Interventional Therapies: Pharmacological Interventions

Interventional Therapies

Interventional pain therapy may take the form of pharmacological treatment, nerve blocks with local anesthetics and steroid or a neurolytic solution, radiofrequency ablation, neuromodulatory tech-niques, or multidisciplinary treatment (psychologi-cal interventions, physical or occupational therapy, or modalities such as acupuncture).

PHARMACOLOGICAL INTERVENTIONS

Pharmacological interventions in pain management include acetaminophen, cyclooxygenase (COX) inhibitors, opioids, antidepressants, neurolepticagents, anticonvulsants, corticosteroids, and sys-temic administration of local anesthetics.

Acetaminophen

Acetaminophen (paracetamol) is an oral analge-sic and antipyretic agent that recently has become available in the United States as an intravenous preparation (Ofirmev) for inpatient use. It inhibits prostaglandin synthesis but lacks significant antiin-flammatory activity. Acetaminophen has few side effects but is hepatotoxic at high doses. The recom-mended adult maximum daily limit is 3000 mg/d, reduced from a previously recommended limit of 4000 mg/d. Isoniazid, zidovudine, and barbiturates can potentiate acetaminophen toxicity.

Nonsteroidal Antiinflammatory Drugs (NSAIDs)

Nonopioid oral analgesics include salicylates, acetaminophen, and NSAIDs (see Table 47–11). NSAIDs inhibit prostaglandin synthesis (COX).

Prostaglandins sensitize and amplify nocicep-tive input, and blockade of their synthesis results in the analgesic, antipyretic, and antiinflamma-tory properties characteristic of NSAIDs. At least two types of COX are recognized. COX-1 is con-stitutive and widespread throughout the body, but COX-2 is expressed primarily with inflammation. Some types of pain, particularly pain that follows orthopedic and gynecological surgery, respond very well to COX inhibitors. COX inhibitors likely have important peripheral and central nervous system actions. Their analgesic action is limited by side effects and toxicity at higher doses. Selective COX-2 inhibitors, such as celecoxib, appear to have lower toxicity, particularly gastrointestinal side effects. Moreover, COX-2 inhibitors do not interfere with platelet aggregation. The COX-2 inhibitor rofecoxib increases the risk of cardiovascular complications; as a result, it has been taken off of the market in the United States.

All of the nonopioid oral analgesic agents are well absorbed enterally. Food delays absorption but otherwise has no effect on bioavailability. Because most of these agents are highly protein bound (>80%), they can displace other highly bound drugs such as warfarin. All undergo hepatic metabolism and are renally excreted. Dosages should therefore be reduced, or alternative medications selected, in patients with hepatic or renal impairment.

The most common side effects of aspirin (ace-tylsalicylic acid, ASA) and other NSAIDs are stom-ach upset, heartburn, nausea, and dyspepsia; some patients develop ulceration of the gastric mucosa, which appears to be due to inhibition of prosta-glandin-mediated mucus and bicarbonate secretion. Diclofenac is available as both an oral preparation and a topical gel or patch that may be less likely to contribute to gastric distress.

Other side effects of NSAIDs include dizziness, headache, and drowsiness. With the exception of selective COX-2 inhibitors, all other COX inhibi-tors induce platelet dysfunction. Aspirin irreversibly acetylates platelets, inhibiting platelet adhesiveness for 1–2 weeks, whereas the antiplatelet effect of other NSAIDs is reversible and lasts approximately five elimination half-lives (24–96 h). This antiplate-let effect does not appear to appreciably increase the incidence of postoperative hemorrhage follow-ing most outpatient procedures. NSAIDs can exac-erbate bronchospasm in patients with the triad of nasal polyps, rhinitis, and asthma. ASA should not be used in children with varicella or influenza infec-tions because it may precipitate Reye’s syndrome. Lastly, NSAIDs can cause acute renal insufficiency and renal papillary necrosis, particularly in patients with underlying renal dysfunction.

Antidepressants

Antidepressants are most useful for patients with neuropathic pain. These medicationsdemonstrate an analgesic effect that occurs at a dose lower than that needed for antidepressant activity,and both of these actions are due to blockade of pre-synaptic reuptake of serotonin, norepinephrine, or both. Older tricyclic agents appear to be more effec-tive analgesics than selective serotonin reuptake inhibitors (SSRIs). Serotonin and norepinephrine reuptake inhibitors (SNRIs) may provide the most favorable balance between analgesic efficacy and side effects. Antidepressants potentiate the action of opioids and frequently help normalize sleep patterns.

All antidepressant medications undergo exten-sive first-pass hepatic metabolism and are highly protein bound. Most are highly lipophilic and have large volumes of distribution. Elimination half-lives of most of these medications vary between 1 and 4 days, and many have active metabolites. Available agents differ in their side effects (see Table 47–13), which include antimuscarinic effects (dry mouth, impaired visual accommodation, urinary retention, and constipation), antihistaminic effects (sedation and increased gastric pH), α-adrenergic blockade (orthostatic hypotension), and a quinidine-like effect (atrioventricular block, QT prolongation, tor-sades de pointes).

Serotonin & Norepinephrine Reuptake Inhibitors (SNRIs)

Milnacipran, along with the SNRI duloxetine and the anticonvulsant pregabalin, has also been approved in the United States by the FDA for the treatment of fibromyalgia. It has an elimination half-life of 8 h, is minimally metabolized by the liver, and is primarily excreted unchanged in the urine.

Duloxetine (Cymbalta) is useful in the treat-ment of neuropathic pain, depression, and fibromy-algia. It has a half-life of 12 h, is metabolized by the liver, and most of its metabolites are excreted in the urine.

Absolute and relative contraindications for the use of SNRIs include known hypersensitivity, usage of other drugs that act on the central nervous system (including monoamine oxidase inhibitors), hepatic and renal impairment, uncontrolled narrow-angle glaucoma, and suicidal ideation. Common side effects include nausea, headache, dizziness, consti-pation, insomnia, hyperhydrosis, hot flashes, vomit-ing, palpitations, dry mouth, and hypertension.

Neuroleptics

Neuroleptic medications may occasionally be use-ful for patients with refractory neuropathic pain, and may be most helpful in patients with marked agitation or psychotic symptoms. The most com-monly used agents are fluphenazine, haloperi-dol, chlorpromazine, and perphenazine. Their therapeutic action appears to be due to blockade of dopaminergic receptors in mesolimbic sites. Unfortunately, the same action in nigrostriatal pathways can produce undesirable extrapyramidal side effects, such as masklike facies, a festinating gait, cogwheel rigidity, and bradykinesia. Some patients also develop acute dystonic reactions such as oculogyric crisis and torticollis. Long-term side effects include akathisia (extreme restlessness) and tardive dyskinesia (involuntary choreoathetoid movements of the tongue, lip smacking, and trun-cal instability). Like antidepressants, many of these drugs also have antihistaminic, antimuscarinic, and α-adrenergic–blocking effects.

Antispasmodics & Muscle Relaxants

Antispasmodics may be helpful for patients with musculoskeletal sprain and pain associated with spasm or contractures. Tizanidine (Zanaflex) is a centrally acting α₂-adrenergic agonist used in the treatment of muscle spasm in conditions such as multiple sclerosis, low back pain, and spastic diple-gia. Cyclobenzaprine (Flexeril) also may be effective for these conditions. Its precise mechanism of action is unknown.

Baclofen (Gablofen, Lioresal), a GABA _B ago-nist, is particularly effective in the treatment of muscle spasm associated with multiple sclerosis or spinal cord injury when administered by continuous intrathecal drug infusion. Abrupt discontinuation of this medication has been associated with fever, altered mental status, pronounced muscle spasticity or rigidity, rhabdomyolysis, and death.

Corticosteroids

Glucocorticoids are extensively used in pain man-agement for their antiinflammatory and possi-bly analgesic actions. They may be given topically, orally, or parenterally (intravenously, subcutane-ously, intrabursally, intraarticularly, or epidurally). Table 47–15 lists the most commonly used agents,which differ in potency, relative glucocorticoid and mineralocorticoid activities, and duration or action. Large doses or prolonged administration result in significant side effects. Excess glucocorticoid activity can produce hypertension, hyperglycemia, increased susceptibility to infection, peptic ulcers, osteoporosis, aseptic necrosis of the femoral head, proximal myopathy, cataracts, and, rarely, psychosis. Patients with diabetes may have elevated blood glu-cose levels after corticosteroid injections. Patients can also develop the physical features characteristic of Cushing’s syndrome. Excess mineralocorticoid

activity causes sodium retention and hypokalemia, and can precipitate congestive heart failure.

Many corticosteroid preparations are suspen-sions, rather than solutions, and the relative par-ticulate size of a given glucocorticoid suspension may affect the risk of neural damage due to arterial occlusion when accidental arterial injection occurs. Because of the relatively small size of its suspension particles, dexamethasone is becoming the preferred corticosteroid for injection procedures involving relatively vascular areas, such as the head and neck region.

Anticonvulsants

Anticonvulsant medications are useful for patients with neuropathic pain, especially trigeminal neuralgia and diabetic neuropathy. These agents block voltage-gated calcium or sodium chan-nels and can suppress the spontaneous neural dis-charges that play a major role in these disorders. The most commonly utilized agents are phenytoin (Dilantin), carbamazepine (Tegretol), valproic acid (Depakene, Stavzor), clonazepam (Klonopin), and gabapentin (Neurontin) (Table 47–14). Pregabalin (Lyrica) is a newer agent that has been approved for the treatment of diabetic peripheral neuropathy and fibromyalgia but is widely prescribed for all forms of neuropathic pain. Lamotrigine (Lamictal) and topiramate (Topamax) may also be effective. All are highly protein bound and have relatively long half-lives. Carbamazepine (Carbatrol, Equetro, Tegretol) has a slow and unpredictable absorption, which requires monitoring of blood levels for optimal effi-cacy. Phenytoin may be effective, but there is a pos-sible side effect of gum hyperplasia. Levetiracetam (Keppra) and oxcarbazepine (Trileptal) have been used as adjuvant pain therapies. Gabapentin and pregabalin may also be effective adjuvants for the treatment of acute postoperative pain.

Local Anesthetics

Systemic infusion of local anesthetic medication produces sedation and central analgesia and is occa-sionally used in the treatment of patients with neuro-pathic pain. The resultant analgesia may outlast the pharmacokinetic profile of the local anesthetic and break the “pain cycle.” Lidocaine, procaine, and chlo-roprocaine are the most commonly used agents. They are given either as a slow bolus or by continuous infu-sion. Lidocaine is given by infusion over 5–30 min for a total of 1–5 mg/kg. Procaine, 200–400 mg, can be given intravenously over the course of 1–2 h, whereas chloroprocaine (1% solution) is infused at a rate of 1 mg/kg/min for a total of 10–20 mg/kg. Monitoring by qualified medical personnel should include electrocardiographic data, blood pressure, respiration, pulse oximetry, and mental status, and full resuscitation equipment should be immediately available. Signs of toxicity, such as tinnitus, slurring of speech, excessive sedation, or nystagmus, neces-sitate slowing or discontinuing the infusion to avoid the progression to seizures.

Patients who do not respond satisfactorily to anticonvulsants but respond to intravenous local anesthetics may benefit from chronic oral antiar-rhythmic therapy. Mexiletine (150–300 mg every 6–8 h) is a class 1B antiarrhythmic that is commonly used and generally well tolerated.

A 5% lidocaine transdermal patch (Lidoderm) containing 700 mg of lidocaine has been approved for the treatment of PHN. One to three patches may be applied to dry, intact skin, alternating 12 h on, then 12 h off. Topical lidocaine preparations, in con-centrations up to 5%, may be helpful in the treat-ment of some neuropathic pain conditions.

α₂-Adrenergic Agonists

The primary effect of α₂-adrenergic agonists is acti-vation of descending inhibitory pathways in the dorsal horn. Epidural and intrathecal α₂-adrenergic agonists are particularly effective in the treatment of neuropathic pain and opioid tolerance. Cloni-dine (Catapres), a direct-acting α₂-adrenergic ago-nist, is effective as an adjunctive medication in the treatment of severe pain. When administered orally, the dosage is 0.1–0.3 mg twice daily; a transdermal patch (0.1–0.3 mg/d) is also available and is usually applied for 7 d. When used in combination with a local anesthetic or opioid in an epidural or intra-thecal infusion, clonidine may contribute to a syn-ergistic or prolonged analgesic effect, especially for neuropathic pain.

Opioids

The most commonly prescribed oral opioid agents are codeine, oxycodone, and hydrocodone. They areeasily absorbed, but hepatic first-pass metabolism lim-its systemic delivery. Like other opioids, they undergo hepatic biotransformation and conjugation before renal elimination. Codeine is transformed by the liver into morphine. The side effects of orally administered opioids are similar to those of systemic opioids. When prescribed on a fixed schedule, stool softeners or laxa-tives are often indicated. Tramadol (Rybix, Ryzolt, Ultram) is a synthetic oral opioid that also blocks neu-ronal reuptake of norepinephrine and serotonin. It appears to have the same efficacy as the combination of codeine and acetaminophen but, unlike others, it is associated with significantly less respiratory depres-sion and has little effect on gastric emptying.

Moderate to severe cancer pain is usually treated with an immediate-release morphine preparation (eg, liquid morphine, Roxanol, 10–30 mg every 1–4 h). These preparations have an effective half-life of 2–4 h. Once the patient’s daily requirements are determined, the same dose can be given in the form of a sustained-release morphine preparation (MS Contin or Oramorph SR), which is dosed every 8–12 h. The immediate-release preparation is then used only for breakthrough pain (PRN). Oral trans-mucosal fentanyl lozenges (Actiq, 200–1600 mcg) can also be used for breakthrough pain. Excessive sedation can be treated with dextroamphetamine (Dexedrine, ProCentra) or methylphenidate (Rit-alin), 5 mg in the morning and 5 mg the early after-noon. Most patients require a stool softener. Nausea may be treated with transdermal scopolamine, oral meclizine, or metoclopramide. Hydromorphone (Dilaudid) is an excellent alternative to morphine, particularly in elderly patients (because of fewer side effects) and in patients with impaired renal function. Methadone (Dolophine) is reported to have a half-life of 15–30 h, but clinical duration is shorter and quite variable (usually 6–8 h).

Patients  who  experience  opioid  tolerance require escalating doses of opioid to main-tain the same analgesic effect. Physical dependencemanifests in opioid withdrawal when the opioid medication is either abruptly discontinued or the dose is abruptly and significantly decreased. Psy-chological dependence, characterized by behavioral changes focusing on drug craving, is rare in can-cer patients. The development of opioid tolerance is highly variable but results in some desirable effects such as decreased opioid-related sedation, nausea, and respiratory depression. Unfortunately, many patients continue to suffer from constipation. Physical dependence occurs in all patients receiving large doses of opioids for extended periods. Opioid withdrawal phenomena can be precipitated by the administration of opioid antagonists. Future con-comitant use of peripheral opioid antagonists that do not cross the blood–brain barrier, such as meth-ylnaltrexone (Relistor) and alvimopan (Entereg), may help reduce systemic side effects without sig-nificantly affecting analgesia.

Tapentadol (Nucynta), a μ-opioid receptor ago-nist that also has norepinephrine reuptake inhibi-tion properties, has recently been introduced for the management of acute and chronic pain. This opioid may be associated with less nausea and vomiting and less constipation. It should not be used concomi-tantly with monoamine oxidase inhibitors due to potentially elevated levels of norepinephrine.

Propoxyphene with and without acetamino-phen (Darvocet and Darvon) was withdrawn from the U.S. market in 2010 due to the risk of cardiac toxicity.

A. Parenteral Opioid Administration

Intravenous, intraspinal (epidural or intrathecal), or transdermal routes of opioid administration must be utilized when the patient fails to adequately respond to, or is unable to tolerate, oral regimens. However, when the patient’s pain increases significantly, or changes markedly in quality, it is equally impor-tant to reevaluate the patient for adequacy of pain diagnosis and for the potential of disease progres-sion. In patients with cancer, adjunctive treatments such as surgery, radiation, chemotherapy, hormonal therapy, and neurolysis may be helpful. Intramuscu-lar opioid administration is rarely optimal because of variability in systemic absorption and resultant delay and variation in clinical effect.

B. Intravenous Opioid Therapy

Parenteral opioid therapy is usually best accom-plished by intermittent or continuous intravenous infusion, or both, but can also be given subcuta-neously. Modern portable infusion devices have patient-controlled analgesia (PCA) capability, allow-ing the patient to self-treat for breakthrough pain.

C. Spinal Opioid Therapy

The use of intraspinal opioids is an excellent alter-native for patients obtaining poor relief with other analgesic techniques or who experience unaccept-able side effects. Epidural and intrathecal opioids offer pain relief with substantially lower total doses of opioid and fewer side effects. Continuous infusion techniques reduce drug requirements (compared with intermittent boluses), minimize side effects, and decrease the likelihood of catheter occlusion. Myoclonic activity may be occasionally observed with intrathecal morphine or hydromorphone.

Epidural or intrathecal catheters can be placed percutaneously or implanted to provide long-term effective pain relief. Epidural catheters can be attached to lightweight external pumps that can be worn by ambulatory patients. A temporary catheter must be inserted first to assess the poten-tial efficacy of the technique. Correct placement of the permanent catheter should be confirmed using fluoroscopy with contrast dye. Completely implantable intrathecal catheters with externally programmable pumps can also be used for con-tinuous infusion (Figure 47–6). The reservoir of the implanted pump (Figure 47–7) is periodicallyrefilled percutaneously. Implantable systems are most appropriate for patients with a life expectancy of several months or longer, whereas tunneled epi-dural catheters are appropriate for patients expected to live only weeks. Formation of an inflammatory

mass (granuloma) at the tip of the intrathecal cath-eter can occur and may reduce efficacy.

The most frequently encountered problem asso-ciated with intrathecal opioids is tolerance. Gener-ally a slow phenomenon, tolerance may develop rapidly in some patients. In such instances, adjuvant therapy must be used, including the intermittent use of local anesthetics or a mixture of opioids with local anesthetics (bupivacaine or ropivacaine 2–24 mg/d), clonidine (2–4 mcg/kg/h or 48–800 mcg/d, respec-tively), or the GABA agonist baclofen. Clonidine is particularly useful for neuropathic pain. In high doses, it is more likely to be associated with hypo-tension and bradycardia.

Complications of spinal opioid therapy include local skin infection, epidural abscess, meningitis, and death or permanent injury from pump programming or drug dilution errors. Superficial infections can be reduced by the use of a silver-impregnated cuff close to the exit site. Other complications of spinal opi-oid therapy include epidural hematoma, which may become clinically apparent either immediately fol-lowing catheter placement or several days later, and respiratory depression. Respiratory depression sec-ondary to spinal opioid overdose can be treated by decreasing the pump infusion rate to its lowest set-ting and initiating a naloxone intravenous infusion.

D. Transdermal Fentanyl

Transdermal fentanyl (Duragesic patch) is an alter-native to sustained-release oral morphine and oxycodone preparations, particularly when oral medication is not possible. The currently available patches are constructed as a drug reservoir that is separated from the skin by a microporous rate-limiting membrane and an adhesive polymer. A very large quantity of fentanyl (10 mg) provides a large force for transdermal diffusion. Transder-mal fentanyl patches are available in 25, 50, 75, and 100 mcg/h sizes that provide drug for 2–3 days. The largest patch is equivalent to 60 mg/d of intravenous morphine. The major obstacle to fentanyl absorp-tion through the skin is the stratum corneum. Because the dermis acts as a secondary reservoir, fentanyl absorption continues for several hours after the patch is removed. The transdermal route avoids hepatic first-pass metabolism.

Major disadvantages of the transdermal route are its slow rate of drug delivery onset and the inabil-ity to rapidly change dosage in response to changing opioid requirements. Blood fentanyl levels rise and reach a plateau in 12–40 h, providing average con-centrations of 1, 1.5, and 2 ng/mL for the 50, 75, and 100 mcg/h patches, respectively. Large inter-patient variability results in actual delivery rates ranging from 50 to 200 mcg/h. This formulation is popu-larly “diverted” for nonmedical uses and has been the cause of numerous deaths from “recreational” pharmacology.

Botulinum Toxin (Botox)

OnabotulinumtoxinA (Botox) injection has been increasingly utilized in the treatment of pain syn-dromes. Studies support its use in the treatment of conditions associated with involuntary muscle con-traction (eg, focal dystonia and spasticity), and it is approved by the FDA for prophylactic treatment of chronic migraine headache. This toxin blocks ace-tylcholine released at the synapse in motor nerve endings but not sensory nerve fibers. Proposed mechanisms of analgesia include improved local blood flow, relief of muscle spasms, and release of muscular compression of nerve fibers