- CONDITION CENTERS
Pain is an ageless, universal phenomenon. With pain presenting as the primary symptom in over 80% of physician visits, the use of opioids has entered the clinical mainstream for the treatment of noncancer pain. Although many protocols recommend continuous dosing, therapy is still frequently provided on an as-needed basis, with older patients, men in general, the cognitively impaired, and racial minorities being undertreated.
The availability of analgesia in a continuously released, transdermal form offers the opportunity to provide more effective pain relief. Topical administration can also prevent some of the adverse effects associated with traditional opioid use.
The lipophilic nature of the opioids, most notably fentanyl, allows for greater and more generalized analgesia through topical absorption. At the central level, fentanyl binds with the mu opiate receptor, increasing tolerance to pain and diminishing its perception.
The lipid solubility of fentanyl keeps most of the drug within the central nervous system (CNS), rather than circulating in the vascular system, which can diminish the nausea often associated with other opioid drugs. The topical administration also circumvents involvement of the stomach, further reducing gastric irritation associated with oral administration of analgesics.
Dosing and Administration
There is no definite test or physical sign that will predict which patient will do well on a therapeutic trial of opioids for pain. Therefore, fentanyl should be given in the smallest effective dose possible to minimize tolerance and physical dependence, with consideration for the patient's clinical status, age, and weight.
Topical fentanyl is available in several strengths, with "opioid-naive" patients being introduced to the 25-mcg patches. The manufacturer warns that, in these patients, this amount should never be exceeded. The 50-, 75-, and 100-mcg strengths are intended only for patients already on, and tolerant to, opioid therapy. For doses exceeding 100 mcg, multiple systems may be simultaneously applied at different sites.
The design of a topical fentanyl patch allows for a continuous amount of drug to be absorbed through the skin over a 72-hour period. Patients should be aware that significant amounts of fentanyl continue to be absorbed from the skin for 17 hours (or more) once a patch is removed.
Patients should press the topical patch onto the application area and hold it in place for 30 seconds. Hair at the application site should be clipped, not shaved, to prevent irritation at the site. In addition, soaps, oils, lotions, alcohol, or other potential sources of irritation should not be used. Patients should avoid exposing the site to external sources of heat, since the increase in cutaneous blood perfusion to the site could alter the expected absorption amounts of fentanyl. Cut or damaged fentanyl patches should not be used. Proper disposal of used patches is essential, keeping them far from children or pets.
The choice of fentanyl for analgesia should be made with care. Since potentially life-threatening respiratory suppression may occur, initial opioid therapy should not exceed 25 mcg/hr. In addition, topical fentanyl is not indicated for the management of acute or postoperative pain, including use in outpatient surgeries, nor is it considered appropriate for the control of mild or intermittent pain potentially responsive to intermittent or nonopioid treatment. Patients with diminished fat stores, whether due to age or nutritional status, should also be restricted initially to the 25-mcg/hr dose. Concurrent use of alcohol or other CNS depressants will result in enhanced sedation and further respiratory depression.
Fentanyl is a Schedule II narcotic. Management of pain with patients having a history of addiction or concurrent psychiatric condition requires special considerations, as the fentanyl patch has been successfully used in suicides.
Fentanyl patches should be used cautiously in patients with brain tumors. In the brain, fentanyl causes increased intracranial pressure and can result in impaired consciousness or coma.
Due to its lipophilic nature, fentanyl will also appear in the breast milk of nursing mothers. Regardless of the source, the safety of fentanyl has not been established in children under the age of 2.
Even with these warnings, the side-effect profile for topical fentanyl remains largely favorable, with a comparatively low incidence of constipation. Clinical trials note that <25% of users experience nausea and sleepiness, with constipation, xerostomia, and confusion being experienced by 13% to 14% of patients.
Fentanyl is metabolized by the CYP3A4 isoenzyme. Therefore, decreased clearance is expected with concurrent administration of macrolide antibiotics, azole antifungals, and protease inhibitors. Increased hepatic clearance, and a diminished analgesic effect, can be expected with simultaneous use of rifampin, carbamazepine, and phenytoin.
Chronic pain is one of the most cost-consuming medical conditions in the United States, with high costs in direct medical care, as well as lost income and productivity.
The transdermal delivery of fentanyl represents a benefit for patients with intractable nausea and vomiting, or having other conditions that make oral pain management difficult. This is a further benefit when active ulcers are present and strong analgesia is desired.
In general, topical fentanyl is well tolerated with a low risk for addiction when judiciously prescribed. Its availability in generic form will offer further relief for patients requiring pain management from an economic standpoint.
Fentanyl patches are available in 25-, 50-, 75-, and 100-mcg strengths from Mylan Pharmaceuticals.
Two neuropathic pain syndromes, diabetic neuropathy and postherpetic neuralgia, have shown a positive response to treatments involving a combination of opioids and gabapentin, with the 2 drugs providing a synergistic effect. The March 12, 2005, edition of the New England Journal of Medicine reports a baseline pain rating of 5.7 becoming 4.49 with placebo, and 3.06 with a combination of morphine and gabapentin (the "placebo" in this study is lorazepam, at a "ceiling" daily dose of 1.6 mg). The combination uses gabapentin 2400 mg daily, with daily morphine up to 120 mg.
The study demonstrated the multiple uses being explored for gabapentin, initially intended as a treatment for epilepsy.
Determining the specific activity of gabapentin is difficult. While structurally similar to gamma-amino butyric acid (GABA), it does not appear to interact with GABA receptors, nor is it metabolized into GABA. Clinically, gabapentin is approved as adjunct treatment of partial epileptic seizures in adults and children. It has also been successful in controlling mixed bipolar states and anxiety in patients not adequately controlled by carbamazepine or valproic acid.
All pharmacologic actions of gabapentin appear due to the activity of the parent compound. The drug is not appreciably metabolized, and is eliminated unchanged, by the kidneys. Because elderly patients are more likely to experience decreases in renal function, doses should be adjusted based on changes in creatinine clearance.
Gabapentin does not appear to interfere with commonly coadministered antiseizure drugs. Concurrent administration of naproxen, however, increases gabapentin absorption by up to 15%. In an interesting bidirectional interaction, gabapentin can decrease blood levels of simultaneously administered hydrocodone by up to 22% in some studies, while hydrocodone can increase gabapentin blood levels by up to 14%. The clinical significance of these interactions remains unexplored.
Gabapentin is available in strengths ranging from 100 to 600 mg. Total effective daily doses generally run from 900 to 1800 mg. As previously mentioned, much higher doses are used for investigational conditions.
The drug may be administered with or without food. Concurrent antacid administration, however, can reduce absorption by about 20%. Patients should be advised to separate dosing of antacids and gabapentin by at least 2 hours.
The short half-life of gabapentin makes it necessary for it to be taken in divided doses over the course of the day. To maintain adequate blood levels, for example, the maximum interval between doses should not exceed 12 hours.
Unlike some antiseizure therapies, it is unnecessary to monitor drug levels of gabapentin during treatment.
For most people, gabapentin has minimal side effects. The side effects that most often cause patients to reject treatment with gabapentin include sleepiness, ataxia, fatigue, nausea, dizziness, and nystagmus.
The use of gabapentin among patients with epilepsy aged 3 to 12 years is associated with neurologic side effects, most notably emotional lability, hostility, aggressive behaviors, concentration problems, and restlessness. Other potential psychiatric side effects at doses used to treat bipolar disorders consist of depersonalization, induction of mania, agitation, paranoia, and alterations in libido.
Patients have survived overdoses of up to 49,000 mg of gabapentin without serious consequences.
Abrupt discontinuation of therapy is associated with an increase in seizures, including status epilepticus. Gabapentin therapy should not be abruptly discontinued unless serious side effects emerge.
Gabapentin has been scrutinized for many uses since its introduction in 1993. Recently, it has been shown to be beneficial as adjunct treatment in reducing hot flashes. This joins the benefits it shows in treating acute herpetic zoster pain when combined with the oral antiviral agent valacyclovir. Other uses continue to be explored.
The IVAX Corporation has received approval to market gabapentin in 100-, 300-, and 400-mg capsules.
Mr. Middleton is an instructor of pharmacology for Kellogg Community College in Battle Creek, Mich.