A new study in the October issue of Neurology weighs in on the controversial issue of opioids used to treat neuropathic pain. Not only did elderly patients with postherpetic neuralgia (PHN) experience pain relief with opioid medication during the study, they showed no cognitive deficits when maintained on the medication for two months. These results were demonstrated by researchers at Johns Hopkins University, whose randomized trial compared tricyclic antidepressants (TCAs) and opioids with placebo in PHN (Neurology 2002;59:1015–1021).
Kathleen M. Foley, MD, an attending neurologist in the Pain and Palliative Care Service at Memorial Sloan Kettering Cancer Center, praised the study for its “useful and practical design, and its attempts to address the real issues that neurologists face when they are asked to manage the pain of a patient with postherpetic neuralgia. The study clearly demonstrates, in a group of elderly patients with well-documented neuropathic pain, that neuropathic pain is in fact opioid-responsive along a continuum.”
FIVE YEARS TO COMPLETE
The study's principal investigator, Srinivasa N. Raja, MD, from the Department of Anesthesiology and Critical Care Medicine at Johns Hopkins Hospital in Baltimore, expressed satisfaction with completion of the study. “It was a long study that took us almost five years to complete, a year and a half to write up and do the analysis. It's nice to see the fruits of so long a labor.”
Dr. Raja and his co-investigators recruited patients for the study between 1995 and 1999. The mean age of participants was 71; 44.7 percent were male and 55.3 percent were female. All had PHN for at least three months after healing of a herpes zoster rash, and the majority (75 percent) exhibited allodynia (a condition in which ordinarily nonpainful stimuli evoke pain) or hyperalgesia to mechanical stimuli. Another 10.5 percent had pain with cold stimuli, and 18.4 percent with warmth.
In addition to neurologic examinations, prospective participants were also given Mini-Mental State examinations to rule out those with significant cognitive impairment. Other exclusion criteria included severe pulmonary disease, dementia, and occurrence of myocardial infarction within the previous three-month period.
Each study participant was scheduled to undergo three treatment periods: one with an opioid, one with a TCA, and one with a placebo. The pharmacist formulated the study drugs in identical gel capsules, and medications were mailed directly to patients' houses. Each treatment period lasted about eight weeks, including titration, maintenance, and taper phases.
Between each treatment period, patients had a one-week drug-free washout period. According to Dr. Raja, the study was designed to be clinically relevant, and to guide clinicians in choosing treatments. Therefore, patients who could not tolerate the study drug's side effects were offered an alternative from the same class of drugs; for example, methadone instead of morphine, desipramine instead of nortriptyline.
Dosages were increased twice weekly until maximum pain relief was reached, or side effects became intolerable. Investigators phoned participants twice a week to assess pain intensity ratings and pain relief. Cognitive function measures (Wechsler Adult Intelligence Scale-Revised for concentration and psychomotor function and the Hopkins Verbal Learning Test, among others) were obtained at the end of the maintenance period for each drug.
Co-investigator Jennifer A. Haythornthwaite, PhD, Associate Professor of Psychiatry and Behavioral Sciences at Johns Hopkins, said, “We have concluded that we do not see any cognitive deficits with these medicines once people are on stable doses. Even though we only sampled certain domains of cognition and behavior [and not driving or reaction time], I can say conservatively that most people do fine on these medicines.” The cognitive tests, she noted, “pick up very subtle changes that some people might not even notice themselves.”
PHN RESPONSIVE TO OPIOIDS
Of the initial 76 randomized volunteers, 44 completed all three study periods. Although not statistically significant, results showed a trend favoring opioids over TCA for pain relief (38 percent versus 32 percent) compared with placebo. When patients were asked which study drug they preferred, 54 percent indicated the opioid study drug, versus 30 percent for the TCAs.
Dr. Foley remarked that the study should put to rest the notion that neuropathic pain is opioid-resistant. Another interesting aspect, said Dr. Raja, was that there was no relationship between those who responded to TCAs and those who responded to opioids. “What this says is that non-responders to TCAs should be tried on other types of medication, and opioids are a reasonable alternative medication for those non-responders,” he said.
BARRIERS TO TREATMENT
Despite growing evidence that opioids can be useful in treating chronic nonmalignant pain, barriers to its acceptance remain. Dr. Raja noted, for example, that in addition to the ongoing controversies that neuropathic pain states may not be amenable to opioids, other objections from physicians may include concerns about tolerance to the drugs with prolonged use, issues of addiction and dependency, and regulatory and drug enforcement issues.
In addition, said Dr. Raja, legal documentation may be a stumbling block. At Johns Hopkins and many other institutions, opioid treatment is preceded by a “contract,” which spells out the issues of opioids and delineates the consequences of misuse or abuse of the drugs. All this takes time to discuss with patients.
Dr. Haythornthwaite noted that “concerns of family members” were among the top three reasons stated for dropping out during the opioid period. The other reasons cited were side effects and other medical problems.
Dr. Haythornthwaite observed that patients sometimes consider withholding information about opioid prescriptions from their families. Most clinicians recognize the social stigma still attached to the use of morphine and synthetic opioids. “These are words that come with cultural, social, and interpersonal meaning,” she said.
RESPONSES TO DIFFERENT NAMES
In a study, soon to be published in the Clinical Journal of Pain, Dr. Haythornthwaite and her colleagues assessed patients' responses to different names for opioid medications. “People are more willing to try ‘narcotics,’ for example, than they are to try ‘morphine’ or ‘methadone,’” she said.
There may be other advantages to including family members in discussions about opioid treatment, said Dr. Raja. Clinicians can educate patients and their family members about the realities of opioid use. Family members can also provide “additional information about the patient's functioning: Is the patient doing better? Is he interacting with others? So, we can discover useful information about whether the drug is not only providing some degree of pain relief, but whether it is improving the quality of life for this individual.”
The study's authors conclude that “it is premature to argue that opioids should be the treatment of first choice in PHN or neuropathic pain in general.” Part of the reason for caution, said Dr. Raja, is that patients were followed for only two months on each study drug. Additional studies indicating that, under controlled circumstances, prolonged use for at least six to nine months of these drugs is still effective would be “helpful additional information,” he said.
Dr. Foley agreed with this assessment of the results, and added, “We also know that PHN is a pain syndrome that improves over 12 to 24 months. So, the study of long-term use of opioids in PHN may not be helpful. The next study should be neurophysiologically based to address which patients might respond to opioid analgesics or antidepressants, versus other topical therapy.”
Dr. Foley said that the study could build on work by Drs. Michael Rowbotham and Howard Fields, of the Department of Neurology at University of California-San Francisco, which suggests that allodynia in some PHN patients is a form of chronic secondary hyperalgesia maintained by a combination of input from primary afferent nociceptors (nerve fibers in the peripheral areas) and sensitization of central pain-transmitting neurons (Neurobiology Dis 1998;5:209–227).
ARTICLE IN BRIEF
- ✓ A study by Johns Hopkins University neuroscientists found that elderly patients with postherpetic neuralgia (PHN) experienced pain relief with opioid medication and showed no cognitive deficits when maintained on the medication for two months.
- ✓ Despite growing evidence that opioids can be useful in treating chronic nonmalignant pain, however, barriers to its acceptance remain. These barriers include ongoing controversies that neuropathic pain states may not be amenable to opioids, concerns about tolerance to the drugs with prolonged use, issues of addiction and dependency, and regulatory and drug enforcement issues.
- ✓ While leading pain management expert and neurologist Kathleen Foley, MD, praised the study for its “useful and practical design,” the study's principal investigator, Srinivasa N. Raja, MD, noted that “it is premature to argue that opioids should be the treatment of first choice in PHN or neuropathic pain in general.”
- ✓ Dr. Raja pointed out that patients were followed for only two months on each study drug, and he suggested that additional studies indicating that, under controlled circumstances, prolonged use for at least six to nine months of these drugs is still effective would be “helpful additional information.”