This systematic review demonstrated that, based on the available trials analyzed:
• Opioids were effective in the treatment of CNCP overall; they reduced pain and improved functional outcomes better than placebo.
• Opioids were more effective than placebo for both nociceptive and neuropathic pain syndromes.
• Tramadol reduced pain and improved functional outcomes in patients with fibromyalgia.
• Strong opioids (oxycodone and morphine) were significantly superior, statistically, to naproxen and nortriptyline (respectively) for pain relief but not for functional outcomes.
• Weak opioids (propoxyphene, tramadol and codeine) did not significantly outperform NSAIDs or TCAs for either pain relief or functional outcomes.
• Clinically (> 10%) and statistically, only constipation and nausea were significantly more common with opioids.
• Although recent studies43,44
have indicated that endocrinological abnormalities and erectile dysfunction can be experienced by patients taking opioid medication for chronic conditions, most researchers did not ask participants about sexual dysfunction. The few studies in our review that collected such data were relatively short for the observation of any endocrinological abnormalities. The only 2 studies29,32
that reported data on sexual function showed that patients taking opioids actually perceived themselves as doing better in terms of sexual behaviour compared with those in the control groups. Improvement of well-being secondary to better pain control may account for this result: the PDI is a patient-rated global rating of function and does not measure variables such as libido, sexual dysfunction or gonadal function, and cannot be used to estimate the risk of hypogonadism.
• Addiction or opioid abuse in patients with chronic pain cannot be assumed not to exist (despite popular statements), because the existing randomized trials are not designed to evaluate it; the duration of the trials was too short to allow for the development or detection of aberrant drug use, even if appropriate screening tools for addiction had been used. An adequate measure of “diagnosis of addiction” is also lacking in every study. For example, it is hazardous to equate reported “drug craving” or “reported symptoms and signs of addiction” with addiction. At best, this analysis suggests that only in a minority of comparative trials have investigators even attempted to approach this question. Furthermore, none of the studies have been methodologically sound enough to allow for conclusions about opioid addiction or abuse.
In regard to the contentious issue of whether opioids for pain patients can improve function, this meta-analysis depends on standardized measures of function that were adopted in the respective studies. Such instruments are often self-reported measures, such as the Pain Disability Index. The specific functional change is measured narrowly in terms of the functional measure used. For example, one cannot assume that functional improvement should be interpreted to mean improvement in any and all functions.
Most trials that compare opioids with other drugs were not adequately designed as equivalence or noninferiority trials.45,46
We therefore have some reservations about declaring any equivalence between opioids and these other drugs. There is a need for well-designed equivalence trials to compare opioids and other drugs.
Chronic pain is a long-term disorder. The studies included in this meta-analysis had various follow-up periods; most trials were not long enough to estimate the duration of efficacy of opioids in chronic pain, the potential for opioid tolerance, or long-range adverse effects such as hypogonadism or opioid abuse.
The majority of the studies included in this review were funded by the pharmaceutical industry. However, there is insufficient information to determine whether or not pharmaceutical-industry funding might introduce publication bias by not publishing small or unfavourable studies.
The results of our review were similar to those of others recently conducted. In 2004, Kalso and colleagues47
systematically reviewed studies of World Health Organization step 3 opioids for CNCP and found the mean decrease with opioids in pain intensity in most studies to be at least 30%, with comparable effects on neuropathic and musculoskeletal pain. Their review did not include evidence from studies of weak opioids (tramadol or codeine), nor did it assess the effectiveness of opioids compared with other analgesics. A Cochrane systematic review by Duhmke and associates48
published in 2004 showed that tramadol is an effective treatment for neuropathic pain. Eisenberg and coworkers' 2005 systematic review49
of 8 randomized controlled trials of opioid agonists (excluding tramadol) for neuropathic pain demonstrated opioid efficacy for spontaneous neuropathic pain with intermediate-term follow-up. Moore and McQuay50
recently published a systematic review of the side effects of opioids for chronic nonmalignant pain; they found the most common adverse effects to be dry mouth (25%), nausea (21%) and constipation (15%).
Our cumulative meta-analyses for placebo-controlled trials of orally administered opioids in regard to pain relief and functional outcomes showed that additional placebo-controlled trials of these outcomes are desirable only for other-than-oral routes of administration. For example, we found no reports of placebo-controlled trials of transdermal or rectal routes of administration of opioids, nor infusion programs for chronic pain. More refined experimental strategies will be required to assess other outcomes such as opioid abuse or addiction, sexual dysfunction and hypogonadism. Solid conclusions about the relative effectiveness and risk or benefit of opioids compared with other nonopioid drugs are still to be determined in adequately designed equivalence trials. Future trials of opioids for CNCP should consistently have well-defined methods and follow-up periods adequate in length to assess long-term complications such as sexual dysfunction or addiction. More attention should be paid to factors affecting methodological rigour, such as success of blinding, avoidance of dropouts, and adequate intention-to-treat analysis.