Last reviewed: 2-2-00

 

PROCEDURAL AND MEDICAL COMPLICATIONS OF CHRONIC PAIN MANAGEMENT

Steven H. Richeimer, M.D.
Assistant Professor of Anesthesiology and Psychiatry

Stephen M. Macres, M.D., Pharm.D.
Assistant Professor of Anesthesiology


INTRODUCTION


An unfortunate but obvious fact is that where there is medical care, there are complications. In this paper, we will review the procedure-related and the pharmacological complications of pain management.


Procedural Complications


Complications from pain management procedures are related to the involved anatomy, physiology, and pharmacology. A thorough understanding of these aspects of neural blockade is critical. For any procedure or injection, the physician should answer the following questions:

1(a) What tissues must the needle pass through?

      Example: For the transarterial approach to the axillary block, the needle must pass through the primary artery supplying the arm. Consider whether any pre-existing vascular damage might represent a contraindication.

(b) What vulnerable tissues and organs are near the path and target of the needle?

      Example: The visceral pleura of the lungs lies in close proximity to the path and target of a splanchnic nerve block. The practitioner must take appropriate precautions, and must watch for signs of pneumothorax.

2(a) Are any nearby nerves or vessels vulnerable to trauma, unintended injection, or spread of injectate?

      Example: The sciatic nerve lies immediately under the piriformis muscle; therefore, the sciatic nerve is vulnerable both to trauma from the needle and to spread of local anesthetic.

(b) What are the results of trauma, bleeding, and infection, or the results of injection or spread to unintended sites?

      Example: The piriformis muscle injection may produce an unexpected motor block. Unintended injection into the vertebral artery, during a stellate ganglion block, will cause loss of consciousness and seizures.

3(a) What are the expected physiological effects of the injection?

      Example: Stellate ganglion blockade will typically cause an ipsilateral Horner's syndrome and vasodilation of the upper extremity. To avoid panic, the patient must be prepared for the temporary Horner's.

(b) Are there other, less common effects that need to considered?

      Example: Right sided stellate ganglion blockade may trigger sinus arrhythmias, even transient sinus arrest. Left sided blocks may impair left ventricular function.

4) Does coexisting illness or prior history make this patient particularly vulnerable to complication?

      Example: Left sided stellate ganglion blockade may be contraindicated in patients with preexisting left ventricular dysfunction. Intercostal blocks are of greater risk in patients with bullous emphysema.

Considering these questions will help the physician to appropriately evaluate the risks of direct nerve damage, infection, vascular, dural or pulmonary compromise, backache, and undesired spread of drug after placement of a block.12 Besides the risks of immediate complications, some major neurologic complications may manifest after a number of days or longer, including epidural hematoma, chemical meningitis, cauda equina syndrome, lumbosacral radiculopathy and adhesive arachnoiditis.12

Nerve Damage
Direct nerve damage can be associated with toxicity of the injected solution or mechanical damage to the nerve.12 Cytotoxicity appears to be directly related to the concentration of local anesthetic and the duration of exposure. The site of deposition of local anesthetic, be it extrafasicular or intrafasicular, is also directly related to the extent of alteration in nerve function. Extrafasicular application appears to have subtle effects on the nerve which include edema formation within the endoneurium with increased fluid pressure within the fascicle, some inflammatory changes and myelin and Schwann cell injury. Intrafasicular injection of local anesthetic is a much more serious matter. Axonal degeneration and barrier changes have been documented with intrafasicular injection of local anesthetic.12 Higher concentrations of local anesthetic can cause correspondingly greater nerve injury. It is good practice to always use the minimum effective concentration of local anesthetic.

Sodium metabisulfite is an anti-oxidant found in local anesthetic solutions containing epinephrine. It has pronounced neurotoxic effects when injected intrathecally; intrafasicular injection should also be avoided. Likewise, intrafasicular injection of epinephrine is a potential problem. The vasoconstrictive effects of epinephrine could theoretically compromise blood flow. This concern about ischemic damage has also raised questions about the use of intrathecal or epidural epinephrine; however, this has not been documented to be a clinical problem. If using epinephrine it is wise, at the time of the block, to add fresh epinephrine (devoid of sodium metabisulfite) to your local anesthetic.

Neuropathy has been reported to occur as a result of exposure to local anesthetic; however, mechanical trauma to the nerve is likely to be the more common culprit.13
Mechanical damage can occur when the needle is inserted into the nerve resulting in interruption of the perineural tissue around nerve fasicles.12, 14 Such a maneuver, which is often times unavoidable, can manifest itself as a paresthesia. Whether or not elicitation of a paresthesia has significant adverse consequences is unknown. In case of a paresthesia, it is our practice to withdraw the needle slightly, and to confirm resolution of the paresthesia, before injection of local anesthetic. If the injection produces intense pain, it should be discontinued and the needle repositioned.

Important guidelines for perineural injections include: 1) use blunt (B-bevel) instead of a sharp-beveled needles, 2) use 22 gauge rather than 25 gauge needles, 3) use gentle technique, preferably in an awake patient who can report parathesias, 4) avoid neural injections in confined fascial spaces, such as the ulnar nerve at the elbow and the peroneal nerve at the fibular head, and 5) use a nerve stimulator which can help illicit parathesias without mechanical damage to the nerve.

Vascular Injury
Vascular puncture can be an unavoidable consequence of a nerve block since nerves, arteries, and veins frequently run in very close proximity to each other. In fact, some regional blocks utilize arterial puncture as part of the technique, in order to verify ideal needle placement. Examples of this approach include the transarterial axillary and transaortic celiac plexus blocks. Although vascular puncture tends to be common, clinically significant hematoma formation is rare. Hematoma formation can be minimized by using gentle technique, preferably with a short beveled needle no larger than 22 gauge. Multiple penetrations of the vessel will increase the risk of hematoma formation, which can obscure anatomic landmarks and interfere with the spread of local anesthetic.13 Hematomas, especially in closed spaces such as the epidural space, can cause major complications, including nerve compression syndromes such as lumbosacral radiculopathy or cauda equina syndrome.15,16

Performance of nerve blocks in the anticoagulated patient presents unique problems. The consensus is that nerve blocks in general, and central neural blockade in particular, are contraindicated in the fully heparinized patient or those with known coagulopathies and significant thrombocytopenia.12,14,17 Placement of an epidural catheter at least one hour prior to heparinization, in patients about to undergo major vascular surgery, has been reported to be safe.15,17 Postoperative removal of the catheter should be performed 4-6 hours after the heparin has been discontinued.17 Perioperative use of thrombolytic agents (TPA, Streptokinase, Urokinase) are an absolute contraindication to placement of an epidural catheter.13,17 Patients on coumadin therapy should discontinue its use at least 3-5 days prior to a procedure. Regional blockade can then be safely performed, if the INR is less than 1.3 (some experts say 1.5), the aPTT is within the upper limit of normal, the platelet count is greater than 80,000/,microliter, and the bleeding time is less than 8 minutes.

Many of our patients, at the University of California-Davis Pain Management Center, have compromised platelet function secondary to the use of aspirin or one of the many non-steroidal anti-inflammatory drugs (NSAIDs). Most regional blocks can be performed safely in these patients, particularly if care is taken to avoid vascular trauma. It is prudent to discontinue aspirin for 7 days and NSAIDs for 2-3 days prior to the procedure. If the patient is scheduled for a cervical or thoracic epidural procedure, such discontinuance is mandatory. These guidelines may also be reasonable for patients who are scheduled for procedures for which the potential bleeding is not readily treatable with direct pressure, such as the celiac plexus.12 A bleeding time may be helpful for these patients, particularly if the platelet count is less than one hundred thousand, however, this test may not be reliably predictive of intraoperative hemostasis.13 For patients with low platelet counts, look for clinical signs of increased bleeding and carefully weigh the potential benefits of the block against the increased risks of harm.

Pulmonary Complications
Pneumothorax is a complication that is bound to occasionally occur when performing regional blocks in and about the chest and neck. Procedures commonly associated with pneumothorax include stellate ganglion, supraclavicular, intercostal and splanchnic nerve blocks. Symptoms include chest pain, coughing and shortness of breath. Physical examination may reveal subcutaneous air and diminished breath sounds on the affected side. Certainly, while performing any of the above procedures, if you should aspirate air, presume the subsequent development of pneumothorax. Often, however, it takes 6-12 hours for interpleural air to accumulate and cause symptoms. Chest x-ray is diagnostic and if the pneumothorax is less than 25% of the lung volume it will usually resolve without treatment. Greater volume loss requires consultation with a surgeon for possible chest tube placement. If there is concomitant hemodynamic compromise associated with the pneumothorax, suspect a tension pneumothorax, and be prepared to place a large bore intravenous needle or catheter into the second intercostal space, at the midclavicular line on the effected side.

Generally speaking, in healthy patients, without significant lung disease, blockade of a single phrenic nerve or blockade of bilateral intercostal nerves from T6 to T12 results in minimal respiratory compromise. However, even in healthy individuals, there is a 25% decrease in vital capacity with bilateral phrenic nerve blocks. We avoid performing almost any bilateral blocks, especially those with the risk of pneumothorax.

Other Tissue Trauma
Fortunately, organ damage is a relatively rare event. However, during the performance of a lumbar sympathetic block, the kidney may be punctured. This can result in some hematuria, but this is rarely associated with adverse sequelae. When neurolytic agents are being used, special care must be taken to assure accurate needle placement. This should be done with fluoroscopic guidance. If urine, blood, or CSF is aspirated, the needle should be repositioned. Bowel puncture is another risk of needle placement, particularly with an anterior, CT guided approach to the celiac plexus. Radiologists report that as long as a 22 gauge or smaller needle is used, the small bowel seals itself without consequence. Puncture of the large bowel must be avoided.

Dural Puncture
Headache is a complication of spinal anesthesia or inadvertent dural puncture. When assessing a post-procedure headache it is necessary to also consider the full range of headache etiologies. Classic post-dural puncture headache (PDPH) is thought to result from a CSF leak through the rent in the dura. The resulting pressure and tension changes in the neuro-axis is the presumed cause of the headache. Traction on the trigeminal, glossopharyngeal, vagal, and upper cervical nerves is thought to contribute to the frontal and occipital head pain and the diffuse neck pain reported by patients. The onset of the headache is usually within 72 hours of the dural puncture and is posture related. The headache is worse when the patient is upright and relieved when recumbent. Associated symptoms include nausea, dizziness, tinnitus, photophobia, auditory and visual disturbances. Hearing loss can occur, and apparently parallels the size of the dural defect. This appears to be a reversible problem.15

The incidence of PDPH can be minimized by using the smallest gauge needle reasonable, such as 25 gauge. Needles much smaller than this however, have higher failure rates and may be associated with poorer mixing of local anesthetic in the CSF, with potentially higher rates of neurotoxicity. Pencil point needles, such as the Sprotte, Green, or Whitaker, gently separate rather than sever dural fibers and appear to decrease the rate of PDPH. Orienting the bevel of both spinal and Touhy needles parallel to the dural fibers may also be beneficial. It also appears that the risk of PDPH decreases with increasing age. The reported incidence of PDPH is approximately 5% in patients over 50 years of age, following dural puncture with a 22 gauge needle. Women, in general, experience PDPH twice as often as men.15

Postdural puncture headaches usually resolve spontaneously within 2-3 days. On occasion, a headache may persist for longer than one week. It is our practice to discuss with the patient both conservative and blood patch treatment, but to initially recommend the conservative approach. Conservative therapy consists of analgesics, bedrest, and hydration (preferably with caffeinated beverages). Intravenous caffeine - sodium benzoate 500 mg, in one liter of lactated ringers, infused over approximately one hour, and followed by ongoing hydration has been recommended. The efficacy of this treatment is unclear, and many patients cannot tolerate the effects of the caffeine.

Should the headache prove refractory to conservative treatment, an autologous blood patch can be attempted. We recommend administering 15-20 milliliters of blood, obtained aseptically from the antecubital vein and placed into the epidural space, preferably one level below the previous dural puncture site, since the blood tends to move primarily in a cephalad direction.18

Use of an autologous blood patch in a septic patient is problematic and runs the risk of precipitating an epidural abscess. Likewise, the HIV positive patient with PDPH is a group at risk for spread of the HIV virus to the CNS. A "dextran patch" may be useful for these situations or for Jehovah's Witnesses.18 Autologous blood patching has been performed successfully in HIV positive patients, without any apparent adverse neurologic sequelae.17,18

Backache
Backache after spinal or epidural procedures can be due to the mild trauma of placing a needle through skin, muscle, and ligament. This can precipitate hematoma formation, ligament injury, and reflex muscle spasm. Symptoms tend to be mild in nature and generally resolve in less than one week. Occasionally, we will prescribe 3-4 days of muscle relaxants, to treat severe spasms.

Infections
The incidence of infection associated with central and peripheral nerve blocks is relatively rare.12,15 In fact, local anesthetics are reported to have antimicrobial activity which may help to decrease the risk of infection. However, local anesthetics are not adequate antiseptics and meticulous aseptic technique is critical. Local skin infections at the insertion site of epidural catheters are not uncommon. Therefore, it is our practice to inspect the epidural catheter site daily to confirm catheter depth, integrity, security of the dressing, and the absence of any signs of infection (e.g. induration, swelling, pronounced tenderness, erythema, or drainage).

Epidural or subarachnoid space infections, although extremely rare, can be devastating. Epidural catheters can act as a wick allowing the spread of infection from the skin to the epidural space. This is of particular concern in the immunocompromised patient.17 Epidural abscess usually manifests itself several days after neural blockade with symptoms of severe low back pain, local tenderness, and fever with leukocytosis. Cord compression can also occur and manifests with pain or motor and sensory symptoms, including lumbosacral radiculopathy or cauda-equina syndrome.16 An MRI exam can rule out epidural abscess or epidural hematomas.16 Surgical intervention within 12 hours of diagnosis improves neurological outcome.17

Often we are consulted for placement of an epidural catheter in a trauma victim with rib fractures and compromised respiratory status. Occasionally, these patients can show signs of systemic infection which can preclude timely placement of an epidural catheter. Once appropriate antibiotic therapy is begun, placement of a catheter in the neuro-axis can be performed with minimal fear of precipitating meningitis or epidural abscess.19

Patients with Acquired Immune Deficiency Syndrome (AIDS) may not be ideal candidates for epidural or spinal analgesia. These patients may be more likely to develop serious infectious complications. Furthermore, the virus can cause degenerative changes in the spinal cord; therefore, it is preferable to avoid seeding virus into the central nervous system. Nevertheless, there are times when this theoretical risk is overshadowed by the potential benefit.

Unintentional Effect or Spread of Local Anesthetic
Unintentional spread of a drug during regional blockade can occur because of communicating tissue planes. Subarachnoid block has occurred following retrobulbar block, brachial plexus block, facet joint injection, and intercostal block. This rare event can occur if drug is injected into a peripheral nerve fascicle, "which topographically is an extension of the central nervous system.12" Epidural spread has been reported after brachial plexus blockade, intercostal blockade, segmental somatic blocks and facet injections. It is not uncommon to get spread from sympathetic blocks to adjacent somatic nerves.

Cephalad spread of spinal or lumbar epidural anesthesia (LEA) can have unintentional consequences. Interruption of the cardiac sympathetic fibers (T1 - T5) can result in significant bradycardia and hypotension. With progression of the block to the C3-5 nerve roots, phrenic nerve paralysis occurs and endotracheal intubation with positive pressure ventilatory support is necessary. Even without cephelad spread, hypotension can result from blockade of sympathetic outflow in the splanchnic distribution. Treatment of hypotension should include administration of fluids, vasopressors, and elevation of the legs.

Unintended spread can be disastrous if a neurolytic agent is used or planned. Abram12 states, "If a diagnosis of a pain mechanism is made on the basis of a block that is in fact more extensive than believed, inappropriate therapeutic procedures might be performed, including surgical ablations. This concern should encourage the use of small volumes when blocks are done for diagnosis," and when performing a chemical neurolysis.

Cardiovascular and respiratory complications, unique to epidural anesthesia result from unintentional injection of local anesthetic into an epidural vein or the subarachnoid space. One method of ruling out intravascular injection is the administration of 15 mcg of epinephrine with the local anesthetic solution, (e.g. 3 ml of 2% lidocaine, with 1:200,000 epinephrine). A 30% increase in the pulse rate 20 seconds following injection confirms intravascular injection.13 Subarachnoid injection is confirmed if the 60 mg of lidocaine produces rapid anesthesia, possibly up to the thoracic dermatomes.

An unusual cardiovascular complication can occur with a right sided stellate ganglion block (SGB). The heart is innervated via the cardiac plexus of nerves which are derived from the cervical and upper thoracic sympathetic ganglion and vagal branches. The sino-atrial node has dual innervation with sympathetic fibers from the right stellate ganglion and parasympathetic innervation via the vagus. Interruption of sympathetic outflow following a right sided SGB may precipitate sinus arrhythmias or even transient sinus arrest, especially if the patient stands up too quickly after the block.20 There is also some evidence that left sided SGB causes a partial sympathetic dennervation of the left ventricular wall. This may lead to left ventricular dysfunction which could be of particular significance in those patients with pre-existing left ventricular disease. 21


PHARMACOLOGICAL COMPLICATIONS


So far, we have discussed complications that can arise from disruption of the psyche or the bodily structure; the remaining major category of complication arises from disruption of the biochemistry. All medications are associated with complications; we will highlight some of the most important problems associated with the more commonly used pain management medications.

Local Anesthetics
Adverse reactions associated with the use of local anesthetics include systemic toxicity, tissue toxicity, and allergic reaction. Probably the most serious and frequent complication is systemic toxicity which produces either central nervous system or, more rarely, cardiovascular symptoms.22

The toxicity of local anesthetics are a direct reflection of plasma concentration. Central nervous system manifestations of toxicity are both drug and dose related. The common complaints of lightheadedness, metallic taste, circumoral numbness, and tinnitus occur at lower plasma levels (3-5 mcg/ml). Skeletal muscle twitching involving the face or extremities (8 mcg/ml) or decreased responsiveness can presage loss of consciousness and tonic-clonic convulsions (10-12 mcg/ml).22,23 An important clinical caveat is that both hypercarbia and acidemia decrease the seizure threshold, which are important points to consider during resuscitation of an overdose.

Whenever significant amounts of local anesthetics are being used in a regional procedure, EKG and blood pressure monitoring are needed, resuscitation equipment should be nearby, and intravenous access should be established prior to the procedure.

Local anesthetics, through inhibition of sodium channels, interfere with the electrical and mechanical activity of the myocardium, and therefore, are direct myocardial depressants. Excessive lidocaine plasma concentrations can prolong both the PR and QRS intervals and cause profound hypotension. Following unintended intravenous injection, and without prior symptoms of CNS toxicity, bupivacaine can precipitate hypotension, cardiac dysrhythmias and atrioventricular heart block.23 Bupivacaine toxicity appears to be particularly profound during pregnancy or with hypoxemia, hypercarbia, or acidosis. Bupivacaine avidly binds to the sodium channel receptor and only slowly dissociates, resulting in persistent myocardial depression, which requires prolonged resuscitation in the event of cardiac arrest. Bretylium is the recommended agent for the treatment of ventricular tachycardia secondary to bupivacaine toxicity. 13,22,23

The likelihood of toxicity from local anesthetics varies according to the 1) the dose administered, 2) the vascularity of the injection site, 3) the use of epinephrine with the local anesthetic, and 4) the choice of drug.23 Obviously, it is most important to avoid intravascular injection; careful pre-injection aspiration is essential. This is particularly important when performing a stellate ganglion or interscalene block, when as little as 1-2 ml of local anesthetic, if injected into the vertebral artery, can precipitate a seizure. Significant serum levels of local anesthetic follow all regional blocks with the highest levels obtained after intercostal blocks, intermediate levels after epidural block, and the lowest levels after brachial plexus blockade and subcutaneous administration.

Opiates
Clinically relevant side effects that occur with acute or chronic administration of opiates include respiratory depression, sedation, constipation, nausea and vomiting, pruritis, dry mouth, sleep disturbance, hallucinations, difficult micturition, mood changes, myoclonus, tolerance, physical dependence, and the potential for addiction.24 We will briefly discuss the most important of these side effects.

Respiratory depression is certainly the most feared complication associated with the use of opiates. The mechanism for respiratory depression is a direct effect on the brain stem resulting in decreased ventilatory rate and tidal volumes in response to increasing PaCO2.25 With chronic use, tolerance develops to this side effect and apnea is rare. Of particular concern is the delayed respiratory depression that can occur approximately 6 to 24 hours after the epidural administration of opiates.23 This is dose dependent, and is more commonly associated with the hydrophilic agents (morphine, hydromorphone) than the lipophilic ones (fentanyl, sufentanil). Fortunately, the incidence of delayed respiratory depression is relatively rare--approximately 1%.23

Sedation and impaired cognition are also common side effect associated with the use of opioids. Tolerance can also develop to this side effect. Occasionally we will add methylphenidate to the drug regimen of patients on long term opiate therapy. This diminishes sedation and can also enhance analgesia.

Opioids diminish peristaltic activity in both the large and small intestines, increase the tone of the pyloric and anal sphincters and the ileocecal valve.23 The result is constipation. Minimal tolerance develops to this side effect, so it is imperative that the patient be placed on an appropriate bowel regimen. Combinations of stool softeners or bulk laxatives together with bowel stimulants are usually effective.

Nausea is a particularly distressing side effect of the opioids. Stimulation of dopaminergic receptors in the medullary chemoreceptor trigger zone is the primary cause but vestibular stimulation and delayed gastric emptying can contribute to the symptoms. Intravenous administration of opioids may produce less nausea than intramuscular administration. Ambulation appears to increase the incidence of nausea and vomiting. Continued use leads to tolerance, but changing to another opiate can often decrease the side effects.

Mu receptor mediated histamine release accounts for the pruritis associated with the opioids. Antihistamines are beneficial. For pruritis precipitated by epidural morphine, small doses of agonist-antagonists (e.g. nalbuphine) may be especially helpful. Switching the epidural narcotic may also decrease the pruritis. True allergic reactions to opioids appears to be a rare event.23,24

Central nervous system effects include, but are not limited to euphoria, dysphoria, sedation, mood changes and miosis.25 There are reports of convulsions with high dose opiates, but no evidence of seizure activity is evident on EEG.23 Normeperidine, the metabolite of meperidene, can produce true seizure activity. Skeletal muscle rigidity and myoclonus are complications associated with opioids, particularly after high dose intravenous fentanyl.23 Finally, sleep disturbance, visual hallucinations, and nightmares have been reported, especially in the elderly. The treatment includes low dose haloperidol and a change of opiate.24

Urinary urgency and retention is associated with all routes of opiate administration. The reported incidence of this side effect, following epidural administration of opioids, is unclear, with estimates between 15 - 90%.14

Tolerance, physical dependence and addiction are major concerns with long term opioid use. Although the actual pathophysiological changes that occur are not clearly understood, up-regulation of opioid receptors appears to play a major rule. Tolerance is demonstrated by a need for ever escalating doses of drug to maintain analgesia previously provided by lower doses. Tolerance can also occur with the ventilatory depressant effects of opiates; however, miosis and constipation seem to persist.

Physical dependence on opioids is present if withdrawal symptoms appear with abrupt discontinuation of the drug,. Withdrawal symptoms are reminiscent of an influenza infection and consist of yawning, lacrimation, rhinorrhea, mydriasis, restlessness, nausea, vomiting, diarrhea, backache, leg pain, and muscle cramps.

The word "addiction" is often misused. It is clear that both tolerance and dependence can be present without the patient being addicted. Most patients with unremitting and incapacitating chronic pain, who are dependent on opioid analgesia, fit this picture. Addiction is defined as loss of control, compulsive use, and continued use of a drug in spite of adverse consequences. Without coexisting psychopathology or a prior history of addiction problems, opiate addiction in the context of pain management is rare. Nevertheless, coexisting psychopathology in the pain clinic population is not rare; therefore, it is valuable to monitor patients for evidence of functional improvement and treatment compliance. Lack of compliance or improvement are indications for a psychological assessment, and it may be appropriate to consider non-narcotic treatment modalities. Should a patient require withdrawal from an opioid analgesic, a rational approach would be to decrease the dose by approximately 10% every 24 - 72 hours; however it is often necessary to individually tailor this regimen.

Neurolytic Agents
Neurolytic agents can be extremely useful in the treatment of intractable, chronic pain, refractory to other treatment modalities. Although there are several agents available, alcohol and phenol are the most widely used. Alcohol, the classic agent, used in concentrations from 50 to 95 % causes extraction of cholesterol, phospholipid and cerebroside, and causes precipitation of liposomes and mucuproteins. Phenol, on the other hand, causes protein denaturation. Both agents can cause wallerian degeneration. Complications that occur with the use of these agents include:
1) damage to peripheral nerves, 2) spread to neuraxial structures, 3) local tissue effects, and 4) systemic effects.12,26

Examples of peripheral nerve damage that can occur include inadvertent spread of neurolytic agent to 1) the facial nerve during trigeminal block, 2) the glossopharyngeal nerve during gasserian ganglion block, 3) the brachial plexus during stellate ganglion block, and 4) the somatic nerve roots during celiac plexus, splanchnic or lumbar sympathetic blocks.12 Careful placement of the needle and utilization of fluoroscopic guidance, together with the use of small volumes of neurolytic drug, can minimize these problems. Even with correct needle placement, peripheral neurolytic blockade can cause neuropathic pain such as neuritis and anesthesia dolorosa. Local tissue effects can include pain, swelling, cellulitis and abscess formation at the site of injection. Tissue damage can be minimized if the needle is flushed with local anesthetic prior to it's removal during neurolytic procedures. The consequences of spread of a neurolytic agent to the neuraxial structures can include loss of sensation, motor blockade, loss of bowel and bladder function, paraplegia and even death.12

Inebriation and sedation will result from an inadvertent intravascular injection of 50 ml. of 50% alcohol. This is usually of no consequence except in the patient taking disulfiram (antabuse). Intravascular injection of phenol, on the other hand, is a more serious matter. Mild symptoms include tinnitus and flushing, but seizures, loss of consciousness, and hypotension can also occur.12

Corticosteroids
Pain states amenable to corticosteroid treatment include the pain of bone cancer, visceral and neuropathic pain, spinal cord compression, brain metastasis, reflex sympathetic dystrophy, post-herpetic and post-traumatic neuralgias, and radicular pain associated with herniated discs or spinal stenosis.27

The side effect profile of corticosteroids is dependent on the duration of treatment. Short-term use has been associated with reversible symptoms of hypertension, hyperglycemia, gastrointestinal bleed, glaucoma, hypokalemic alkalosis, mood disorders, psychotic reactions, pancreatitis, proximal myopathy, and sodium and water retention. Long-term adverse effects include amenorrhea, aseptic necrosis of bone, cataracts, cushingoid appearance, hypothalamic-pituitary axis suppression, hyperlipidemia, hypertension, mood disorders, muscle weakness and osteoporosis.27,28

No matter what the route of administration, side effects can occur. Even the epidural administration of corticosteroids is not without systemic effects. Cushing's syndrome, congestive heart failure and adrenal suppression have all been reported to occur.29 Hyperglycemia is certainly a risk in the insulin dependent diabetic.30 Hypothalamic- pituitary axis suppression has been reported to persist for up to 5 weeks following three weekly injections of epidural triamcinolone 80 mg.31

Nonsteroidal Anti-inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are valuable analgesics. There is evidence that they have direct antinociceptive properties distinct from their anti-inflammatory effects. These drugs do not produce alterations in cognitive functions, respiratory depression, pruritis, or nausea. Nevertheless, the NSAIDs are associated with significant side effects, especially with long-term use. In particular, the elderly have reduced renal clearance of NSAIDs, and require appropriately reduced doses.32

NSAIDs inhibit the formation of thromboxane A2 and prostaglandin endoperoxides which are necessary for platelet aggregation. Bleeding times do increase, but generally remain below the normal, reference, upper limits. With most NSAIDs, these effects last only until the drug has been eliminated (1-2 days); however, aspirin produces prolonged effects of 7-10 days. Regarding perioperative blood loss, well controlled studies have not clearly demonstrated increased losses; however, some concern remains regarding this potential problem.33,34 Regarding wound healing, there is some evidence for impairment of healing of intestinal anastomoses; but no effect or even mildly beneficial effects have been documented on corneal wound healing. Little or no effect of nonsteroidals have been demonstrated on bone remodelling.33

In hypovolemic patients, or other patients with reduced renal blood flow, prostaglandins appear to be important mediators of vasodilation and maintenance of renal perfusion. In this setting, NSAIDs may decrease the glomerular filtration rate and result in release of renin from the juxtaglomerular cells, resulting in a further reduction in renal blood flow and function. This does not appear to be a clinically significant danger in the relatively healthy postoperative patient; however, considerable caution must be used when giving NSAIDs to patients with congestive heart failure, renal insufficiency, cirrhosis, or other patients with potentially impaired renal perfusion. For these patients, NSAIDs should only be used together with careful monitoring of renal function and serum electrolytes.33

Blockade of the cyclo-oxygenase pathway may lead to the shunting of more arachidonic acid to the lipooxygenase pathway, where it is converted to leukotrines and slow reacting substances of anaphylaxis, thereby increasing the risk of an asthmatic episode in susceptible patients.33

Prostaglandins support gastric mucosal integrity by inhibiting gastric acid secretion via blockade of histamine activation of parietal cells, and by other cytoprotective mechanisms. NSAIDs produce gastroduodenal damage by local irritation and by inhibiting the production of the protective prostaglandins. Long term treatment with NSAIDs, increases the risk of serious gastroduodenal complications 3-fold, and this worsens with age. Short term treatment with NSAIDs does produce endoscopically detectable mucosal lesions, but not a clinically significant risk of bleeding or perforation. The risks of NSAID treatment, even short term, for patients with prior histories ulcer disease is unknown, and usually considered contraindicated.34,35,36

All NSAIDs are approximately, equally efficacious, though individuals show considerable variation of response. There may be some differences in the side effects of the NSAIDs, but these differences are not well established. Relatively weak platelet inhibition is seen with choline magnesium trisalicylate, salsalate, and nabumetone; therefore, these drugs may be cause less alteration of hemostasis and less gastrointestinal bleeding.33,34 Nabumetone is not active until after first pass metabolism, and therefore appears to be associated with less gastric mucosal injury.35

Acetaminophen
Acetaminophen is an analgesic of equipotency to aspirin, but free of hematologic or ulcerogenic side effects. The analgesic effect reaches a ceiling at a dose of 1 g. Acetaminophen is the preferred analgesic in children because of the lack of association with Reye's Syndrome. Large doses of acetaminophen, 15 g as a single dose, or chronically more that 5 g per day, may cause severe liver damage and death. Malnourished or chronic alcohol abusing patients may be particularly susceptible to toxic hepatic injury. There is also some evidence of risk of renal injury with chronic use.37

Antidepressant Medications
There is considerable evidence that the tricyclic antidepressants are effective for the treatment of a variety of pain conditions, such as migraine headaches and neuropathic pain. The practitioner should be aware of the potential risks and side effects of these drugs. Most of the side effects can be attributed to the anticholinergic, antihistaminic, anti-alpha-adrenergic, and quinidine-like effects of the tricyclics. Except for the cardiac, quinidine-like effects, most the other side effects are less prominent with nortriptyline and desipramine.38 In the elderly, dose escalation should be slower and stop earlier. In this population, we typically use nortriptyline rather than amitriptyline, imipramine, or doxepin.

It is relatively easy to achieve a lethal overdose with the tricyclic antidepressants. The average lethal dose is 30 mg/kg in healthy adults, and 20 mg/kg in children.38

Toxic plasma levels can also occur secondary to drug interactions. Levels are increased by the selective serotonin reuptake inhibitors (SSRIs), especially fluoxetine and paroxetine. Neuroleptics, cimetidine, methylphenidate, and estrogens may all increase TCA plasma levels. The level of phenytoin may be increased by TCAs. Clonidine may be a less effective antihypertensive when coadministered with TCAs. TCAs should not be given to patients taking monoamine oxidase inhibitors (MAOIs); potentially fatal complications can result. Additive side effects can occur with administration with alcohol, sedatives, or other anticholinergics. Co-administration with sympathomimetics may produce hypertension and hyperpyrexia.38,39

Cardiovascular side effects include sinus tachycardia and conduction changes with potential for AV or bundle branch blocks, or re-entrant excitation. Marked postural hypotension may occur in 20% of patients and is a particular problem in the elderly.
Other fairly common problems include: constipation, weight gain, dry mouth, and sedation.38,39

Anticonvulsants
Anticonvulsants are extensively used adjunctive analgesics for central or peripheral neuropathic pain. The most commonly used drugs are phenytoin, carbamazepine, valproic acid, clonazepam, and most recently, gabapentin.

Carbamazepine: CNS side effects include sedation, headache, impairment of cognitive learning, and visual changes. Other side effects include nausea, vomiting, rash, thrombocytopenia (reversible), and mild leukopenia (which does not require discontinuing treatment). There are rare, but potentially fatal complications, including agranulocytosis, aplastic anemia, Stevens-Johnson syndrome, cardiac toxicity, hyponatremia, and hepatotoxicity. Carbamazepine is chemically similar to the TCAs, and may produce additive side effects. Of note, is that propoxyphene may increase carbamazepine plasma levels. Appropriate monitoring of drug levels, liver functions, and CBC is necessary.40
Phenytoin: Side effects include rash and nystagmus (usually at the upper end of the therapeutic range of serum concentrations). Above 20 mcg/ml the patient may experience symptoms of drowsiness, ataxia, and diplopia. With long term use there are risks of gingival hyperplasia, facial coarsening, and hirsutism. Serious complications, including hepatitis, are rare. Appropriate monitoring of drug levels, liver functions, and CBC is necessary.40
Valproate (valproic acid): Side effects include mild drowsiness, nausea, weight gain, tremor, menstrual disturbances, and dose-related thrombocytopenia. Serious, but rare complications include liver failure, pancreatitis, and interstitial nephritis.40
Clonazepam: The side effects of clonazepam are similar to other benzodiazepines, and include sedation, ataxia, and cognitive impairment.40
Gabapentin: This drug is not metabolized by the liver, and is primarily excreted by the kidneys. It does not affect the metabolism of other anticonvulsants or the tricyclic antidepressants. Side effects are usually mild and include sedation, dizziness, ataxia, and nystagmus. No special laboratory monitoring is required.40


CONCLUSION


Efforts to understand pain require serious attempts to grapple with the intertwining of psyche and soma. It is impossible to treat either one without affecting the other. Knowledge of the full variety of psychological, procedural, and pharmacological complications is necessary if we hope to anticipate and side-step the hazards that are inherent in our treatments.


BIBLIOGRAPHY


1. Fordyce WE: Wilbert E. Fordyce Clinical Investigator Award Lecture. American Pain Society, Annual Scientific Meeting, Los Angeles, November 1995.
2. Freud S: Introductory Lectures On Psychoanalysis. London, Hogarth Press, 1959.
3. Fishbain DA, Rosomoff HL, Cutler RB: Secondary Gain: A Review of the Scientific Evidence. The Clinical Journal of Pain 11:6-21, 1995.
4. Loeser JD, Sullivan M: Disability in the Chronic Low Back Pain Patient May Be Iatrogenic. Pain Forum 4:114-121, 1995.
5. Sternbach RA: Varieties of Pain Games. Advances in Neurology, Vol 4:423-430, 1974.
6. Swanson DW, Swenson WM, Maruta T, Floreen AC: The Dissatisfied Patient with Chronic Pain. Pain 4:367-378, 1978.
7. Groves JE: Taking Care of the Hateful Patient. New England Journal of Medicine 298:883-887, 1978.
8. Lipowski ZJ: Somatization: the concept and its clinical application. American Journal of Psychiatry 145:1358-1368, 1988.
9. Kellner R: Functional Somatic Symptoms and Hypochondriasis: A survey of empirical studies. Archives of General Psychiatry 42:821-833, 1985.
10. Sullivan M, Katon W: Somatization: the path between distress and somatic symptoms. APS Journal 2:141-149, 1993.
11. Domar AD, Friedman R, and Benson H: Behavioral Therapy, in Warfield CA (ed.): Principles and Practice of Pain Management, McGraw-Hill, 1993, pp 437-444.
12. Abram SE, Hogan QH: Complications of nerve blocks, in Benumof JL, Saidman LJ (eds.): Anesthesia & Perioperative Complications. Mosby Year Book, Inc., 1992.
13. Liu S, Carpenter RL, Neal JM: Epidural anesthesia and Analgesia. Anesthesiology 82:6, 1995.
14. Mulroy MF: Regional Anesthesia. Boston, Little Brown & Company, 1989, pp31-44.
15. Murphy TM: Complications of Spinal, Epidural, and Caudal Anesthesia, in Benumof JL, Saidman LJ (eds.): Anesthesia and Perioperative Complications. Mosby Year Book, Inc., 1992.
16. Yuen EC, Layzer RB, Weitz SR, Olney RK: Neurologic Complications of Lumbar Epidural Anesthesia and Analgesia, Neurology 45:1795-1801, 1995.
17. Wedel DJ: Neurologic Complications and Central Neural Blockade, in Barash PG (ed.): ASA Refresher Courses in Anesthesiology, Vol 21, chp 3, 1993, pp 27-39.
18. Rawal N: Postoperative Regional Anesthesia and Analgesia. Current Opinion in Anaesthesiology 7:430-435, 1994.
19. Chestnut DH: Spinal Anesthesia in the Febrile Patient. Anesthesiology 76:5:667-669, 1992.
20. Masuda A, Fujiki A: Sinus Arrest After Right Stellate Ganglion Block. Anesthesia Analgesia 79:607, 1994.
21. Schlack W, Schafer S, Thamer V: Left Stellate Ganglion Block Impairs Left Ventricular Function. Anesthesia Analgesia 79:1082-8,1994.
22. Datta S: Pharmacology of Local Anesthetic Agents, in Barash PG (ed.): ASA Refresher Courses in Anesthesiology, Vol 21, chp 19, 1993, pp 241-254.
23. Stoelting RK: Pharmacology and Physiology in Anesthetic Practice, Philadelphia, Lippincott 1991.
24. Sjogren P, Eriksen J: Opiod Toxicity. Current Opinion in Anaesthesiology 7:465-469, 1994.
25. Drug Facts and Comparisons. St. Louis, Facts and Comparisons, 1994, pp 1140.
26. Myers RM, Katz J: Neuropathology of Neurolytic and Semi-Destructive Agents, in Cousins MJ, Bridenbaugh PO (eds): Neural Blockade in Clinical Anesthesia and Management of Pain, 1988. pp 1031-1051.
27. Watanabe S, Bruera E: Corticosteroids as Adjuvant Analgesias. Journal of Pain and Symptoms Management 9:442 - 445, 1994.
28. Small RE, Cooksey LJ: Connective Tissue Disorders: The Clinical Use of Corticosteroids, in Young LY, Koda-Kimble MA (eds.): Applied Therapeutics: The Clinical Use of Drugs, 1995, pp 42:1-42:11.
29. Hammonds WD: Epidural Steroid Injections: An Unproven Therapy for Pain. APS Journal 3(1):31-32, 1994.
30. Abram S.E: Risk versus Benefit of Epidural Steroids: Lets Remain Objective. APS Journal 3(1):28-30, 1994.
31. Rowlingson JC: Epidural Steroids: Do They Have A Place In Pain Management. APS Journal 3(1):20-27, 1994.
32. Mather LE: Do the Pharmacodynamics of the Nonsteroidal Anti-inflammatory Drugs Suggest a Role in the Management of Postoperative Pain? Drugs 44 (Suppl. 5):1-13, 1992.
33. Kenny GNC: Potential Renal, Haematological and Allergic Adverse Effects Associated with Nonsteroidal Anti-inflammatory Drugs. Drugs 44 (Suppl. 5):31-37, 1992.
34. Willkens RF: The Selection of a Nonsteroidal Antiinflammatory Drug: Is There a Difference? Journal of Rheumatology 19 (suppl 36):9-12, 1992.
35. Roth SH: Upper Gastrointestinal Safety with Nabumetone. Journal of Rheumatology 19 (suppl 36):74-79,1992.
36. Kehlet H, Dahl JB: Are Perioperative Nonsteroidal Anti-inflammatory Drugs Ulcerogenic in the Short Term? Drugs 44 (Suppl. 5):38-41, 1992.
37. Drug Evaluations, American Medical Association, Vol I, Pain-1:29-30, 1994.
38. Guze BH, Ferng HK, Szuba MP, Richeimer SH: The Psychiatric Drug Handbook, St. Louis, Mosby Year Book, 1992.
39. Csernansky JG, Whiteford HA: Clinically Significant Psychoactive Drug Interactions, in Hales RE, Frances AJ (eds.): Psychiatry Update, Annual Review, Vol 6, American Psychiatric Press, 1987, pp 802-815.
40. Drugs for Epilepsy, in Abramowicz M (ed.): The Medical Letter 37:37-40, 1995.

 



The information on this internet site is not intended to be a substitute for professional medical advice. You should not use this information to diagnose or treat a health problem or disease without consulting with a qualified healthcare provider. Please consult your healthcare provider with any questions or concerns you may have regarding your condition. Helpforpain.com and The University of Southern California may provide links to other organizations as a service to the users of this website. The University of Southern California and helpforpain.com are not responsible for the information provided in any other website.

Steven Richeimer, MD
Copyright © 2000. All rights reserved.