Adjuvant Treatments
Karla Hayes
My heart aches, and a drowsy numbness pains
My senses, as though of hemlock I had drunk,
Or emptied some dull opiate to the drains
One minute past, and Lethe-wards had sunk.
—John Keats, “Ode to a Nightingale,” 1795–1821
The opioids and the antiinflammatory agents are the primary analgesics used in pain management. These drugs have the unique property of providing immediate (within minutes to hours) pain relief. The opioids are the only drugs indicated for the treatment of moderate to severe pain. The antiinflammatory drugs are useful for the treatment of osteoarthritis and rheumatoid arthritis, as well as for various mild to moderate acute and chronic pain conditions, and as adjuncts in the case of severe pain. The remaining categories of analgesic drugs, called adjuvant analgesics, have primary indications [U.S. Food and Drug Administration (FDA) approved] for nonpain diagnoses, their analgesic effects being secondary. These nonpain diagnoses include epilepsy, depression, and cardiac arrhythmia. Characteristically, the adjuvant drugs do not provide immediate pain relief; rather, their effects are noticeable only after days or weeks of therapy (see Table 1).
There are many categories of drugs in the adjuvant class, including the tricyclic antidepressants, the selective serotonin reuptake inhibitors, the sodium channel blockers, the GABAergics, the benzodiazepines, and the α-adrenergics. This chapter focuses on the use of anticonvulsants, local anesthetics, corticosteroids, and antispasmodics in the treatment of chronic pain (including cancer pain). The psychotropic medications are described in Chapter 11, and analgesics for headache are described in Chapter 28. A brief review of all the adjuvant analgesics is presented in Appendix VIII.
Table 1. Adjuvant analgesic indications (RCTs) | ||||||||||||||||||||||||||||||
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I. GENERAL CONSIDERATIONS
The decision to begin a particular analgesic medication for any individual patient involves many issues. The potential benefit of the drug must be weighed against its side effects. The patient should be made aware of the state of evidence concerning the drug’s analgesic efficacy and should have realistic expectations. A check of the patient’s medical background is needed to identify areas of susceptibility, and the patient’s current medications must be reviewed for drug interactions. Appropriate patient selection is important. Patient and physician should be aware that the side effects of adjunctive agents may be noticed within days of initiating treatment, whereas the analgesic effect may not be apparent for 1 to 2 weeks.
Another consideration is the drug’s mechanism of action, which can direct treatment strategies if the cause of the pain is known. Over the past several years, the treatment algorithm for chronic pain has seen a shift toward a mechanism-based approach. This concept is underscored in the following statement:
“As we approach the new millennium, it is clear that we are on the brink of a major change in clinical pain management. We are poised to move from a treatment paradigm that has been almost entirely empirical to one that will be derived from an understanding of the actual mechanisms involved in the pathogenesis of pain…· The implications of this are immense and will necessitate major changes … to a mechanism-based classification…· The aim in the future will be to identify in individual patients what mechanisms are responsible for their pain and to target treatment specifically at those mechanisms.” (Clifford Woolf, 1999)
This approach will make it possible to match a medication (with a known mechanism of action) to a pain syndrome in which this physiologic mechanism has been disrupted. In addition, this approach will allow pairing of medications with different mechanisms of action to provide synergistic effects. Finally, we will be able to use agents with the same mechanism of action in place of drugs that are effective but are not tolerated because of side effects.
II. ANTICONVULSANTS
Anticonvulsant drugs have been used in the management of pain since the 1960s, soon after they were introduced for the treatment of epilepsy. This group of medications is also known as antiepileptic drugs, and we refer to them in their commonly abbreviated form (AEDs). For years, it was thought that the primary indication for these drugs was specific neuropathic pain disorders such as trigeminal neuralgia (TN) or other syndromes that had predominately lancinating or burning pain. The newer anticonvulsants that have been introduced in recent years have been used with some success for a variety of indications. Eight anticonvulsants currently are useful in neuropathic pain states: carbamazepine, oxcarbazepine, topiramate, levetiracetam, pregabalin, zonisamide, gabapentin, and lamotrigine.
Although the mechanism of action of each AED is different, the mechanisms underlying their anticonvulsant effects likely contribute to their analgesic effects because the pathophysiology of epilepsy and neuropathic pain may be similar. AEDs have many potential side effects, and their individual side effect profiles differ. Gabapentin has a uniquely favorable side effect profile and also a lack of drug–drug interactions. It is widely used in the treatment of pain, largely because of its good safety record. It also seems effective in a wide range of pain conditions, both neuropathic and nonneuropathic.
1. Indications
The following are indications for AEDs in patients with chronic pain:
Neuralgias–trigeminal, glossopharyngeal, and postherpetic
Central pain states (e.g., thalamic pain syndrome and poststroke pain)
Postsympathectomy pain
Posttraumatic neuralgia
Porphyria, Fabry disease, and others
Painful diabetic neuropathy
Paroxysmal pain in multiple sclerosis
Migraine headaches
Phantom limb pain and postamputation stump pain
Peripheral neuropathy secondary to a variety of disease states [e.g., alcoholism, amyloidosis, diabetes mellitus, HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome), malabsorption, porphyria, toxic exposure, sarcoidosis, and drug induced]
2. Clinical Guidelines
(i) Dosing Regimes
A 4- to 6-week trial is the minimum required to adequately assess the analgesic efficacy of a new drug. The patient is given instructions about dosing and a titration schedule. In general, the phrase “start low and go slow” is adhered to when a new anticonvulsant analgesic is started. This allows the body to adjust to the new drug and decreases the likelihood of major side effects. Doses are generally increased until therapeutic effects or limiting adverse effects are observed. A review of previous analgesic drug trials is valuable, with special attention being paid to pain relief and side effects. Serum levels do not appear to correlate well with pain response. Both physician and patient must understand that this process may take months to years (several medication trials). The medications should not be discontinued abruptly, but should be tapered slowly to avoid withdrawal symptoms.
(ii) Choice of Drug
On the basis of their proven efficacy, carbamazepine and gabapentin have been approved by the U.S. FDA for the management of pain. Because of its favorable side effect profile, gabapentin is often used as a first-line agent. The unfavorable side effect profile of carbamazepine and the need for monitoring of hematologic function are major drawbacks that have influenced physicians to utilize other drugs, especially oxcarbazepine, its keto-analog. Because the various anticonvulsants have different mechanisms of action, the lack of response to one drug cannot probably predict the response to another drug.
3. Drug Characteristics
(i) Carbamazepine
MECHANISM OF ACTION.
Carbamazepine is chemically and pharmacologically related to the tricyclic antidepressants. It inhibits norepinephrine uptake and prevents repeated discharges in neurons. Carbamazepine likely blocks sodium channels. This observation is consistent with its ability to relieve lancinating pain in neuralgia states.
PHARMACOLOGY.
Carbamazepine is absorbed slowly and unpredictably after oral intake. Peak concentrations are seen in 2 to 8 hours. It is moderately protein bound and has active metabolites. Metabolism is hepatic, and excretion is urinary. It has a serum half-life of 10 to 20 hours, averaging 14 hours.
RECOMMENDED DOSAGE.
Start at 200 mg per day and increase by 200 mg every 1 to 3 days to a maximum of 1,500 mg per day. If side effects are encountered, the dosage should be decreased to the previous level for several days and then gradually increased. Therapeutic dosages usually range from 800 to 1,200 mg per day. Carbamazepine is a gastric irritant and therefore should be taken with food.
ADVERSE EFFECTS.
Sedation, nausea, diplopia, and vertigo occur most frequently with carbamazepine. Hematologic abnormalities such as aplastic anemia, agranulocytosis, pancytopenia, and
thrombocytopenia can occur. Other side effects include jaundice (hepatocellular and cholestatic), oliguria, hypertension, and acute left ventricular heart failure.
thrombocytopenia can occur. Other side effects include jaundice (hepatocellular and cholestatic), oliguria, hypertension, and acute left ventricular heart failure.
Baseline and periodic complete blood counts (CBCs), and liver function studies should be performed. Blood counts are obtained at baseline, then every 2 weeks for a month, monthly for 3 months, twice over the following year, and then yearly. If a patient exhibits low white cell or platelet counts, the patient should be monitored closely. The drug should be discontinued if considerable bone marrow depression develops. Liver function studies should be obtained for patients with a history of liver dysfunction. Carbemazepine should be discontinued immediately in cases of aggravated liver dysfunction or acute liver disease.
CLINICAL APPLICATIONS.
The analgesic effects of carbamazepine for TN were first reported in 1962. Analgesic efficacy has been most frequently documented in TN and in painful diabetic neuropathy. Efficacy in postherpetic neuralgia, tabetic pain, and central pain is less well documented.
(ii) Oxcarbazepine
MECHANISM OF ACTION.
Oxcarbazepine (OXC) is a 10-keto analog of carbamazepine. It reduces the number of spikes elicited by a train of high-frequency stimuli (similar to carbamazepine), probably by suppressing the generation of high-frequency firing and by prolonging the refractory period. It also likely binds to sodium channels in their inactive state, as well as increases potassium conductance and modulates high-voltage-activated calcium channels.
PHARMACOLOGY
Following oral administration, OXC is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD). The half-life of the parent drug (OXC) is 2 hours, whereas the half-life of MHD is approximately 9 hours. Steady-state plasma concentrations are reached within 2 to 3 days. Food has no effect on the rate and extent of absorption.
RECOMMENDED DOSAGE.
For pain management, OXC is typically titrated more slowly than when used for epilepsy. It should be initiated at 150 mg bid and increased by 150 to 300 mg per day at weekly intervals. The recommended daily dosage for seizure control is 1,200 mg. Typical maintenance dosages for pain management are 600 to 1,200 mg per day.
ADVERSE EFFECTS.
The most commonly observed adverse events in association with OXC are dizziness, somnolence, diplopia, fatigue, ataxia, nausea, and abnormal vision. Hyponatremia can occur, so sodium levels should be monitored.
CLINICAL APPLICATIONS
Surprisingly, there have been very few studies examining OXC and pain. Nevertheless, because of its favorable side effect profile, it is now the drug of choice for TN in the United States. It is widely used with success for a variety of neuropathic pain syndromes.
(iii) Topiramate
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