Long-term opioid therapy is associated with little risk for addiction when given to selected patients with chronic noncancer pain (CNCP) and no history of substance addiction or abuse, according to a review published online in the January issue of The Cochrane Library.
Meredith Noble, MS, ECRI Institute, Plymouth Meeting, Pennsylvania, and colleagues found that only 7 (0.27%) of 2613 patients in the studies reviewed who received opioids for CNCP for at least 6 months reportedly developed an addiction to the medication or took the medication inappropriately. Most of the participants in the reviewed clinical trials had chronic back pain after failed surgery, severe osteoarthritis, or neuropathic pain.
Importantly, however, a significant percentage of patients taking opioids in any form, but especially oral formulations, withdrew from the study because of adverse effects or insufficient pain relief.
"I think one of the most important things to note is that patients in this review were screened for any history of addiction, so findings may not be applicable to the population as a whole or to people with substance misuse problems," Ms. Noble told Medscape Psychiatry. "But the most important message about this review is that we still don’t have an answer for many people living with chronic pain."
For the review, investigators analyzed findings from 26 studies with 27 treatment groups involving a total of 4893 subjects. Twenty-five of the studies were cases series or uncontrolled long-term trial continuations, whereas the remaining study was a randomized controlled trial comparing 2 opioids.
Oxycodone, morphine, and methadone were among the opioids prescribed, and they were taken orally (n = 3040), transdermally (n = 1628), or intrathecally (n = 225). Nonopioid therapy had to have failed in the patients before study entry. "Just as opioid and route of administration varied among studies, so too did dosage," the investigators write, "and doses also varied considerably within studies due to individual differences in pain level, opioid tolerance, and titration."
Of all the study participants, 22.9% of those taking oral opioids discontinued their participation in the trials because of adverse effects, as did 12.1% of patients using a transdermal patch and 8.9% of patients using an intrathecal pump. The most commonly reported adverse events were nausea and other gastrointestinal disturbances, headache, fatigue, and urinary disturbances.
A significant proportion of patients also discontinued opioid therapy because of insufficient pain relief: 10.3% discontinued oral treatment, 7.6% discontinued intrathecal therapy, and 5.8% discontinued transdermal therapy.
Findings on quality-of-life outcomes were inconclusive for all modes of administration.
Table. Reasons for Study Discontinuation
| ||Discontinuation Because of AEs |
(95% CI), %
|Discontinuation Because of Insufficient Pain Relief (95% CI), %|
|Oral opioids||22.9 (15.3 – 32.8)||10.3 (7.6 – 13.9)|
|Transdermal opioids||12.1 (4.9 – 27)||5.8 (4.2 – 7.9)|
|Intrathecal opioids||8.9 (4 – 26.1)||7.6 (3.7 – 14.8)|
|AEs = adverse events; CI = confidence interval|
According to Ms. Noble, long-term use of opioids to relieve noncancer pain remains controversial. Some patients with CNCP who have been unresponsive to other forms of treatment will not consider opioids because of concerns about addiction. Concerns on practitioners’ part that patients treated with opioids may develop dependence on them also represent a barrier to treatment. On the other hand, severe chronic pain clearly impinges on quality of life and may be a risk factor for suicide.
Although the study authors suggest that the evidence supporting long-term opioid use in selected CNCP patients is "weak," those who are able to continue with opioid therapy can achieve clinically significant pain relief, and the risk of inducing opioid addiction in these individuals is "rare."
"We need a lot more work to find more therapies for CNCP that are safe and effective. In the meantime, physicians should have frank discussions with patients to ascertain their potential for opioid abuse and discuss their potential benefits as well as potential harms, because both patients and physicians should know that not every patient will either tolerate an opioid or get adequate pain relief from them," she said.
Nice Piece of Work
Richard Chapman, MD, University of Utah, thought the review was "a nice piece of work," especially given that the evidence investigators had to work with was not derived from well-done controlled clinical trials, as they would have preferred.
Most of the studies included in the review also involved patients with chronic back pain who almost by definition are going to be refractory to opioid therapy after living with the pain for many years. Perhaps more important is the potential for long-term opioid therapy to interfere with multiple systems.
Although the studies analyzed by Noble and colleagues would not have detailed such effects, "opioid drugs look to the body like β-endorphins, and [over time] they can confuse and dysregulate the immune system, induce opioid hyperanalgesia, and lead to endocrine deficiency," Dr. Chapman told Medscape Psychiatry.
Patients undergoing long-term opioid therapy thus may be at increased risk for infections and tumors, hurt more and longer after a surgical procedure and other painful stimuli, and develop prematurely low levels of testosterone in men and estrogen in women, with their attendant consequences.
"Chronic pain is an enormous problem in the population, and physicians often don’t know what else to do for patients so they write a prescription for the opioids and hope for the best," said Dr. Chapman. "But as we saw in this study, many patients don’t do that well on these medications or they end up staying on the medication because there is nothing else we can rely on, and we need to do a better job of fitting our patients to the therapies we have available."
The study authors and Dr. Chapman have disclosed no relevant financial relationships.
Cochrane Database Syst Rev. 2010:(1).
Pam G. Harrison is a freelance writer for Medscape.
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