The study is the first to systematically compare younger versus older patients' desires/needs to escalate the dose of opioid pain medications they take -- a class of drugs including morphine, methadone and oxycodone (sold as OxyContin, Percocet among others). Based on the new findings, the researchers suggest that the drugs may be under-prescribed for older patients, yet pose unique risks for younger patients.
Opioids have long been used for unremitting pain caused by nerve damage, arthritis and other diseases, but clinicians and patients often worry that use of the drugs will lead to patient requests for ever-increasing doses. Extended opioid use at high doses can alter immune and hormonal function and, ironically, increase pain sensitivity. The escalating drug need, stemming from "tolerance" to a given dose, also can become very costly.
The new findings show that patients 60 or older faced a much lower risk of opioid "dose escalation" than did younger patients. Older patients also received long-term pain relief from the opioids whereas younger patients showed no long-term benefit.
The discovery about opioid tolerance and age was uncovered from a study of patient records, and confirmed in animal studies. The findings are being published in two papers in the June issue of Anesthesia and Analgesia.
"We have found that older patients, often discouraged from using opioids for pain management, actually gain significant long-term relief with minimal risk of excessive dose escalation or toxicity," said Pamela Palmer, MD, PhD, professor of anesthesia at UCSF and senior author of the two papers. Palmer is director of the UCSF Pain Management Center.
In addition, long-term use of opioids at moderate levels does not pose an increased risk for cardiac or kidney damage or gastric ulcers, as some Cox-2 inhibitors do -- a risk of greater concern for older patients than younger ones, Palmer said. Sedation and constipation are the main opioid side effects, but these can be managed by modifying the selection of the opioid, the dosage and proper bowel medications.
Researchers examined the medical records of 206 patients who had been treated for two years for severe, non-cancer-related pain, either from nerve damage (called neuropathic pain) or from arthritis, fibromyalgia and related conditions that cause what is known as nociceptive pain. Patients were divided into younger (less than 50 years old) and older (over 60) age groups.
The records showed that both groups started with similar doses of morphine-like drugs and both took about 14 to 15 months to reach their peak dose. But the average peak dose of the younger group was more than twice that of the older group. In many cases, peak doses for younger patients were well over half a gram per day of morphine or related opioid.
Younger patients with nociceptive pain escalated the drug dosage at a "tremendous rate" for more than a year, the researchers report. Yet they did not achieve any long-term pain relief from these high doses according to standard self-assessment scores. In contrast, the older patients, with less than half the dose escalation, reported significant relief from pain, the scientists found.
The researchers speculate that the difference between the older and younger patients may be the result of molecular changes in neurons that occur with aging, and they cite this as a particularly important area for future research. They also recognize the importance of a prospective study rather than a retrospective one, and they are planning a follow-up study.
In an animal study, the scientists sought to confirm the age-related difference in tolerance to opioid drugs. They note that no study had systematically evaluated how quickly rats develop tolerance to opioid pain medication as a function of age. Rats aged three weeks, three months, six months and a year were given twice-daily injections of morphine proportional to their weight, and pain-relief was assessed in a standard procedure of applying heat to the rat's tail and measuring how quickly the animal flicked its tail away from the heat source.
The researchers found that the youngest rats experienced drug tolerance more than five times sooner than the oldest rats. Six-month-old and three-month-old rats showed a 250 percent and a 150 percent increase in time to tolerance compared with the three-week-old rats, they reported. The findings are consistent with the human studies in which older patients continue to experience benefit from a given opioid dosage while younger patients need to escalate the dosage.
Why the older patients found long-lasting pain relief at lower doses -- a finding confirmed in the animal studies -- is not certain, Palmer says. But the results suggest to the UCSF scientists that use of opioids for pain relief in both the young and the old should be reconsidered.
For older patients, opioids appear to be a safe, effective medication to treat long-lasting, serious pain without the increased risks posed by Cox-2 inhibitors and other anti-inflammatory drugs, Palmer concludes. On the other hand, younger people should be cautious of using daily opioids to treat chronic pain.
"Younger people are more vulnerable to opioid tolerance and ever-escalating doses, and they are at much lower risk than older patients for heart attack and gastrointestinal bleeding linked to anti-inflammatory drugs," she said. In sum, younger patients may be better candidates for the newer non-steroidal anti-inflammatories and poorer candidates for opioids, while older patients might benefit more from opioids but are at greater risk for serious side effects from anti-inflammatory drugs, Palmer says.
Lead author on the retrospective patient pain study is Chante Buntin-Mushock, MD, research fellow in the UCSF neurology and anesthesia departments. Co-authors are Lisa Phillip, MD, and Kumi Moriyama, MD, both in the anesthesia department at UCSF.
The research is supported in part by the U.S. Public Health Service. Lead author on the animal study is Yan Wang, MD, postdoctoral fellow in anesthesia at UCSF. Co-authors are James Mitchell, MD; Kumi Moriyama, MD; Ki-jun Kim, MD, PhD; Manhoar Sharma, PhD; and Guo-xi Xie, MD, PhD, all in the UCSF anesthesia department.
Support comes from the National Institutes of Health.