse transmission. The local anesthetic molecules diffuse across neural membranes to block sodium channels and inhibit the influx of sodium ions; therefore, proximity of the local anesthetic to the nerve to be blocked is required. Only a short segment of the nerve (5 to 10 mm) needs to be affected to cease neural firing. Epidural analgesia from local anesthetic is believed by some to occur because of uptake across the dura, a back door approach to spinal block.
The ability of a local anesthetic to diffuse through tissues and then block sodium channels relies on the ability of these molecules to dissociate at physiologic pH of 7.4. The pK a s for local anesthetics are greater than the pH found in tissue. As a result, local anesthetics in vivo exist primarily as cations, the form of the molecule that blocks the sodium channel. The base form of the local anesthetic allows it to penetrate the hydrophobic tissues and arrive at the axoplasm.
In addition to host factors, neural blockade by local anesthetics is affected by the volume and concentration of local anesthetic injected, the absence or presence of vasoconstrictor additives, the site of injection, the addition of bicarbonate, and temperature of the local anesthetic. Increasing the total milligrams of a local anesthetic dose shortens the onset and increases the duration of the local anesthetic. Epinephrine, norepinephrine, and phenylephrine are sometimes added to local anesthetics to reverse the intrinsic vasodilation effects of many of the local anesthetics and thereby reduce their systemic absorption. This increases the amount of local anesthetic available to block the nerve. More anesthetic means a quicker onset and longer duration. Application of the local anesthetic close to the nerve improves its ability to diffuse across the axon and block sodium channels. Highly vascular sites such as the intercostal nerve and caudal epidural space tend to result in slightly shorter duration of action. The addition of bicarbonate or CO 2 (700 mm Hg) to local anesthetics hasten their onset. Bicarbonate raises the pH and the amount of uncharged local anesthetic for diffusion through the nerve membrane. CO 2 will diffuse across the axonal membrane and lower the intracellular pH making more of the charged form of the local anesthetic available intracellularly to block the sodium channels. Temperature elevations decrease the pK a of the local anesthetic and hasten the onset of action.
Individual Agents
Local anesthetics are administered in the intradermal, subcutaneous, intraarticular, intramuscular, perineural, and epidural spaces during pain management procedures. Injections into vascular regions such as the oral mucosa and epidural space may result in rapid absorption and higher systemic concentrations. Local anesthetics administered into or near the epidural space should be preservative free. Methylparaben is a common preservative in multidose vials and is also a common allergen.
Lidocaine
Lidocaine is the most versatile and widely used of the local anesthetics. It has a short onset of action, 0.5 to 15 minutes, and short duration of action, typically 0.5 to 3 hours. The difference between the effective dose and the toxic does is wide, resulting in a high therapeutic index compared to other common local anesthetics. Maximum doses are variably reported in the range of 400 to 500 mg of lidocaine. Typical concentrations are 0.5% to 2%. Final concentration is often diluted by the addition of a corticosteroid.
Concentration percentages are easily converted to milligrams. For example, a 1% solution of lidocaine has 1 g of lidocaine in 100 mL of fluid. This is equivalent to 1000 mg/100 mL or 10 mg/mL. Volume of lidocaine injected varies widely with location and practitioner. Using the aforementioned guidelines, total injection of 1% lidocaine should remain below 40 mL (40 mL × 10 mg/mL = 400 mg).
Bupivicaine
Bupivacaine (Marcaine) is another widely used local anesthetic. Bupivacaine’s duration of action (2 to 5 hr) is longer than lidocaine’s as is its onset of action (5 to 20 min). Bupivacaine is commonly used in concentrations of 0.125% to 0.75%. Final concentrations are often diluted by 30% to 50% by the addition of a corticosteroid. The higher concentrations generally have a faster onset of action. Bupivacaine has more cardiotoxicity than lidocaine, especially if an injection is given intravenously inadvertently. The toxic dose of bupivacaine is only 80 mg (16 mL of a 0.5% solution) when given intravascularly, but may be up to 225 mg with an extravascular injection.
Toxicity
Action of local anesthetics is affected by numerous factors reviewed above. Location of injection plays a primary role in determining the onset, duration, and toxic dose of these agents ( Table 2-1 ). Vasoconstrictors such as epinephrine reduce local bleeding and thereby prolong the onset and duration, but are generally not employed in a pain management practice.
| Clinical Uses | Usual Concentration (%) | Usual Onset | Usual Duration (hours) | Maximum ∗ Single Dose (mg) | Unique Characteristics | |
|---|---|---|---|---|---|---|
| Aminoesters | ||||||
| 2-Chloroprocaine | Infiltration PNB Epidural | 1 2 2-3 | Fast Fast Fast | 0.5-1.0 0.5-1.0 0.5-1.5 | 1000 + EPI 1000 + EPI 1000 + EPI | Lowest systemic toxicity Intrathecal route may be neurotoxic |
| Procaine | Infiltration PNB Spinal | 1 1-2 10 | Fast Slow Moderate | 0.5-1.0 0.5-1.0 0.5-1.0 | 1000 1000 200 | Used for differential spinal |
| Tetracaine | Topical Spinal | 2 0.5 | Slow Fast | 0.5-1.0 2-4 | 80 20 | |
| Aminoamides | ||||||
| Lidocaine | Topical Infiltration IV regional PNB Epidural Spinal | 4 0.5-1.0 0.25-0.5 1.0-1.5 1-2 5 | Fast Fast Fast FastFast | 0.5-1.0 1-2 1-3 0.5-1.5 | 500 + EPI 500 + EPI 500 500 + EPI 500 + EPI 100 | |
| Prilocaine | IV regional PNB Epidural | 4 1.5-2.0 1-3 | Fast | 1.5-3.0 | 600 600 600 | Least toxic amide Methemoglobinemia possible when >600 mg |
| Mepivacaine | PNB Epidural | 1.0-1.5 1-2 | Fast Fast | 2-3 1.0-2.5 | 500 + EPI 500 + EPI | Duration of plain solutions longer than lidocaine with EPI, useful when EPI contraindicated |
| Bupivacaine | PNB Epidural Spinal | 0.25-0.5 0.25-0.75 0.5-0.75 | Slow Moderate Fast | 4-12 2-4 2-4 | 200 + EPI 200 + EPI 20 | Exaggerated cardiotoxicity with accidental IV injection Low doses produce sensory > motor blockade |
| Etidocaine | PNB Epidural | 0.5-1.0 1.0-1.5 | Fast Fast | 3-12 2-4 | 300 + EPI 300 + EPI | Motor > sensory blockade |
∗ Maximum single dosage is affected by many factors, this is only a guide.
Excess amounts of local anesthetics may cause CNS effects including confusion, convulsions, respiratory arrest, seizures, and even death. The risk for complications increases if the local anesthetics are given intravascularly. Other potential adverse reactions to local anesthetics include cardiodepression, anaphylaxis, and malignant hyperthermia. Patients with decreased renal function, hepatic function or plasma esterases eliminate local anesthetics more slowly and, therefore, have an increased risk of toxicity. Toxic blood levels of lidocaine are approximately 5 to 10 μg/mL, but adverse effects can be seen at lower blood levels.
Patients should be monitored for signs of toxicity including restlessness, anxiety, incoherent speech, lightheadedness, numbness, and tingling of the mouth and lips, blurred vision, tremors, twitching, depression or drowsiness. Injections into the head and neck area require the utmost care. Even small doses of local anesthetic may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. Deaths have been reported.
Resuscitative equipment and drugs should be immediately available when local anesthetics are used. Management of local anesthetic overdose begins with prevention by monitoring total dose administered, frequently aspirating for vascular uptake, and use of contrast to avoid vascular uptake when appropriate. Recognition of symptoms of toxicity and support of oxygenation with supplemental oxygen are keys to the initial management. Airway must be maintained and respiratory support should be provided as needed. Hypotension is the most common circulatory effect and should be treated with intravenous fluids and a vasopressor such as ephedrine in appropriate candidates. Convulsions persisting despite respiratory support are often treated with a benzodiazepine such as diazepam. If cardiac arrest occurs, standard cardiopulmonary resuscitative measures should be instituted.
Corticosteroids
Corticosteroids are administered in a pain practice for their potent antiinflammatory properties. These injections to relieve pain and inflammation work well temporarily, but questions remain regarding their role in the management of many chronic musculoskeletal conditions. Corticosteroids may result in significant side effects. The potential for these adverse effects, ranging from a relatively innocuous facial flushing effect to joint destroying avascular necrosis, must be weighed against potential benefits. Some locally injected corticosteroids are absorbed systemically and can produce transient systemic effects.
Corticosteroids can be helpful in a variety of conditions including rheumatoid arthritis, bursitis, tenosynovitis, entrapment neuropathies, crystal-induced arthropathies in patients who cannot tolerate systemic treatment well, radiculopathies, and at times, osteoarthritis (OA). Corticosteroids should never be injected directly into a tendon or nerve, subcutaneous fat, or an infected joint, bursa, or tendon ( Table 2-2 ).
| Agent | Antiinflammatory Potency ∗ | Salt Retention Property | Plasma Half-life (min) | Duration † | Equivalent Oral Dose (mg) |
|---|---|---|---|---|---|
| Hydrocortisone (cortisol) | 1 | 2+ | 90 | S | 20 |
| Cortisone | 0.8 | 2+ | 30 | S | 25 |
| Prednisone | 4-5 | 1+ | 60 | I | 5 |
| Prednisolone | 4-5 | 1+ | 200 | I | 5 |
| Methylprednisolone (Medrol, Depo-Medrol) | 5 | 0 | 180 | I | 4 |
| Triamcinolone (Aristocort, Kenalog) | 5 | 0 | 300 | I | 4 |
| Betamethasone (Celestone) | 25-35 | 0 | 100-300 | L | 0.6 |
| Dexamethasone (Decadron) | 25-30 | 30 | 100-300 | L | 0.75 |
Mechanism of Action
All corticosteroids have both glucocorticoid, antiinflammatory, and mineralocorticoid activity. Agents with significant glucocorticoid and minimal mineralocorticoid activity include betamethasone (Celestone), dexamethasone (Decadron), methylprednisolone acetate (Depo-Medrol) and triamcinolone hexacetonide (Aristospan). Corticosteroids can be mixed in the same syringe with local anesthetics.
Corticosteroids produce both antiinflammatory and immunosuppressive effects in humans. The primary mechanism of action may be their ability to inhibit the release of cytokines by immune cells. The effects of corticosteroids are species specific. Lymphocytes in humans are much less sensitive to the effects of corticosteroids than lymphocytes in common laboratory animals including the mouse, rat, and rabbit. In humans, corticosteroids reduce the accumulation of lymphocytes at inflammatory sites by a migratory effect. In contrast to this lymphopenia, is the neutrophilia seen by demargination of neutrocytes from the endothelium and an accelerated rate of release from the bone marrow. A temporary rise in white blood cell count is commonly observed for this reason after a corticosteroid dose and in isolation does not mark a post injection infection.
The antiinflammatory effects of corticosteroid also occur at the microvascular level. They block the passage of immune complexes across the basement membrane, suppress superoxide radicals, and reduce capillary permeability and blood flow. Corticosteroids inhibit prostaglandin synthesis, decrease collagenase formation, and inhibit granulation tissue formation.
The immunosuppressant effects of corticosteroids are generally via effects on T cells. These effects are not the desired effect of corticosteroid used in pain management procedures and are not observed following epidural injections. A review of these immunosuppressant effects can be found in other texts.
Individual Agents
Commonly used corticosteroid preparations include betamethasone, methylprednisolone, triamcinolone, dexamethasone, prednisolone, and hydrocortisone. Of these, betamethasone and dexamethasone have the strongest glucocorticoid or antiinflammatory effects. Corticosteroid effects can be highly variable between individuals and it is not possible to definitively state a safe dosage of corticosteroid. The following should serve only as a guide and must be tailored to each individual.
Betamethasone
An equal mixture of two betamethasone salts, Celestone Soluspan, allows for both immediate and delayed corticosteroid responses. Betamethasone sodium phosphate acts within hours, whereas betamethasone acetate is a suspension that is slowly absorbed over approximately 2 weeks. Betamethasone (Celestone Soluspan) is approved for intraarticular or soft tissue injection to provide short-term adjuvant therapy in osteoarthritis, tenosynovitis, gouty arthritis, bursitis, epicondylitis, and rheumatoid arthritis. It is also commonly employed in epidural injections. Typical intraarticular doses vary with the size of the joint and range from 0.25 to 2 mL (1.5 mg to 12 mg). Typically epidural injections range from 1 to 3 mL (6 to 18 mg). Betamethasone should not be mixed with local anesthetics that contain preservatives such as methylparaben as these may cause flocculation of the steroid.
Dexamethasone
Dexamethasone acetate (Decadron-LA) has a rapid onset and long duration of action. It is usually given in doses of 8 to 16 mg intramuscularly or 4 to 16 mg for intraarticular or soft tissue injections. The most common preparations have 8 mg of dexamethasone acetate per milliliter, therefore 0.5 to 2 mL quantities are the most common. Most preparations contain sodium bisulfite that can trigger allergic reactions in susceptible individuals. It contains long-acting particulates and it is not used for intravenous administration.
Dexamethasone sodium phosphate (Decadron Phosphate) is a rapid onset, short duration formulation of dexamethasone. It is available in a variety of strengths ranging from 4 mg/mL to 24 mg/mL. Large joints are often injected with 2 to 4 mg, small joints 0.8 to 1 mg, bursae 2 to 3mg, tendon sheaths 0.4 to 1mg, soft tissue infiltration 2 to 6 mg. Sulfites are common in the preparations of this salt also. Dexamethasone is approved for the treatment of osteoarthritis, bursitis, tendonitis, rheumatoid arthritis flares, epicondylitis, tenosynovitis, and gouty arthritis. Because it is considered to be a nonparticulate steroid it is also used off-label for epidural steroid injections as discussed subsequently.
Methylprednisolone
Methylprednisolone acetate (Depo-Medrol) has 1/5 to 1/6 the glucocorticoid potency of betamethasone but similar antiinflammatory effects to prednisolone. It has an intermediate duration of action. It, like the other corticosteroids, is approved for intraarticular and soft tissue injections for short-term adjuvant therapy of osteoarthritis, bursitis, tenosynovitis, gouty arthritis, epicondylitis, and rheumatoid arthritis. Depo-Medrol has been used for epidural administration also. Preparations of methylprednisolone acetate include polyethylene glycol as a suspending agent. Concerns developed as to whether the polyethylene glycol can cause arachnoiditis with (inadvertent) intrathecal injections. Animal studies have not demonstrated any adverse effects on neural tissues from the application of glucocorticoid. Methylprednisolone is now available without polyethylene glycol, PEG free. Typical doses range from 4 to 80 mg. Small joints are typically injected with 4 to 10 mg, medium joints 10 to 40mg, large joints 20 to 80 mg, bursae and peritendon 4 to 30 mg.
Triamcinolone
Triamcinolone is available as three different salts: triamcinolone diacetate (Aristocort Forte), triamcinolone hexacetonide (Aristospan), and triamcinolone acetonide (Kenalog). Duration of action is shortest with the diacetate and longest with the acetonide formulations. Triamcinolone has similar glucocorticoid activity to methylprednisolone with a long half-life. The approved uses are the same as for the agents listed earlier and it, too, is used in epidural injections. Unfortunately, it has a higher incidence of adverse reactions including fat atrophy and hypopigmentation.
Spinal Injections
Unique considerations are taken into account when considering corticosteroids for spinal injections. In particular, cervical transforaminal injections have lead to rare but significant neurologic complications such as spinal cord injury, stroke, and even death.
The postulated cause of the majority of these complications is undetected vascular injections in the vertebral or spinal radicular arteries with particulate steroids causing embolic infarctions.
Thoracic and lumbar transforaminal injections have similarly been implicated in neurologic complications with particulate steroids. Major complications are thought to arise from embolic events associated with injections into radicular arteries or the reinforcing radicular artery known as the artery of Adamkiewicz. This artery typically arises at thoracic levels but it can occur as low as L2 or L3 in about 1% of patients and more rarely at lower levels.
Anatomic studies show that the size of particles in commonly used steroid preparations such as triamcinolone, methylprednisolone, and betamethasone equals or exceeds the caliber of many radicular arteries. These particulate steroids either are larger in diameter than a red blood cell or tend to aggregate and/or pack together to be larger than a red blood cell. This is not the case with dexamethasone sodium phosphate, which is a nonparticulate steroid. Thus, dexamethasone sodium phosphate should reduce the risk of embolic infarcts following intravascular injections.
Consistent with this, a study looked at vertebral artery injection of particulate and nonparticulate steroids in pigs while under general anesthesia. The animals that were injected with particulate steroids never regained consciousness. Subsequent magnetic resonance images (MRIs) revealed upper cervical cord and brain stem edema and histologic analysis showed ischemic changes. The animals injected with nonparticulate steroids did not have ischemic events and recovered without apparent adverse effects. The MRIs and subsequent histologic analysis were also normal in this group of animals.
The risk with particulate steroids in cervical and thoracic transforaminal injections has led to the common use of dexamethasone sodium phosphate in these procedures. Thoracic and lumbar transforaminal injections may also lead to embolic events and this must be taken into consideration. The choice corticosteroids in lumbosacral transforaminal injections is debatable, especially if appropriate safety measures are used, such as contrast administration under live fluoroscopy and use of digital subtraction angiography. If vascular uptake is noted, the needle should be repositioned or the procedure aborted. Other spinal procedures such as interlaminar epidural injections or intraarticular injections have not been associated with embolic events with particulate steroids.
Both particulate and nonparticulate steroids appear to be effective but studies suggest that particulate steroids may be slightly more efficacious than nonparticulate steroids. Further studies are needed to clarify this.
Adverse Reactions
Corticosteroid use should be carefully considered and avoided if possible in patients at increased risk for adverse reactions, including patients with active ulcer disease, ulcerative colitis with impending perforation or abscess, poorly controlled hypertension, congestive heart failure, renal disease, psychiatric illness or history of steroid psychosis, or a history of severe or multiple allergies. Intraarticular injections have been associated with osteonecrosis, infection, tendon rupture, postinjection flare, hypersensitivities, and systemic reactions. Intraspinal injections have been associated with adhesive arachnoiditis, meningitis, and conus medullaris syndrome.
Adverse reactions to injected corticosteroids include a transient flare of pain for 24 to 48 hours in up to 10% of patients. Diabetics and those individuals with a predisposition to diabetes may become hyperglycemic and appropriate monitoring and corrective measures should be instituted. Adrenal cortical insufficiency is generally not seen associated with intermittent injections of corticosteroids, but remains a serious adverse reaction that could be precipitated by indiscriminate, frequent high-dose corticosteroid injections. Allergic reactions to systemic glucocorticoids have been reported and if slow release formulations are used, the allergic response may not occur until a week after the injection. Even with local injections of corticosteroids, some systemic response may occur.
Generally less serious side effects of corticosteroids include facial flushing, injection site hypopigmentation, subcutaneous fat atrophy, increased appetite, peripheral edema or fluid retention, dyspepsia, malaise, and insomnia. Prolonged or repeated doses can result in cushingoid changes.
Drug Interactions
A number of drug-drug interactions for corticosteroids have been reported. Some of the more common ones encountered in a pain management practice are mentioned here. Estrogens and oral contraceptives may potentiate the effect of the corticosteroid. Macrolide antibiotics (e.g., erythromycin, azithromycin) may greatly increase the effect of methylprednisolone by decreasing its clearance. In contrast, the hydantoins (e.g., phenytoin), rifampin, phenobarbital, and carbamazepine may increase corticosteroid clearance and decrease the antiinflammatory therapeutic effect. Theophylline and oral anticoagulants can interact variably with corticosteroids.
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